Clinical and Pathological Characteristics of KEAP1- and NFE2L2-Mutated Non-Small Cell Lung Carcinoma (NSCLC)

Purpose: KEAP1 and NFE2L2 mutations are associated with impaired prognosis in a variety of cancers and with squamous cell carcinoma formation in non–small cell lung cancer (NSCLC). However, little is known about frequency, histology dependence, molecular and clinical presentation as well as response to systemic treatment in NSCLC.

Experimental Design: Tumor tissue of 1,391 patients with NSCLC was analyzed using next-generation sequencing (NGS). Clinical and pathologic characteristics, survival, and treatment outcome of patients with KEAP1 or NFE2L2 mutations were assessed.

Results: KEAP1 mutations occurred with a frequency of 11.3% (n = 157) and NFE2L2 mutations with a frequency of 3.5% (n = 49) in NSCLC patients. In the vast majority of patients, both mutations did not occur simultaneously. KEAP1 mutations were found mainly in adenocarcinoma (AD; 72%), while NFE2L2 mutations were more common in squamous cell carcinoma (LSCC; 59%). KEAP1 mutations were spread over the whole protein, whereas NFE2L2 mutations were clustered in specific hotspot regions. In over 80% of the patients both mutations co-occurred with other cancer-related mutations, among them also targetable aberrations like activating EGFR mutations or MET amplification. Both patient groups showed different patterns of metastases, stage distribution and performance state. No patient with KEAP1 mutation had a response on systemic treatment in first-, second-, or third-line setting. Of NFE2L2-mutated patients, none responded to second- or third-line therapy.

Conclusions: KEAP1- and NFE2L2-mutated NSCLC patients represent a highly heterogeneous patient cohort. Both are associated with different histologies and usually are found together with other cancer-related, partly targetable, genetic aberrations. In addition, both markers seem to be predictive for chemotherapy resistance. Clin Cancer Res; 24(13); 3087–96. ©2018 AACR.

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Goldilocks Dosing of TKIs: A Dose that Is Just Right Leads to Optimal Outcomes

Higher concentrations of TKIs, such as pazopanib, are associated with improved outcomes in advanced RCC. A phase III trial failed to show disease-free survival benefit to pazopanib in the adjuvant setting, but improved DFS was seen in patients with higher C_trough levels, supporting adequate drug exposure for optimal clinical outcome. Clin Cancer Res; 24(13); 2979–80. ©2018 AACR.

See related article by Sternberg et al., p. 3005

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SMAD4 Gene Mutation Renders Pancreatic Cancer Resistance to Radiotherapy through Promotion of Autophagy

Purpose: Understanding the mechanism of radioresistance could help develop strategies to improve therapeutic response of patients with PDAC. The SMAD4 gene is frequently mutated in pancreatic cancer. In this study, we investigated the role of SMAD4 deficiency in pancreatic cancer cells' response to radiotherapy.

Experimental Design: We downregulated SMAD4 expression with SMAD4 siRNA or SMAD4 shRNA and overexpressed SMAD4 in SMAD4 mutant pancreatic cancer cells followed by clonogenic survival assay to evaluate their effects on cell radioresistance. To study the mechanism of radioresistance, the effects of SMAD4 loss on reactive oxygen species (ROS) and autophagy were determined by flow cytometry and immunoblot analysis, respectively. Furthermore, we measured radioresistance by clonogenic survival assay after treatment with autophagy inhibitor (Chloroquine) and ROS inhibitor (N-acetyl-l-cysteine) in SMAD4-depleted pancreatic cancer cells. Finally, the effects of SMAD4 on radioresistance were also confirmed in an orthotopic tumor model derived from SMAD4-depleted Panc-1 cells.

Results: SMAD4-depleted pancreatic cancer cells were more resistant to radiotherapy based on clonogenic survival assay. Overexpression of wild-type SMAD4 in SMAD4-mutant cells rescued their radiosensitivity. Radioresistance mediated by SMAD4 depletion was associated with persistently higher levels of ROS and radiation-induced autophagy. Finally, SMAD4 depletion induced in vivo radioresistance in Panc-1-derived orthotopic tumor model (P = 0.038). More interestingly, we observed that the protein level of SMAD4 is inversely correlated with autophagy in orthotopic tumor tissue samples.

Conclusions: Our results demonstrate that defective SMAD4 is responsible for radioresistance in pancreatic cancer through induction of ROS and increased level of radiation-induced autophagy. Clin Cancer Res; 24(13); 3176–85. ©2018 AACR.

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Cycling Toward Progress: Ribociclib, a CDK 4/6 Inhibitor for Breast Cancer

Ribociclib is an orally active, highly selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6. It is the second CDK 4/6 inhibitor approved for hormone receptor–positive breast cancer. The addition of ribociclib to an aromatase inhibitor has resulted in marked improvements in progression-free survival for patients with metastatic breast cancer. Clin Cancer Res; 24(13); 2981–3. ©2018 AACR.

See related article by Shah et al., p. 2999

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Inositol Trisphosphate Receptor Type 3-mediated Enhancement of EGFR and MET Cotargeting Efficacy in Non-Small Cell Lung Cancer Detected by 18F-fluorothymidine

Purpose: Our aim was to test whether imaging with ¹⁸F-fluorothymidine (¹⁸F-FLT) PET/CT was able to detect the combined effects of EGFR and MET inhibitors in oncogene-driven non–small cell lung cancer (NSCLC) and to elucidate the mechanisms underlying the enhanced efficacy of drug combination.

Experimental Design: NSCLC cells bearing MET amplification (H1993 and H820) were treated with EGFR and MET inhibitors either alone or in combination and then tested for cell viability and inhibition of signaling. Nude mice bearing H1993 tumors underwent ¹⁸F-FLT PET/CT scan before and after treatment with erlotinib and crizotinib alone or in combination (1:1 ratio) and posttreatment changes of ¹⁸F-FLT uptake in tumors were determined. The role of inositol trisphosphate receptor type 3 (IP3R3) in mediating the combined action of EGFR and MET inhibitors was tested by transfecting NSCLC cells with IP3R3-targeted siRNA.

Results: Imaging studies showed a significant reduction of ¹⁸F-FLT uptake in response to combined treatment with EGFR and MET inhibitors that was higher than that obtained with single agents (ANOVA, F-ratio = 6.215, P = 0.001). Imaging findings were confirmed by analysis of surgically excised tumors. Levels of IP3R3 were significantly reduced in both cells and tumors after treatment with crizotinib, whereas EGFR inhibitors caused a reduction of IP3R3 interaction with K-Ras mainly through dephosphorylation of serine residues of K-Ras.

Conclusions: Our findings indicate that ¹⁸F-FLT PET/CT is able to detect the enhanced efficacy of EGFR and MET inhibitors in oncogene-driven NSCLC and that such enhancement is mediated by IP3R3 through its interaction with K-Ras. Clin Cancer Res; 24(13); 3126–36. ©2018 AACR.

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The Airway Transcriptome as a Biomarker for Early Lung Cancer Detection

Lung cancer remains the leading cause of cancer-related death due to its advanced stage at diagnosis. Early detection of lung cancer can be improved by better defining who should be screened radiographically and determining which imaging-detected pulmonary nodules are malignant. Gene expression biomarkers measured in normal-appearing airway epithelium provide an opportunity to use lung cancer–associated molecular changes in this tissue for early detection of lung cancer. Molecular changes in the airway may result from an etiologic field of injury and/or field cancerization. The etiologic field of injury reflects the aberrant physiologic response to carcinogen exposure that creates a susceptible microenvironment for cancer initiation. In contrast, field cancerization reflects effects of "first-hit" mutations in a clone of cells from which the tumor ultimately arises or the effects of the tumor on the surrounding tissue. These fields might have value both for assessing lung cancer risk and diagnosis. Cancer-associated gene expression changes in the bronchial airway have recently been used to develop and validate a 23-gene classifier that improves the diagnostic yield of bronchoscopy for lung cancer among intermediate-risk patients. Recent studies have demonstrated that these lung cancer–related gene expression changes extend to nasal epithelial cells that can be sampled noninvasively. While the bronchial gene expression biomarker is being adopted clinically, further work is necessary to explore the potential clinical utility of gene expression profiling in the nasal epithelium for lung cancer diagnosis, lung cancer risk assessment, and precision medicine for lung cancer treatment and chemoprevention. Clin Cancer Res; 24(13); 2984–92. ©2018 AACR.

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Vitamin D-Binding Protein Enhances Epithelial Ovarian Cancer Progression by Regulating the Insulin-like Growth Factor-1/Akt Pathway and Vitamin D Receptor Transcription

Purpose: Malignant ascites of epithelial ovarian cancer (EOC) helps identify prognostic biomarkers or mechanisms of tumor progression. Vitamin D–binding protein (DBP) was revealed to be upregulated in EOC ascites in our previous proteomic study. Here, we examined the role of DBP in EOC.

Experimental Design: We analyzed ascites, serum, and tissue samples of patients with newly diagnosed EOC to determine the prognostic effects of DBP. We verified DBP function using orthotopic animal models and DBP regulation in ovarian cancer cell lines.

Results: Elevated ascitic DBP was significantly associated with poor response to chemotherapy, short progression-free interval, increased cancer progression, and death. Ascitic DBP overexpression was an independent unfavorable biomarker for progression-free survival; DBP overexpression in cancerous tissue was significantly related to chemoresistance. In vivo and in vitro investigations demonstrated an important role for DBP in ovarian cancer progression. Orthotopic model mice inoculated with DBP knockdown ovarian cancer cells displayed a significant reduction in tumor formation, malignant cell number, ascitic DBP levels, invasiveness, and metastasis, and increased survival compared with controls. In presence of vitamin D receptor (VDR), DBP promoted cell aggression (invasion and doubling time) via activation of the insulin-like growth factor-1/insulin-like growth factor–binding protein-2/Akt axis, and induced suppression of vitamin D–responsive genes. A NF-B p65-binding site in the VDR promoter was identified as a major determinant of DBP-dependent VDR promoter activation.

Conclusions: This study highlights the importance of DBP in ovarian tumor progression and the potential application of DBP as a therapeutic target for EOC. Clin Cancer Res; 24(13); 3217–28. ©2018 AACR.

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Report of the 14th International Conference on Malignant Lymphoma (ICML) Closed Workshop on Future Design of Clinical Trials in Lymphomas

The 14th ICML held in Lugano in June 2017 was preceded by a closed workshop (organized in collaboration with the American Association for Cancer Research and the European School of Oncology) where experts in preclinical and clinical research in lymphomas met to discuss the current drug development landscape focusing on critical open questions that need to be addressed in the future to permit a more efficient drug development paradigm in lymphoma. Topics discussed included both preclinical models that can be used to test new drugs and drug combinations, as well as the optimal design of clinical trials and the endpoints that should be used to facilitate accelerated progress. This report represents a summary of the workshop. Clin Cancer Res; 24(13); 2993–8. ©2018 AACR.

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Concurrent Alterations in EGFR-Mutant Lung Cancers Associated with Resistance to EGFR Kinase Inhibitors and Characterization of MTOR as a Mediator of Resistance

Purpose: To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled EGFR-mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing.

Experimental Design: Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic EGFR-mutant lung cancer. Clinical data were collected and correlated with somatic mutation data. Erlotinib resistance due to acquired MTOR mutation was functionally evaluated by in vivo and in vitro studies.

Results: In 200 EGFR-mutant pretreatment samples, the most frequent concurrent alterations were mutations in TP53, PIK3CA, CTNNB1, and RB1 and focal amplifications in EGFR, TTF1, MDM2, CDK4, and FOXA1. Shorter time to progression on EGFR TKI was associated with amplification of ERBB2 (HR = 2.4, P = 0.015) or MET (HR = 3.7, P = 0.019), or mutation in TP53 (HR = 1.7, P = 0.006). In the 136 posttreatment samples, we identified known mechanisms of acquired resistance: EGFR T790M (51%), MET (7%), and ERBB2 amplifications (5%). In the 38 paired samples, novel acquired alterations representing putative resistance mechanisms included BRAF fusion, FGFR3 fusion, YES1 amplification, KEAP1 loss, and an MTOR E2419K mutation. Functional studies confirmed the contribution of the latter to reduced sensitivity to EGFR TKI in vitro and in vivo.

Conclusions: EGFR-mutant lung cancers harbor a spectrum of concurrent alterations that have prognostic and predictive significance. By utilizing paired samples, we identified several novel acquired alterations that may be relevant in mediating resistance, including an activating mutation in MTOR further validated functionally. Clin Cancer Res; 24(13); 3108–18. ©2018 AACR.

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FDA Approval: Ribociclib for the Treatment of Postmenopausal Women with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer

On March 13, 2017, the FDA approved ribociclib (KISQALI; Novartis Pharmaceuticals Corp.), a cyclin-dependent kinase 4/6 inhibitor, in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)–positive, HER2-negative advanced or metastatic breast cancer. The approval was based on a randomized, double-blind, placebo-controlled, international clinical trial (MONALEESA-2). A total of 668 patients were randomized to receive either ribociclib plus letrozole (n = 334) or placebo plus letrozole (n = 334). An improvement in progression-free survival (PFS) was observed in patients receiving ribociclib plus letrozole compared with patients receiving placebo plus letrozole [HR = 0.556; 95% confidence interval (CI), 0.429–0.720]. Overall response rate (ORR) in patients with measurable disease was 52.7% (95% CI, 46.6–58.9) in the ribociclib plus letrozole arm and 37.1% (95% CI, 31.1–43.2) in the placebo plus letrozole arm. Overall survival data were immature. The most common adverse reactions observed in 20% or more of patients taking ribociclib were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain. This article summarizes FDA decision-making and data supporting the approval of ribociclib. Clin Cancer Res; 24(13); 2999–3004. ©2018 AACR.

See related commentary by Spring and Bardia, p. 2981

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Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)

Purpose: Persistent androgen receptor (AR) signaling drives castration-resistant prostate cancer (CRPC) and confers resistance to AR-targeting therapies. Novel therapeutic strategies to overcome this are urgently required. We evaluated how bromodomain and extra-terminal (BET) protein inhibitors (BETi) abrogate aberrant AR signaling in CRPC.

Experimental Design: We determined associations between BET expression, AR-driven transcription, and patient outcome; and the effect and mechanism by which chemical BETi (JQ1 and GSK1210151A; I-BET151) and BET family protein knockdown regulates AR-V7 expression and AR signaling in prostate cancer models.

Results: Nuclear BRD4 protein expression increases significantly (P ≤ 0.01) with castration resistance in same patient treatment-naïve (median H-score; interquartile range: 100; 100–170) and CRPC (150; 110–200) biopsies, with higher expression at diagnosis associating with worse outcome (HR, 3.25; 95% CI, 1.50–7.01; P ≤ 0.001). BRD2, BRD3, and BRD4 RNA expression in CRPC biopsies correlates with AR-driven transcription (all P ≤ 0.001). Chemical BETi, and combined BET family protein knockdown, reduce AR-V7 expression and AR signaling. This was not recapitulated by C-MYC knockdown. In addition, we show that BETi regulates RNA processing thereby reducing alternative splicing and AR-V7 expression. Furthermore, BETi reduce growth of prostate cancer cells and patient-derived organoids with known AR mutations, AR amplification and AR-V7 expression. Finally, BETi, unlike enzalutamide, decreases persistent AR signaling and growth (P ≤ 0.001) of a patient-derived xenograft model of CRPC with AR amplification and AR-V7 expression.

Conclusions: BETi merit clinical evaluation as inhibitors of AR splicing and function, with trials demonstrating their blockade in proof-of-mechanism pharmacodynamic studies. Clin Cancer Res; 24(13); 3149–62. ©2018 AACR.

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Pazopanib Exposure Relationship with Clinical Efficacy and Safety in the Adjuvant Treatment of Advanced Renal Cell Carcinoma

Purpose: PROTECT, a phase III, randomized, placebo-controlled study, evaluated pazopanib efficacy and safety in the adjuvant renal cell carcinoma setting. The relationship between pazopanib exposure (C_trough) and efficacy and safety was evaluated.

Patients and Methods: Evaluable steady-state blood trough concentrations were collected from 311 patients at week 3 or 5 (early C_trough) and 250 patients at week 16 or 20 (late C_trough). Pazopanib pharmacokinetic (PK) data were analyzed via a population model approach. Relationship between C_trough or dose intensity and disease-free survival (DFS) was explored via Kaplan–Meier and multivariate analysis. Adverse events (AE) and AE-related treatment discontinuation proportions were summarized by C_trough quartiles.

Results: Most (>90%) patients with early or late C_trough data started on 600 mg. Mean early and late C_trough overlapped across dose levels. Patients with higher early C_trough quartiles achieved longer DFS (adjusted HR, 0.58; 95% confidence interval, 0.42–0.82; P = 0.002). Patients achieving early or late C_trough >20.5 μg/mL had significantly longer DFS: not estimable (NE) versus 29.5 months, P = 0.006, and NE versus 29.9 months, P = 0.008, respectively. Dose intensity up to week 8 did not correlate with DFS, consistent with population PK model–based simulations showing overlapping pazopanib exposure with 600 and 800 mg doses. The proportion of AE-related treatment discontinuation and grade 3/4 AEs, with the exception of hypertension, was not correlated to C_trough.

Conclusions: In the adjuvant setting, higher pazopanib C_trough was associated with improved DFS and did not increase treatment discontinuations or grade 3/4 AEs, with the exception of hypertension. Clin Cancer Res; 24(13); 3005–13. ©2018 AACR.

See related commentary by Rini, p. 2979

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Adjuvant Treatment for POLE Proofreading Domain-Mutant Cancers: Sensitivity to Radiotherapy, Chemotherapy, and Nucleoside Analogues

Purpose: Pathogenic POLE proofreading domain mutations are found in many malignancies where they are associated with ultramutation and favorable prognosis. The extent to which this prognosis depends on their sensitivity to adjuvant treatment is unknown, as is the optimal therapy for advanced-staged or recurrent POLE-mutant cancers.

Experimental Design: We examined the recurrence-free survival of women with POLE-mutant and POLE–wild-type endometrial cancers (EC) in the observation arm of the randomized PORTEC-1 endometrial cancer trial (N = 245 patients with stage I endometrial cancer for analysis). Sensitivity to radiotherapy and selected chemotherapeutics was compared between Pole-mutant mouse-derived embryonic stem (mES) cells, generated using CRISPR-Cas9 (Pole mutations D275A/E275A, and cancer-associated P286R, S297F, V411L) and isogenic wild-type cell lines.

Results: In the observation arm of the PORTEC-1 trial (N = 245), women with POLE-mutant endometrial cancers (N = 16) had an improved recurrence-free survival (10-year recurrence-free survival 100% vs. 80.1% for POLE–wild-type; HR, 0.143; 95% confidence interval, 0.001–0.996; P = 0.049). Pole mutations did not increase sensitivity to radiotherapy nor to chemotherapeutics in mES cells. In contrast, Pole-mutant cells displayed significantly increased sensitivity to cytarabine and fludarabine (IC₅₀Pole P286R–mutant vs. wild-type: 0.05 vs. 0.17 μmol/L for cytarabine, 4.62 vs. 11.1 μmol/L for fludarabine; P < 0.001 for both comparisons).

Conclusions: The favorable prognosis of POLE-mutant cancers cannot be explained by increased sensitivity to currently used adjuvant treatments. These results support studies exploring minimization of adjuvant therapy for early-stage POLE-mutant cancers, including endometrial and colorectal cancers. Conversely, POLE mutations result in hypersensitivity to nucleoside analogues, suggesting the use of these compounds as a potentially effective targeted treatment for advanced-stage POLE-mutant cancers. Clin Cancer Res; 24(13); 3197–203. ©2018 AACR.

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Folate Receptor Alpha Peptide Vaccine Generates Immunity in Breast and Ovarian Cancer Patients

Purpose: Folate receptor alpha (FR) is overexpressed in several cancers. Endogenous immunity to the FR has been demonstrated in patients and suggests the feasibility of targeting FR with vaccine or other immune therapies. CD4 helper T cells are central to the development of coordinated immunity, and prior work shows their importance in protecting against relapse. Our previous identification of degenerate HLA-class II epitopes from human FR led to the development of a broad coverage epitope pool potentially useful in augmenting antigen-specific immune responses in most patients.

Patients and Methods: We conducted a phase I clinical trial testing safety and immunogenicity of this vaccine, enrolling patients with ovarian cancer or breast cancer who completed conventional treatment and who showed no evidence of disease. Patients were initially treated with low-dose cyclophosphamide and then vaccinated 6 times, monthly. Immunity and safety were examined during the vaccine period and up to 1 year later.

Results: Vaccination was well tolerated in all patients. Vaccine elicited or augmented immunity in more than 90% of patients examined. Unlike recall immunity to tetanus toxoid (TT), FR T-cell responses developed slowly over the course of vaccination with a median time to maximal immunity in 5 months. Despite slow development of immunity, responsiveness appeared to persist for at least 12 months.

Conclusions: The results demonstrate that it is safe to augment immunity to the FR tumor antigen, and the developed vaccine is testable for therapeutic activity in most patients whose tumors express FR, regardless of HLA genotype. Clin Cancer Res; 24(13); 3014–25. ©2018 AACR.

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Highlights of This Issue

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5-Fluorouracil Enhances Protoporphyrin IX Accumulation and Lesion Clearance during Photodynamic Therapy of Actinic Keratoses: A Mechanism-Based Clinical Trial

Purpose: Actinic keratoses (AK) are precancerous lesions that can progress to squamous cell carcinoma. Photodynamic therapy (PDT) and topical 5-fluorouracil (5FU) are commonly used agents for AK. Empirical reports suggest that combining them can improve the therapeutic response. However, the optimal combined regimen was not clear in terms of proper sequence, timing, and mechanism. This clinical study explored mechanisms of action for neoadjuvantal 5FU and PDT for treatment of AK.

Patients and Methods: A bilaterally controlled trial (17 patients) was performed. One side of the body (face, scalp, forearms) received 5FU pretreatment for 6 days, whereas the other side served as no-pretreatment control. Methylaminolevulinate cream was applied to both sides for 3 hours, and protoporphyrin IX (PpIX) levels were measured by noninvasive fluorimetry and skin biopsy. After red light illumination, lesion clearance was assessed at 3, 6, 9, and 12 months after PDT.

Results: PpIX levels were increased 2- to 3-fold in 5FU-pretreated lesions versus controls. Altered expression of heme-synthetic enzymes (coproporphyrinogen oxidase and ferrochelatase) and induction of p53 were observed, probably accounting for increased PpIX and subsequent cancer cell death. Relative clearance rates after PDT with or without 5FU pretreatment were 75% versus 45% at 3 months, and 67% versus 39% at 6 months, respectively; these differences were statistically significant.

Conclusions: Serial 5FU and PDT improve AK clearance by at least two mechanisms, enhanced photosensitizer accumulation and p53 induction. Because 5FU and PDT are FDA-approved modalities, the combined regimen can be readily employed in clinical practice to reduce AK burden and reduce SCC risk. Clin Cancer Res; 24(13); 3026–35. ©2018 AACR.

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Investigating Novel Resistance Mechanisms to Third-Generation EGFR Tyrosine Kinase Inhibitor Osimertinib in Non-Small Cell Lung Cancer Patients

Purpose: The third-generation EGFR tyrosine kinase inhibitor osimertinib is approved to treat patients with EGFR T790M-positive non–small cell lung cancer (NSCLC) who have developed resistance to earlier-generation drugs. Acquired EGFR C797S mutation has been reported to mediate osimertinib resistance in some patients. However, the remaining resistance mechanisms are largely unknown.

Experimental Design: We performed mutation profiling using targeted next-generation sequencing (NGS) for 416 cancer-relevant genes on 93 osimertinib-resistant lung cancer patients' samples, mainly cell-free DNAs (cfDNAs), and matched pretreatment samples of 12 patients. In vitro experiments were conducted to functionally study the secondary EGFR mutations identified.

Results: EGFR G796/C797, L792, and L718/G719 mutations were identified in 24.7%, 10.8%, and 9.7% of the cases, respectively, with certain mutations coexisting in one patient with different prevalence. L792 and L718 mutants markedly increased the half inhibitory concentration (IC₅₀) of osimertinib in vitro, among which the L718Q mutation conferred the greatest resistance to osimertinib, as well as gefitinib resistance when not coexisting with T790M. Further analysis of the 12 matched pretreatment samples confirmed that these EGFR mutations were acquired during osimertinib treatment. Alterations in parallel or downstream oncogenes such as MET, KRAS, and PIK3CA were also discovered, potentially contributing to the osimertinib-resistance in patients without EGFR secondary mutations.

Conclusions: We present comprehensive mutation profiles of a large cohort of osimertinib-resistance lung cancer patients using mainly cfDNA. Besides C797 mutations, novel secondary mutations of EGFR L718 and L792 residues confer osimertinib resistance, both in vitro and in vivo, and are of great clinical and pharmaceutical relevance. Clin Cancer Res; 24(13); 3097–107. ©2018 AACR.

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CD103+ Tumor-Resident CD8+ T Cells Are Associated with Improved Survival in Immunotherapy-Naïve Melanoma Patients and Expand Significantly During Anti-PD-1 Treatment

Purpose: Therapeutic blockade of immune checkpoints has revolutionized cancer treatment. Durable responses, however, occur in less than half of those treated, and efforts to improve treatment efficacy are confounded by a lack of understanding of the characteristics of the cells that initiate antitumor immune response.

Patients and Methods: We performed multiparameter flow cytometry and quantitative multiplex immunofluorescence staining on tumor specimens from immunotherapy-naïve melanoma patients and longitudinal biopsy specimen obtained from patients undergoing anti–PD-1 therapy.

Results: Increased numbers of CD69⁺CD103⁺ tumor-resident CD8⁺ T cells were associated with improved melanoma-specific survival in immunotherapy-naïve melanoma patients. Local IL15 expression levels strongly correlated with these tumor-resident T-cell numbers. The expression of several immune checkpoints including PD-1 and LAG3 was highly enriched in this subset, and these cells significantly expanded early during anti–PD-1 immunotherapy.

Conclusions: Tumor-resident CD8⁺ T-cell numbers are more prognostic than total CD8⁺ T cells in metastatic melanoma. In addition, they are likely to initiate response to anti–PD-1 and anti–LAG-3 treatments. We propose that the immune profile of these cells prior to treatment could inform strategies for immune checkpoint blockade. Clin Cancer Res; 24(13); 3036–45. ©2018 AACR.

https://ift.tt/2lLoVIR

Accuracy of a Novel Handheld Wireless Platform for Detection of Cardiac Dysfunction in Anthracycline-Exposed Survivors of Childhood Cancer

Purpose: Childhood cancer survivors are at risk for anthracycline-related cardiac dysfunction, often developing at a time when they are least engaged in long-term survivorship care. New paradigms in survivorship care and chronic disease screening are needed in this population. We compared the accuracy of a novel handheld mHealth platform (Vivio) as well as echocardiography for assessment of cardiac function [left ventricular ejection fraction (EF)] in childhood cancer survivors with cardiac magnetic resonance (CMR) imaging (reference).

Experimental Design: Cross-sectional study design was used. Concurrent evaluation of EF was performed using Vivio, two-dimensional (2D) echocardiography, and CMR. Differences in mean EF (2D echocardiography vs. CMR; Vivio vs. CMR) were compared using Bland–Altman plots. Linear regression was used to evaluate proportional bias.

Results: A total of 191 consecutive survivors participated [50.7% female; median time from diagnosis: 15.8 years (2–44); median anthracycline dose: 225 mg/m² (25–642)]. Echocardiography overestimated mean EF by 4.9% (P < 0.001); linear regression analysis confirmed a proportional bias, when compared with CMR (t = 3.1, P < 0.001). There was no difference between mean EF derived from Vivio and from CMR (–0.2%, P = 0.68). The detection of cardiac dysfunction via echocardiography was poor when compared with CMR [Echo EF < 45% (sensitivity 14.3%), Echo EF < 50% (sensitivity 28.6%)]. Sensitivity was substantially better for Vivio-based measurements [EF < 45% or EF < 50% (sensitivity 85.7%)].

Conclusions: This accessible technology has the potential to change the day-to-day practice of clinicians caring for the large number of patients diagnosed with cardiac dysfunction and heart failure each year, allowing real-time monitoring and management of their disease without the lag-time between imaging and interpretation of results. Clin Cancer Res; 24(13); 3119–25. ©2018 AACR.

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p95HER2 Methionine 611 Carboxy-Terminal Fragment Is Predictive of Trastuzumab Adjuvant Treatment Benefit in the FinHer Trial

Purpose: Expression of p95HER2 (p95), a truncated form of the HER2 receptor, which lacks the trastuzumab binding site but retains kinase activity, has been reported as a prognostic biomarker for poor outcomes in patients with trastuzumab-treated HER2-positive metastatic breast cancer. The impact of p95 expression on trastuzumab treatment efficacy in early HER2-positive breast cancer is less clear. In the current study, p95 was tested as a predictive marker of trastuzumab treatment benefit in the HER2-positive subset of the FinHer adjuvant phase III trial.

Experimental Design: In the FinHer trial, 232 patients with HER2-positive early breast cancer were randomized to receive chemotherapy plus 9 weeks of trastuzumab or no trastuzumab treatment. Quantitative p95 protein expression was measured in formalin-fixed paraffin-embedded samples using the p95 VeraTag assay (Monogram Biosciences), specific for the M611 form of p95. Quantitative HER2 protein expression was measured using the HERmark assay (Monogram Biosciences). Distant disease-free survival (DDFS) was used as the primary outcome measure.

Results: In the arm receiving chemotherapy only, increasing log₁₀(p95) correlated with shorter DDFS (HR, 2.0; P = 0.02). In the arm receiving chemotherapy plus trastuzumab (N = 95), increasing log₁₀(p95) was not correlated with a shorter DDFS. In a combined analysis of both treatment arms, high breast tumor p95 content was significantly correlated with trastuzumab treatment benefit in multivariate models (interaction P = 0.01).

Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies. Further investigation of the p95HER2/HER2 ratio as a potential prognostic or predictive biomarker for HER2-targeted therapy is warranted. Clin Cancer Res; 24(13); 3046–52. ©2018 AACR.

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Erasing CD33 in Normal Myeloid Cells Averts CAR T Cell-Driven Toxicity [Leukemia]

Inactivation of CD33 in HSPCs permits CD33-directed CAR T-cell treatment of AML.

https://ift.tt/2KDnxpY

The cis-Regulatory DERARE Element Regulates Leukemogenesis [Leukemia]

DERARE methylation suppresses HOXB gene expression and leukemogenesis to maintain normal hematopoiesis.

https://ift.tt/2KEDd9d

FDA Tackles Underage E-cigarette Use [News in Brief]

In recent weeks, the FDA has taken steps to address underage use of e-cigarettes: The agency has identified and warned retailers selling to minors, issued warning letters to companies selling e-cigarette cartridges in adolescent-appealing packaging, and requested information from e-cigarette companies. The steps are part of the FDA's ongoing effort to prevent middle- and high-school students from using e-cigarette products.

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Microbial Signals Promote Preleukemic Myeloproliferation in Tet2-/- Mice [Microbiome]

TET2 deficiency increases systemic bacterial dissemination to promote preleukemic myeloproliferation (PMP).

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9/11 Firefighters at Risk for Multiple Myeloma [News in Brief]

The largest study to date of responders to the World Trade Center attacks in New York, NY, on 9/11 reports that exposed firefighters have roughly twice the risk of developing multiple myeloma precursor disease as the general population. Moreover, firefighters who go on to develop multiple myeloma exhibit a younger age of onset and more aggressive disease than is typical.

https://ift.tt/2IIX7Ok

Precision Targeted Therapy with BLU-667 for RET-Driven Cancers [Research Articles]

The receptor tyrosine kinase rearranged during transfection (RET) is an oncogenic driver activated in multiple cancers, including non–small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and papillary thyroid cancer. No approved therapies have been designed to target RET; treatment has been limited to multikinase inhibitors (MKI), which can have significant off-target toxicities and limited efficacy. BLU-667 is a highly potent and selective RET inhibitor designed to overcome these limitations. In vitro, BLU-667 demonstrated ≥10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants. In vivo, BLU-667 potently inhibited growth of NSCLC and thyroid cancer xenografts driven by various RET mutations and fusions without inhibiting VEGFR2. In first-in-human testing, BLU-667 significantly inhibited RET signaling and induced durable clinical responses in patients with RET-altered NSCLC and MTC without notable off-target toxicity, providing clinical validation for selective RET targeting.

Significance: Patients with RET-driven cancers derive limited benefit from available MKIs. BLU-667 is a potent and selective RET inhibitor that induces tumor regression in cancer models with RET mutations and fusions. BLU-667 attenuated RET signaling and produced durable clinical responses in patients with RET-altered tumors, clinically validating selective RET targeting. Cancer Discov; 8(7); 836–49. ©2018 AACR.

See related commentary by Iams and Lovly, p. 797.

This article is highlighted in the In This Issue feature, p. 781

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Anatomic Gene Expression Atlas Fuels Glioblastoma Discovery [News in Brief]

The Ivy Glioblastoma Atlas provides detailed information about genes expressed in different anatomic regions of human brain tumors. Researchers are already drawing upon the resource to identify novel therapeutic targets for this deadly cancer.

https://ift.tt/2KA1qgN

MLL3 Mutations Disrupt COMPASS Recruitment to Enhancer Chromatin [Epigenetics]

Mutations in the MLL3 PHD domain promote oncogenesis by disrupting its interaction with BAP1.

https://ift.tt/2KqF1X4

Companies Scaling Back IDO1 Inhibitor Trials [News in Depth]

Based on negative results of the ECHO-301 trial in melanoma, as well as in the pancreatic cancer cohort of ECHO-203, Incyte halted several trials of its IDO inhibitor epacadostat. Other companies, including NewLink Genetics and Bristol-Myers Squibb, also decided to scale back and/or halt trials of their IDO inhibitors. However, researchers offered reasons for the disappointing trial results and said that trials of IDO inhibitors should not be abandoned.

https://ift.tt/2KDwxYZ

Macropinocytosis Fuels Prostate Cancer [In the Spotlight]

Summary: Kim and colleagues identify necrotic debris as a macropinocytic cargo in PTEN-deficient prostate cancer cells, which is catabolized to generate the nutrients and biomass necessary to support tumor cell growth and metabolism in nutrient-limiting conditions. Cancer Discov; 8(7); 800–2. ©2018 AACR.

See related article by Kim et al., p. 866.

https://ift.tt/2KxUbsT

[177Lu]-PSMA-617 Has Activity in Castration-Resistant Prostate Cancer [Clinical Trials]

Radionuclide treatment with [¹⁷⁷Lu]-PSMA-617 (LuPSMA) reduced PSA levels by ≥50% in 57% of patients.

https://ift.tt/2KDwv3j

Shared Decision Making Emphasized for Prostate Screening [News in Brief]

The U.S. Preventive Services Task Force (USPSTF) now recommends that men ages 55 to 69 individually decide, in consultation with their physician, whether to undergo PSA screening for prostate cancer. The guidelines represent a change from 2012, when the USPSTF recommended against screening for all men.

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A Bispecific Antibody Targeting HER2 and HER3 Suppresses Tumor Growth [Drug Discovery]

Unbiased phenotypic combinatorial screening uncovers a bispecific antibody (bAb) targeting HER2 and HER3.

https://ift.tt/2IIWRyQ

3' UTR Shortening Represses Tumor Suppressor Genes in Trans [Noncoding RNA]

3' UTR shortening of ceRNA genes disrupts miRNA binding, freeing miRNAs to repress tumor suppressors.

https://ift.tt/2KAuyrC

UTX Promotes Chromatin Remodeling to Suppress Leukemogenesis [Epigenetics]

UTX-mediated suppression of myeloid leukemogenesis is independent of its demethylase activity.

https://ift.tt/2IHAVEw

The BET Inhibitor Birabresib Is Safe in Patients with Solid Tumors [Clinical Trials]

Birabresib achieved partial responses in 3 of 10 patients with NUT midline carcinoma.

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ARID1A Deficiency May Predict Response to Immune Checkpoint Blockade [Immunotherapy]

ARID1A deficiency impairs mismatch repair to increase tumor mutation load and promote tumor progression.

https://ift.tt/2KAqEvs

Epistatic Oncogenic Interactions Determine Cancer Susceptibility to Immunotherapy [In the Spotlight]

Summary: Cancer genetic alterations and epigenetics control the malignant phenotype of tumor cells and the stroma. Synergistic oncogenic alterations may cooperatively dictate immunogenicity, level of infiltration by immune system cells, and response to immunotherapy in an epistatic fashion. The work of Skoulidis and colleagues shows that concomitant RAS and STK11/LKB1 mutations in non–small cell lung adenocarcinomas result in primary resistance to PD-1–based immunotherapy and poor T-cell infiltration. Cancer Discov; 8(7); 794–6. ©2018 AACR.

See related article by Skoulidis et al., p. 822.

https://ift.tt/2KByBUo

Efficacy of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Inhibitor, in Patients with Previously Treated Advanced Urothelial Carcinoma with FGFR3 Alterations [Research Articles]

BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of FGFR3 alterations. Patients (N = 67) who were unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite. Further examination of BGJ398 in this disease setting is warranted.

Significance: BJG398 is active in patients with alterations in FGFR3, resulting in both reductions in tumor volume and stabilization of disease. Our data highlight putative mechanisms of resistance to the agent, which may be useful in following disease status. Cancer Discov; 8(7); 812–21. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 781

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Targeting Glutaminase May Overcome Resistance to mTOR Inhibition [Lung Cancer]

mTOR inhibitor–mediated suppression of glycolysis results in a compensatory increase in glutaminolysis.

https://ift.tt/2KED8SX

Contemporary approaches to High-risk, Early-Stage Serous Endometrial Cancer: Clinical Equipoise Persists

No abstract available

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Dose Escalation in Stereotactic Body Radiation Therapy for Pancreatic Cancer: A Meta-Analysis

Objective: To determine whether increasing biologically effective dose (BED) with stereotactic body radiation therapy (SBRT) is associated with improved local control (LC) or toxicities in patients with locally advanced pancreatic cancer. Methods: A PICOS/PRISMA/MOOSE selection protocol was used to identify 15 studies across 12 institutions in 5 countries where patients received definitive SBRT for nonmetastatic disease. Biologically equivalent doses were calculated with an α/β of 10 (ie, BED10) for LC and acute toxicity and 3 (ie, BED3) for late toxicity. Fixed and random effects models were used to characterize LC and grade 3/4 toxicities by BED. Results: There were 508 patients included with a median follow-up time of 9.1 months. The median dose was 30 Gy, and the most common regimen was 30 Gy/5 fractions. There was no significant difference in LC rates at 1 year between the BED10200 Gy. Conclusions: SBRT for pancreatic cancer results in LC rates of 60% to 83% and clinically significant toxicity of

https://ift.tt/2lMEznx

Treatment Patterns and Survival of Elderly Patients With Breast Cancer Brain Metastases

Objectives: The main objective of this study was to analyze treatment patterns of elderly patients with breast cancer brain metastases (BCBM), evaluate characteristics associated with treatment selection, and to analyze trends in overall survival (OS) over time. Materials and Methods: We included women with BCBM reported to the Surveillance, Epidemiology, and End Results Medicare Program from 1992 to 2012. Treatments were recorded from Medicare claims from the date of brain metastases diagnosis until 60 days after. Treatments included resection, radiation, and chemotherapy. Cochran-Armitage tests were used for analysis of treatment patterns. Multinomial logistic regression was applied to determine factors associated with treatment selection. Cox regression modelled OS trends within each treatment modality across time. Results: Among 5969 patients included, treatment rates increased from 50% in 1992 to 64.1% in 2012 (P

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Correction: Cancer Self-Defense: An Immune Stealth

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Tumor-Educated Platelets as a Noninvasive Biomarker Source for Cancer Detection and Progression Monitoring

Liquid biopsies represent a potential revolution in cancer diagnostics as a noninvasive method for detecting and monitoring diseases, complementary to or even replacing current tissue biopsy approaches. Several blood-based biosources and biomolecules, such as cell-free DNA and RNA, proteins, circulating tumor cells, and extracellular vesicles, have been explored for molecular test development. We recently discovered the potential of tumor-educated blood platelets (TEP) as a noninvasive biomarker trove for RNA biomarker panels. TEPs are involved in the progression and spread of several solid tumors, and spliced TEP RNA surrogate signatures can provide specific information on the presence, location, and molecular characteristics of cancers. So far, TEP samples from patients with different tumor types, including lung, brain, and breast cancers, have been tested, and it has been shown that TEPs from patients with cancer are distinct from those with inflammatory and other noncancerous diseases. It remains to be investigated how platelets are "educated," which mechanisms cause intraplatelet RNA splicing, and whether the relative contribution of specific platelet subpopulations changes in patients with cancer. Ultimately, TEP RNA may complement currently used biosources and biomolecules employed for liquid biopsy diagnosis, potentially enhancing the detection of cancer in an early stage and facilitating noninvasive disease monitoring. Cancer Res; 78(13); 3407–12. ©2018 AACR.

https://ift.tt/2IK7aCW

miRNA Profiling of Magnetic Nanopore-Isolated Extracellular Vesicles for the Diagnosis of Pancreatic Cancer

Improved diagnostics for pancreatic ductal adenocarcinoma (PDAC) to detect the disease at earlier, curative stages and to guide treatments is crucial to progress against this disease. The development of a liquid biopsy for PDAC has proven challenging due to the sparsity and variable phenotypic expression of circulating biomarkers. Here we report methods we developed for isolating specific subsets of extracellular vesicles (EV) from plasma using a novel magnetic nanopore capture technique. In addition, we present a workflow for identifying EV miRNA biomarkers using RNA sequencing and machine-learning algorithms, which we used in combination to classify distinct cancer states. Applying this approach to a mouse model of PDAC, we identified a biomarker panel of 11 EV miRNAs that could distinguish mice with PDAC from either healthy mice or those with precancerous lesions in a training set of n = 27 mice and a user-blinded validation set of n = 57 mice (88% accuracy in a three-way classification). These results provide strong proof-of-concept support for the feasibility of using EV miRNA profiling and machine learning for liquid biopsy.Significance: These findings present a panel of extracellular vesicle miRNA blood-based biomarkers that can detect pancreatic cancer at a precancerous stage in a transgenic mouse model. Cancer Res; 78(13); 3688–97. ©2018 AACR.

https://ift.tt/2Kn0cJD

Novel Richter Syndrome Xenograft Models to Study Genetic Architecture, Biology, and Therapy Responses

Richter syndrome represents the evolution of chronic lymphocytic leukemia into an aggressive tumor, most commonly diffuse large B-cell lymphoma. The lack of in vitro and in vivo models has severely hampered drug testing in a disease that is poorly responsive to common chemoimmunotherapeutic combinations as well as to novel kinase inhibitors. Here we report for the first time the establishment and genomic characterization of two patient-derived tumor xenograft (PDX) models of Richter syndrome, RS9737 and RS1316. Richter syndrome xenografts were genetically, morphologically, and phenotypically stable and similar to the corresponding primary tumor. RS9737 was characterized by biallelic inactivation of CDKN2A and TP53, monoallelic deletion of 11q23 (ATM), and mutations of BTK, KRAS, EGR2, and NOTCH1. RS1316 carried trisomy 12 and showed mutations in BTK, KRAS, MED12, and NOTCH2. RNA sequencing confirmed that in both cases >80% of the transcriptome was shared between primary tumor and PDX. In line with the mutational profile, pathway analyses revealed overactivation of the B-cell receptor, NFκB, and NOTCH pathways in both tumors, potentially providing novel tumor targets. In conclusion, these two novel models of Richter syndrome represent useful tools to study biology and response to therapies of this highly aggressive and still incurable tumor.Significance: Two patient-derived xenograft models of Richter syndrome represent the first ex vivo model to study biology of the disease and to test novel therapeutic strategies. Cancer Res; 78(13); 3413–20. ©2018 AACR.

https://ift.tt/2IK7gdM

The Autotaxin—Lysophosphatidic Acid Axis Promotes Lung Carcinogenesis

Pathogenesis and progression of lung cancer are governed by complex interactions between the environment and host genetic susceptibility, which is further modulated by genetic and epigenetic changes. Autotaxin (ATX, ENPP2) is a secreted glycoprotein that catalyzes the extracellular production of lysophosphatidic acid (LPA), a growth-factor–like phospholipid that is further regulated by phospholipid phosphatases (PLPP). LPA's pleiotropic effects in almost all cell types are mediated through at least six G-protein coupled LPA receptors (LPAR) that exhibit overlapping specificities, widespread distribution, and differential expression profiles. Here we use both preclinical models of lung cancer and clinical samples (from patients and healthy controls) to investigate the expression levels, activity, and biological role of the above components of the ATX/LPA axis in lung cancer. ENPP2 was genetically altered in 8% of patients with lung cancer, whereas increased ATX staining and activity were detected in patient biopsies and sera, respectively. Moreover, PLPP3 expression was consistently downregulated in patients with lung cancer. Comparable observations were made in the two most widely used animal models of lung cancer, the carcinogen urethane–induced and the genetically engineered K-rasG12D–driven models, where genetic deletion of Enpp2 or Lpar1 resulted in disease attenuation, thus confirming a procarcinogenic role of LPA signaling in the lung. Expression profiling data analysis suggested that metabolic rewiring may be implicated in the procarcinogenic effects of the ATX/LPA axis in K-ras-G12D–driven lung cancer pathogenesis.Significance: These findings establish the role of ATX/LPA in lung carcinogenesis, thus expanding the mechanistic links between pulmonary fibrosis and cancer. Cancer Res; 78(13); 3634–44. ©2018 AACR.

https://ift.tt/2Ksz9wz

SETD2 Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma

Osteosarcoma is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of osteosarcoma spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that osteosarcoma tumors show a high frequency of somatic copy-number alterations (SCNA), affecting key oncogenes and tumor-suppressor genes. The across-breed results are similar to what has been observed for human osteosarcoma, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported) and 11 significantly mutated genes were identified. TP53 was the most frequently altered gene (83% of dogs have either mutations or SCNA in TP53), recapitulating observations in human osteosarcoma. The second most frequently mutated gene, histone methyltransferase SETD2, has known roles in multiple cancers, but has not previously been strongly implicated in osteosarcoma. This study points to the likely importance of histone modifications in osteosarcoma and highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine osteosarcoma may serve as an excellent model for developing treatment strategies in both species.Significance: Canine osteosarcoma genomics identify SETD2 as a possible oncogenic driver of osteosarcoma, and findings establish the canine model as a useful comparative model for the corresponding human disease. Cancer Res; 78(13); 3421–31. ©2018 AACR.

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Tau Mutations Serve as a Novel Risk Factor for Cancer

In addition to its well-recognized role in neurodegeneration, tau participates in maintenance of genome stability and chromosome integrity. In particular, peripheral cells from patients affected by frontotemporal lobar degeneration carrying a mutation in tau gene (genetic tauopathies), as well as cells from animal models, show chromosome numerical and structural aberrations, chromatin anomalies, and a propensity toward abnormal recombination. As genome instability is tightly linked to cancer development, we hypothesized that mutated tau may be a susceptibility factor for cancer. Here we conducted a retrospective cohort study comparing cancer incidence in families affected by genetic tauopathies to control families. In addition, we carried out a bioinformatics analysis to highlight pathways associated with the tau protein interactome. We report that the risk of developing cancer is significantly higher in families affected by genetic tauopathies, and a high proportion of tau protein interactors are involved in cellular processes particularly relevant to cancer. These findings disclose a novel role of tau as a risk factor for cancer, providing new insights in the various pathologic roles of mutated tau.Significance: This study reveals a novel role for tau as a risk factor for cancer, providing new insights beyond its role in neurodegeneration. Cancer Res; 78(13); 3731–9. ©2018 AACR.

https://ift.tt/2KnESUp

High USP6NL Levels in Breast Cancer Sustain Chronic AKT Phosphorylation and GLUT1 Stability Fueling Aerobic Glycolysis

USP6NL, also named RN-tre, is a GTPase-activating protein involved in control of endocytosis and signal transduction. Here we report that USP6NL is overexpressed in breast cancer, mainly of the basal-like/integrative cluster 10 subtype. Increased USP6NL levels were accompanied by gene amplification and were associated with worse prognosis in the METABRIC dataset, retaining prognostic value in multivariable analysis. High levels of USP6NL in breast cancer cells delayed endocytosis and degradation of the EGFR, causing chronic AKT (protein kinase B) activation. In turn, AKT stabilized the glucose transporter GLUT1 at the plasma membrane, increasing aerobic glycolysis. In agreement, elevated USP6NL sensitized breast cancer cells to glucose deprivation, indicating that their glycolytic capacity relies on this protein. Depletion of USP6NL accelerated EGFR/AKT downregulation and GLUT1 degradation, impairing cell proliferation exclusively in breast cancer cells that harbored increased levels of USP6NL. Overall, these findings argue that USP6NL overexpression generates a metabolic rewiring that is essential to foster the glycolytic demand of breast cancer cells and promote their proliferation.Significance: USP6NL overexpression leads to glycolysis addiction of breast cancer cells and presents a point of metabolic vulnerability for therapeutic targeting in a subset of aggressive basal-like breast tumors.Graphical Abstract: https://ift.tt/2Krno9N. Cancer Res; 78(13); 3432–44. ©2018 AACR.

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Autocrine Adenosine Regulates Tumor Polyfunctional CD73+CD4+ Effector T Cells Devoid of Immune Checkpoints

The production of CD73-derived adenosine (Ado) by Tregs has been proposed as a resistance mechanism to anti-PD-1 therapy in murine tumor models. We reported that human Tregs express the ectonucleotidase CD39, which generates AMP from ATP, but do not express the AMPase CD73. In contrast, CD73 defined a subset of effector CD4+ T cells (Teffs) enriched in polyfunctional Th1.17 cells characterized by expression of CXCR3, CCR6, and MDR1, and production of IL17A/IFNγ/IL22/GM-CSF. CD39+ Tregs selectively targeted CD73+ Teffs through cooperative degradation of ATP into Ado inhibiting and restricting the ability of CD73+ Teffs to secrete IL17A. CD73+ Teffs infiltrating breast and ovarian tumors were functionally blunted by Tregs expressing upregulated levels of CD39 and ATPase activity. Moreover, tumor-infiltrating CD73+ Teffs failed to express inhibitory immune checkpoints, suggesting that CD73 might be selected under pressure from immune checkpoint blockade therapy and thus may represent a nonredundant target for restoring antitumor immunity.Significance: Polyfunctional CD73+ T-cell effectors lacking other immune checkpoints are selectively targeted by CD39 overexpressing Tregs that dominate the breast tumor environment. Cancer Res; 78(13); 3604–18. ©2018 AACR.

https://ift.tt/2IK7b9Y

GFPT2-Expressing Cancer-Associated Fibroblasts Mediate Metabolic Reprogramming in Human Lung Adenocarcinoma

Metabolic reprogramming of the tumor microenvironment is recognized as a cancer hallmark. To identify new molecular processes associated with tumor metabolism, we analyzed the transcriptome of bulk and flow-sorted human primary non–small cell lung cancer (NSCLC) together with 18FDG-PET scans, which provide a clinical measure of glucose uptake. Tumors with higher glucose uptake were functionally enriched for molecular processes associated with invasion in adenocarcinoma and cell growth in squamous cell carcinoma (SCC). Next, we identified genes correlated to glucose uptake that were predominately overexpressed in a single cell–type comprising the tumor microenvironment. For SCC, most of these genes were expressed by malignant cells, whereas in adenocarcinoma, they were predominately expressed by stromal cells, particularly cancer-associated fibroblasts (CAF). Among these adenocarcinoma genes correlated to glucose uptake, we focused on glutamine-fructose-6-phosphate transaminase 2 (GFPT2), which codes for the glutamine-fructose-6-phosphate aminotransferase 2 (GFAT2), a rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), which is responsible for glycosylation. GFPT2 was predictive of glucose uptake independent of GLUT1, the primary glucose transporter, and was prognostically significant at both gene and protein level. We confirmed that normal fibroblasts transformed to CAF-like cells, following TGFβ treatment, upregulated HBP genes, including GFPT2, with less change in genes driving glycolysis, pentose phosphate pathway, and TCA cycle. Our work provides new evidence of histology-specific tumor stromal properties associated with glucose uptake in NSCLC and identifies GFPT2 as a critical regulator of tumor metabolic reprogramming in adenocarcinoma.Significance: These findings implicate the hexosamine biosynthesis pathway as a potential new therapeutic target in lung adenocarcinoma. Cancer Res; 78(13); 3445–57. ©2018 AACR.

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Identification of a Small Molecule That Selectively Inhibits ERG-Positive Cancer Cell Growth

Oncogenic activation of the ETS-related gene (ERG) by recurrent gene fusions (predominantly TMPRSS2–ERG) is one of the most validated and prevalent genomic alterations present in early stages of prostate cancer. In this study, we screened small-molecule libraries for inhibition of ERG protein in TMPRSS2–ERG harboring VCaP prostate cancer cells using an In-Cell Western Assay with the highly specific ERG-MAb (9FY). Among a subset of promising candidates, 1-[2-Thiazolylazo]-2-naphthol (NSC139021, hereafter ERGi-USU) was identified and further characterized. ERGi-USU selectively inhibited growth of ERG-positive cancer cell lines with minimal effect on normal prostate or endothelial cells or ERG-negative tumor cell lines. Combination of ERGi-USU with enzalutamide showed additive effects in inhibiting growth of VCaP cells. A screen of kinases revealed that ERGi-USU directly bound the ribosomal biogenesis regulator atypical kinase RIOK2 and induced ribosomal stress signature. In vivo, ERGi-USU treatment inhibited growth of ERG-positive VCaP tumor xenografts with no apparent toxicity. Structure-activity–based derivatives of ERGi-USU recapitulated the ERG-selective activity of the parental compound. Taken together, ERGi-USU acts as a highly selective inhibitor for the growth of ERG-positive cancer cells and has potential for further development of ERG-targeted therapy of prostate cancer and other malignancies.Significance: A highly selective small-molecule inhibitor of ERG, a critical driver of early stages of prostate cancer, will be imperative for prostate cancer therapy. Cancer Res; 78(13); 3659–71. ©2018 AACR.

https://ift.tt/2IIQvzA

PSMD5 Inactivation Promotes 26S Proteasome Assembly during Colorectal Tumor Progression

Protein degradation by the ubiquitin–proteasome system (UPS) is central to protein homeostasis and cell survival. The active 26S proteasome is a large protease complex consisting of a catalytic 20S subunit and 19S regulatory particles. Cancer cells are exposed to considerable protein overload due to high metabolic rates, reprogrammed energy metabolism, and aneuploidy. Here we report a mechanism that facilitates the assembly of active 26S proteasomes in malignant cells. Upon tumorigenic transformation of the gut epithelium, 26S proteasome assembly was significantly enhanced, but levels of individual subunits were not changed. This enhanced assembly of 26S proteasomes increased further with tumor progression and was observed specifically in transformed cells, but not in other rapidly dividing cells. Moreover, expression of PSMD5, an inhibitor of proteasome assembly, was reduced in intestinal tumors and silenced with tumor progression. Reexpression of PSMD5 in tumor cells caused decreased 26S assembly and accumulation of polyubiquitinated proteins. These results suggest that inhibition of cancer-associated proteasome assembly may provide a novel therapeutic strategy to selectively kill cancer cells.Significance: Enhanced cancer-associated proteasome assembly is a major stress response that allows tumors to adapt to and to withstand protein overload.Graphical Abstract: https://ift.tt/2KDXpYI. Cancer Res; 78(13); 3458–68. ©2018 AACR.

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NK Cells Mediate Synergistic Antitumor Effects of Combined Inhibition of HDAC6 and BET in a SCLC Preclinical Model

Small-cell lung cancer (SCLC) has the highest malignancy among all lung cancers, exhibiting aggressive growth and early metastasis to distant sites. For 30 years, treatment options for SCLC have been limited to chemotherapy, warranting the need for more effective treatments. Frequent inactivation of TP53 and RB1 as well as histone dysmodifications in SCLC suggest that transcriptional and epigenetic regulations play a major role in SCLC disease evolution. Here we performed a synthetic lethal screen using the BET inhibitor JQ1 and an shRNA library targeting 550 epigenetic genes in treatment-refractory SCLC xenograft models and identified HDAC6 as a synthetic lethal target in combination with JQ1. Combined treatment of human and mouse SCLC cell line–derived xenograft tumors with the HDAC6 inhibitor ricolinostat (ACY-1215) and JQ1 demonstrated significant inhibition of tumor growth; this effect was abolished upon depletion of NK cells, suggesting that these innate immune lymphoid cells play a role in SCLC tumor treatment response. Collectively, these findings suggest a potential new treatment for recurrent SCLC.Significance: These findings identify a novel therapeutic strategy for SCLC using a combination of HDAC6 and BET inhibitors. Cancer Res; 78(13); 3709–17. ©2018 AACR.

https://ift.tt/2KAsGPC

TNFRSF19 Inhibits TGF{beta} Signaling through Interaction with TGF{beta} Receptor Type I to Promote Tumorigenesis

Genetic susceptibility underlies the pathogenesis of cancer. We and others have previously identified a novel susceptibility gene TNFRSF19, which encodes an orphan member of the TNF receptor superfamily known to be associated with nasopharyngeal carcinoma (NPC) and lung cancer risk. Here, we show that TNFRSF19 is highly expressed in NPC and is required for cell proliferation and NPC development. However, unlike most of the TNF receptors, TNFRSF19 was not involved in NFκB activation or associated with TRAF proteins. We identified TGFβ receptor type I (TβRI) as a specific binding partner for TNFRSF19. TNFRSF19 bound the kinase domain of TβRI in the cytoplasm, thereby blocking Smad2/3 association with TβRI and subsequent signal transduction. Ectopic expression of TNFRSF19 in normal epithelial cells conferred resistance to the cell-cycle block induced by TGFβ, whereas knockout of TNFRSF19 in NPC cells unleashed a potent TGFβ response characterized by upregulation of Smad2/3 phosphorylation and TGFβ target gene transcription. Furthermore, elevated TNFRSF19 expression correlated with reduced TGFβ activity and poor prognosis in patients with NPC. Our data reveal that gain of function of TNFRSF19 in NPC represents a mechanism by which tumor cells evade the growth-inhibitory action of TGFβ.Significance: TNFRSF19, a susceptibility gene for nasopharyngeal carcinoma and other cancers, functions as a potent inhibitor of the TGFβ signaling pathway.Graphical Abstract: https://ift.tt/2KmKv5j. Cancer Res; 78(13); 3469–83. ©2018 AACR.

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Correction: Heterochromatin Protein HP1{gamma} Promotes Colorectal Cancer Progression and Is Regulated by miR-30a

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A G3BP1-Interacting lncRNA Promotes Ferroptosis and Apoptosis in Cancer via Nuclear Sequestration of p53

Long noncoding RNAs (lncRNA) have been associated with various types of cancer; however, the precise role of many lncRNAs in tumorigenesis remains elusive. Here we demonstrate that the cytosolic lncRNA P53RRA is downregulated in cancers and functions as a tumor suppressor by inhibiting cancer progression. Chromatin remodeling proteins LSH and Cfp1 silenced or increased P53RRA expression, respectively. P53RRA bound Ras GTPase-activating protein-binding protein 1 (G3BP1) using nucleotides 1 and 871 of P53RRA and the RRM interaction domain of G3BP1 (aa 177-466). The cytosolic P53RRA–G3BP1 interaction displaced p53 from a G3BP1 complex, resulting in greater p53 retention in the nucleus, which led to cell-cycle arrest, apoptosis, and ferroptosis. P53RRA promoted ferroptosis and apoptosis by affecting transcription of several metabolic genes. Low P53RRA expression significantly correlated with poor survival in patients with breast and lung cancers harboring wild-type p53. These data show that lncRNAs can directly interact with the functional domain of signaling proteins in the cytoplasm, thus regulating p53 modulators to suppress cancer progression.Significance: A cytosolic lncRNA functions as a tumor suppressor by activating the p53 pathway. Cancer Res; 78(13); 3484–96. ©2018 AACR.

https://ift.tt/2KwdtPB

Highlights from Recent Cancer Literature

https://ift.tt/2IJGUJ3

Specificity Protein Transcription Factors and Cancer: Opportunities for Drug Development

Specificity protein (Sp) transcription factors (TFs) such as Sp1 are critical for early development but their expression decreases with age and there is evidence that transformation of normal cells to cancer cells is associated with upregulation of Sp1, Sp3, and Sp4, which are highly expressed in cancer cells and tumors. Sp1 is a negative prognostic factor for pancreatic, colon, glioma, gastric, breast, prostate, and lung cancer patients. Functional studies also demonstrate that Sp TFs regulate genes responsible for cancer cell growth, survival, migration/invasion, inflammation and drug resistance, and Sp1, Sp3 and Sp4 are also nononcogene addiction (NOA) genes and important drug targets. The mechanisms of drug-induced downregulation of Sp TFs and pro-oncogenic Sp-regulated genes are complex and include ROS-dependent epigenetic pathways that initially decrease expression of the oncogene cMyc. Many compounds such as curcumin, aspirin, and metformin that are active in cancer prevention also exhibit chemotherapeutic activity and these compounds downregulate Sp TFs in cancer cell lines and tumors. The effects of these compounds on downregulation of Sp TFs in normal cells and the contribution of this response to their chemopreventive activity have not yet been determined. Cancer Prev Res; 11(7); 371–82. ©2018 AACR.

https://ift.tt/2Kq5NPt

Ultraviolet Radiation Inhibits Mammary Carcinogenesis in an ER-Negative Murine Model by a Mechanism Independent of Vitamin D3

Three decades ago, the Garlands postulated that vitamin D₃ produced in the skin by ultraviolet radiation (UVR)-induced conversion of 7-dehydrocholesterol to pre-D₃ has anticancer effects, thus triggering more than 9,500 publications on D₃ and cancer. Here, we report that UVR treatment of transgenic mice of the well-established C3(1)/SV40 Tag mammary cancer model significantly inhibits both autochthonous carcinogenesis and allograft tumor growth, but in contrast neither dietary nor topical D₃ influences mammary carcinogenesis in this specific mouse model. Furthermore, UVR's inhibitory effects occur irrespective of whether or not the treatment increases circulating D₃ in the mice. The inhibitory effect of UVR on autochthonous tumors occurs at or before the stage of ductal carcinoma in situ. Our studies indicate clearly that UVR can exert D₃-independent anticancer effects in C3(1)/SV40 Tag mice. Therefore, supplemental D₃ may not mimic all possible beneficial effects of UVR, and uncovering non–D₃-mediated mechanisms of UVR tumor inhibition may lead to novel strategies for cancer prevention. Cancer Prev Res; 11(7); 383–92. ©2018 AACR.

https://ift.tt/2ME6T6N

Evaluation of Biodistribution of Sulforaphane after Administration of Oral Broccoli Sprout Extract in Melanoma Patients with Multiple Atypical Nevi

Broccoli sprout extract containing sulforaphane (BSE-SFN) has been shown to inhibit ultraviolet radiation–induced damage and tumor progression in skin. This study evaluated the toxicity and potential effects of oral BSE-SFN at three dosages. Seventeen patients who each had at least 2 atypical nevi and a prior history of melanoma were randomly allocated to 50, 100, or 200 μmol oral BSE-SFN daily for 28 days. Atypical nevi were photographed on days 1 and 28, and plasma and nevus samples were taken on days 1, 2, and 28. Endpoints assessed were safety, plasma and skin sulforaphane levels, gross and histologic changes, IHC for phospho-STAT3(Y705), Ki-67, Bcl-2, HMOX1, and TUNEL, plasma cytokine levels, and tissue proteomics. All 17 patients completed 28 days with no dose-limiting toxicities. Plasma sulforaphane levels pooled for days 1, 2, and 28 showed median postadministration increases of 120 ng/mL for 50 μmol, 206 ng/mL for 100 μmol, and 655 ng/mL for 200 μmol. Median skin sulforaphane levels on day 28 were 0.0, 3.1, and 34.1 ng/g for 50, 100, and 200 μmol, respectively. Plasma levels of proinflammatory cytokines decreased from day 1 to 28. The tumor suppressor decorin was increased from day 1 to 28. Oral BSE-SFN is well tolerated at daily doses up to 200 μmol and achieves dose-dependent levels in plasma and skin. A larger efficacy evaluation of 200 μmol daily for longer intervals is now reasonable to better characterize clinical and biological effects of BSE-SFN as chemoprevention for melanoma. Cancer Prev Res; 11(7); 429–38. ©2018 AACR.

https://ift.tt/2KzW9cm

Spatial Variation of the Native Colon Microbiota in Healthy Adults

The microbiome has been implicated in the development of colorectal cancer and inflammatory bowel diseases. The specific traits of these diseases vary along the axis of the digestive tract. Further, variation in the structure of the gut microbiota has been associated with both diseases. We profiled the microbiota of the healthy proximal and distal mucosa and lumen to better understand how bacterial populations vary along the colon. We used a two-colonoscope approach to sample proximal and distal mucosal and luminal contents from the colons of 20 healthy subjects that had not undergone any bowel preparation procedure. The biopsies and home-collected stool were subjected to 16S rRNA gene sequencing, and random forest classification models were built using taxa abundance and location to identify microbiota specific to each site. The right mucosa and lumen had the most similar community structures of the five sites we considered from each subject. The distal mucosa had higher relative abundance of Finegoldia, Murdochiella, Peptoniphilus, Porphyromonas, and Anaerococcus. The proximal mucosa had more of the genera Enterobacteriaceae, Bacteroides, and Pseudomonas. The classification model performed well when classifying mucosal samples into proximal or distal sides (AUC = 0.808). Separating proximal and distal luminal samples proved more challenging (AUC = 0.599), and specific microbiota that differentiated the two were hard to identify. By sampling the unprepped colon, we identified distinct bacterial populations native to the proximal and distal sides. Further investigation of these bacteria may elucidate if and how these groups contribute to different disease processes on their respective sides of the colon. Cancer Prev Res; 11(7); 393–402. ©2018 AACR.

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Calcium-Induced Differentiation of Human Colon Adenomas in Colonoid Culture: Calcium Alone versus Calcium with Additional Trace Elements

Previous murine studies have demonstrated that dietary Aquamin, a calcium-rich, multi-mineral natural product, suppressed colon polyp formation and transition to invasive tumors more effectively than calcium alone when provided over the lifespan of the animals. In the current study, we compared calcium alone to Aquamin for modulation of growth and differentiation in human colon adenomas in colonoid culture. Colonoids established from normal colonic tissue were examined in parallel. Both calcium alone at 1.5 mmol/L and Aquamin (provided at 1.5 mmol/L calcium) fostered differentiation in the adenoma colonoid cultures as compared with control (calcium at 0.15 mmol/L). When Aquamin was provided at an amount delivering 0.15 mmol/L calcium, adenoma differentiation also occurred, but was not as complete. Characteristic of colonoids undergoing differentiation was a reduction in the number of small, highly proliferative buds and their replacement by fewer but larger buds with smoother surface. Proliferation marker (Ki67) expression was reduced and markers of differentiation (CK20 and occludin) were increased along with E-cadherin translocalization to the cell surface. Additional proteins associated with differentiation/growth control [including histone-1 family members, certain keratins, NF2 (merlin), olfactomedin-4 and metallothioneins] were altered as assessed by proteomics. Immunohistologic expression of NF2 was higher with Aquamin as compared with calcium at either concentration. These findings support the conclusions that (i) calcium (1.5 mmol/L) has the capacity to modulate growth and differentiation in large human colon adenomas and (ii) Aquamin delivering 0.15 mmol/L calcium has effects on proliferation and differentiation not observed when calcium is used alone at this concentration. Cancer Prev Res; 11(7); 413–28. ©2018 AACR.

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Evaluation of Cancer-Associated DNA Copy Number Events in Colorectal (Advanced) Adenomas

About 5% of colorectal adenomas are estimated to progress to colorectal cancer. However, it is important to identify which adenomas actually carry a high risk of progression, because these serve as intermediate endpoints, for example, in screening programs. In clinical practice, adenomas with a size of ≥10 mm, villous component and/or high-grade dysplasia, called advanced adenomas, are considered high risk, although solid evidence for this classification is lacking. Specific DNA copy number changes are associated with adenoma-to-carcinoma progression. We set out to determine the prevalence of cancer-associated events (CAE) in advanced and nonadvanced adenomas. DNA copy number analysis was performed on archival tissues from three independent series of, in total, 297 adenomas (120 nonadvanced and 177 advanced) using multiplex ligation-dependent probe amplification or low-coverage whole-genome DNA sequencing. Alterations in two or more CAEs were considered to mark adenomas as high risk. Two or more CAEs were overall present in 25% (95% CI, 19.0–31.8) of advanced adenomas; 23% (11/48), 36% (12/33), and 23% (22/96) of the advanced adenomas in series 1, 2, and 3, respectively, and 1.7% (1/58) and 4.8% (3/62) of the nonadvanced adenomas, in series 1 and 2, respectively. The majority of advanced adenomas do not show CAEs, indicating that only a subset of these lesions is to be considered high risk. Nonadvanced adenomas have very low prevalence of CAEs, although those with CAEs should be considered high risk as well. Specific DNA copy number alterations may better reflect the true progression risk than the advanced adenoma phenotype. Cancer Prev Res; 11(7); 403–12. ©2018 AACR.

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Mutations of the PDE5A Gene Confer a Survival Advantage in Patients with Colon Cancer

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Newborn Screening Saves Lives but Cannot Replace the Need for Clinical Vigilance

Newborn screening for cystic fibrosis (CF) enables early diagnosis and treatment leading to improved health outcomes for patients with CF. Although the sensitivity of newborn screening is high, false-negative results can still occur which can be misleading if clinicians are not aware of the clinical presentation of CF. We present a case of a young male with negative newborn screen diagnosed for CF. He was diagnosed at 3 years of age despite having symptoms indicative of CF since infancy. The delayed diagnosis resulted in diffuse lung damage and poor growth.

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Combination of cytokine-directed and anti-programmed cell death protein 1 therapy – a new attractive option in melanoma treatment?

The use of monoclonal antibodies against programmed cell death protein 1 (anti-PD-1) has markedly transformed the management of melanoma. However, only a minority of patients treated with anti-PD-1 therapy show a response to therapy and some of them develop immune-related adverse events that can be managed with steroids or anticytokine therapy. A recent study published in Nature Communications has reported that treatment with anti-PD-1 in a tumor necrosis factor-deficient environment may lead to higher response rates to immunotherapy by reducing tumor-infiltrating lymphocytes death, accumulating dendritic cells within cancer, and downregulating T-cell immunoglobulin and mucin-domain-containing-3 expression. This research provides the first proof-of-concept of combining immunotherapy and antitumour necrosis factor-α in the melanoma treatment. Correspondence to Vincas Urbonas, MD, PhD, National Cancer Institute, Santariskiu 1, LT 08660, Vilnius, Lithuania Tel: +370 6456 5101; fax: +370 5272 0164; e-mail: vincas.urbonas@nvi.lt Received February 28, 2018 Accepted May 10, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Nivolumab induced inflammation of seborrheic keratoses: a novel cutaneous manifestation in a metastatic melanoma patient

Immune checkpoint inhibitors targeting the programmed cell death (PD)-1 receptor have dramatically changed the landscape of metastatic melanoma treatment. Nevertheless, these immuno-modulatory agents have associated side effects, including dermatologic manifestations. To this end, we report a patient with metastatic melanoma that was treated with PD-1 inhibitor, and subsequently developed inflammation of existing seborrheic keratosis lesions and new verrucous keratoses, a cutaneous side effect that has not been previously reported to our knowledge. The etiology of seborrheic and verrucous keratoses is not well understood, although their physical and histopathologic similarities to chronic viral-derived lesions, such as human papilloma virus, suggest a potential viral association. Chronic viral infections are known to result in T-cell tolerance because of persistent antigen stimulation. PD-1 inhibition is able to reinvigorate exhausted T cells, which are accordingly able to decrease viral load. Thus, the inflammatory reaction, seen in our patient, may be the result of PD-1 inhibition reactivating virally driven T lymphocytes. Correspondence to Joshua Arbesman, MD, Department of Dermatology, Case Western Reserve University, 2109 Adelbert Road, Cleveland, OH 44106, USA Tel: +1 216 368 6085; fax: +1 216 844 8993; e-mail: jxa248@case.edu Received February 23, 2018 Accepted May 30, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Scalp Block for Management of Subarachnoid Hemorrhage (SAH)-induced Headache

No abstract available

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Bilateral Ultasound Guided Erector Spinae Plane Block for Postoperative Pain Management in Lumbar Spine Surgery: A Case Series

No abstract available

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Regional chemotherapy by isolated limb perfusion prior to surgery compared with surgery and post-operative radiotherapy for primary, locally advanced extremity sarcoma: a comparison of matched cohorts

Abstract

Background

Induction chemotherapy by isolated limb perfusion (ILP) with melphalan and tumour necrosis factor-α is an effective strategy to facilitate limb-conserving surgery in locally advanced extremity sarcoma. In a comparison of cohorts matched for grade, size and surgical resectability, we compared the outcome of patients undergoing induction ILP prior to limb-conserving surgery and selective post-operative radiotherapy with patients undergoing limb-conserving surgery and routine post-operative radiotherapy.

Methods

Patients with primary, grade 2/3 sarcomas of the lower limbs over 10 cm in size were identified from prospectively maintained databases at 3 centres. Patients treated at a UK centre underwent limb-conserving surgery and post-operative radiotherapy (Standard cohort). Patients at two German centres underwent induction ILP, limb-conserving surgery and selective post-operative radiotherapy (ILP cohort).

Results

The Standard cohort comprised 80 patients and the ILP cohort 44 patients. Both cohorts were closely matched in terms of tumour size, grade, histological subtype and surgical resectability. The median age was greater in the Standard vs the ILP cohort (60.5 years vs 56 years, p = 0.033). The median size was 13 cm in both cohorts. 5-year local-recurrence (ILP 12.2%, Standard 20.1%, p = 0.375) and distant metastases-free survival rates (ILP 49.6%, Standard 46.0% p = 0.821) did not differ significantly between cohorts. Fewer patients received post-operative radiotherapy in the ILP cohort compared with the Standard cohort (27% vs 82%, p < 0.001).

Conclusion

In comparative cohorts, the outcomes of patients undergoing induction ILP prior to surgery did not differ from those undergoing standard management, although induction ILP was associated with a reduced need for adjuvant radiation.

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Isolated limb perfusion for unresectable extremity cutaneous squamous cell carcinoma; an effective limb saving strategy

Isolated limb perfusion for unresectable extremity cutaneous squamous cell carcinoma; an effective limb saving strategy

Isolated limb perfusion for unresectable extremity cutaneous squamous cell carcinoma; an effective limb saving strategy, Published online: 02 July 2018; doi:10.1038/s41416-018-0149-z

Isolated limb perfusion for unresectable extremity cutaneous squamous cell carcinoma; an effective limb saving strategy

https://ift.tt/2tMuLy7

Early metabolic response in sequential FDG-PET/CT under cetuximab is a predictive marker for clinical response in first-line metastatic colorectal cancer patients: results of the phase II REMOTUX trial

Early metabolic response in sequential FDG-PET/CT under cetuximab is a predictive marker for clinical response in first-line metastatic colorectal cancer patients: results of the phase II REMOTUX trial

Early metabolic response in sequential FDG-PET/CT under cetuximab is a predictive marker for clinical response in first-line metastatic colorectal cancer patients: results of the phase II REMOTUX trial, Published online: 02 July 2018; doi:10.1038/s41416-018-0152-4

Early metabolic response in sequential FDG-PET/CT under cetuximab is a predictive marker for clinical response in first-line metastatic colorectal cancer patients: results of the phase II REMOTUX trial

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Reply to ‘Comment on ‘Dairy, calcium, vitamin D and ovarian cancer risk in African–American women’’

Reply to 'Comment on 'Dairy, calcium, vitamin D and ovarian cancer risk in African–American women''

Reply to 'Comment on 'Dairy, calcium, vitamin D and ovarian cancer risk in African–American women'', Published online: 02 July 2018; doi:10.1038/s41416-018-0163-1

Reply to 'Comment on 'Dairy, calcium, vitamin D and ovarian cancer risk in African–American women''

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Patients with early-stage oropharyngeal cancer can be identified with label-free serum proteomics

Patients with early-stage oropharyngeal cancer can be identified with label-free serum proteomics

Patients with early-stage oropharyngeal cancer can be identified with label-free serum proteomics, Published online: 02 July 2018; doi:10.1038/s41416-018-0162-2

Patients with early-stage oropharyngeal cancer can be identified with label-free serum proteomics

https://ift.tt/2IJ6Nsq

Comment on ‘Dairy, calcium, vitamin D, and ovarian cancer risk in African-American women’

Comment on 'Dairy, calcium, vitamin D, and ovarian cancer risk in African-American women'

Comment on 'Dairy, calcium, vitamin D, and ovarian cancer risk in African-American women', Published online: 02 July 2018; doi:10.1038/s41416-018-0166-y

Comment on 'Dairy, calcium, vitamin D, and ovarian cancer risk in African-American women'

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Slipping Rib Syndrome in a Female Adult with Longstanding Intractable Upper Abdominal Pain

Slipping rib syndrome is a rare cause of abdominal or lower chest pain that can remain undiagnosed for many years. Awareness among health care personnel of this rare but significant disorder is necessary for early recognition. Prompt treatment can avoid unnecessary testing, radiographic exposure, and years of debilitating pain. A 52-year-old female was evaluated for a 3-year history of recurrent abdominal and lower chest pain. Pain was sharp, primarily located in the lower chest and subcostal region left more than right, waxing and waning, nonradiating, and aggravates with specific movements. She underwent frequent physical therapies, treated with multiple muscle relaxants and analgesics with minimal improvement. Imaging modalities including CT scan, MRI, and X-rays performed on multiple occasions failed to signify any underlying abnormality. Complete physical examination was unremarkable except for positive hooking maneuver. Dynamic flow ultrasound of lower chest was performed which showed slipping of the lowest rib over the next lowest rib bilaterally left worse than right, findings consistent with slipping rib syndrome. Slipping rib syndrome is caused by hypermobility of the floating ribs (8 to 12) which are not connected to the sternum but attached to each other with ligaments. Diagnosis is mostly clinical, and radiographic tests are rarely necessary. Hooking maneuver is a simple clinical test to reproduce pain and can aid in the diagnosis. Reassurance and avoiding postures that worsen pain are usually helpful. In refractory cases, nerve block and surgical intervention may be required.

https://ift.tt/2KAIvm8

Cronkhite-Canada Syndrome: Sustained Clinical Response with Anti-TNF Therapy

Cronkhite-Canada syndrome (CCS) is a rare, nonfamilial syndrome that occurs in the sixth to seventh decades of life. It is characterized by acquired gastrointestinal polyposis with an associated ectodermal triad, including alopecia, onchodystrophy, and hyperpigmentation. CCS is characteristically a progressive disease, with a high mortality rate despite medical interventions. Disease complications are typically secondary to severe malnutrition, malignancy, GI bleeding, and infection. CCS is believed secondary to immune dysregulation; however, the underlying etiology remains to be determined. Treatment for CCS is largely anecdotal, and randomized controlled therapeutic trials are lacking due to the rarity of the disease. Aggressive nutritional support in conjunction with immunosuppression has been used previously with inconsistent results. In this report, we describe the presentation and diagnosis of a case of CCS and report encouraging treatment response with anti-TNF therapy.

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Comment on ‘Dairy, calcium, vitamin D, and ovarian cancer risk in African-American women’

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Reply to ‘Comment on ‘Dairy, calcium, vitamin D and ovarian cancer risk in African–American women’’

https://ift.tt/2z0Zvk7

Patients with early-stage oropharyngeal cancer can be identified with label-free serum proteomics

https://ift.tt/2lNJDaY

Isolated limb perfusion for unresectable extremity cutaneous squamous cell carcinoma; an effective limb saving strategy

https://ift.tt/2tUabLu

Early metabolic response in sequential FDG-PET/CT under cetuximab is a predictive marker for clinical response in first-line metastatic colorectal cancer patients: results of the phase II REMOTUX trial

https://ift.tt/2lNJnJ2

Asymptomatic progressive multifocal leukoencephalopathy: a case report and review of the literature

We report the development of asymptomatic progressive multifocal leukoencephalopathy in a patient with multiple sclerosis on natalizumab therapy. Progressive multifocal leukoencephalopathy often presents with ...

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LTBK-01. UPDATES ON THE PHASE II AND RE-TREATMENT STUDY OF AZD6244 (SELUMETINIB) FOR CHILDREN WITH RECURRENT OR REFRACTORY PEDIATRIC LOW GRADE GLIOMA: A PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) STUDY

Abstract

The PBTC is conducting a phase II study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/refractory LGG assigned to 6 strata. We present the updated data on Stratum 2 and 5. Also, data on subsequent progression after treatment completion in patients enrolled on Stratum 1 and 3 will be discussed. Finally, we present details on the re-treatment study (PBTC-029C). Both stratum 2 (pilocytic astrocytoma [PA] without common BRAF aberrations) and Stratum 5 (non-pilocytic LGG with BRAF aberrations) met response criteria for expansion (> 2 objective responses in 16 patients), and accrual to a total of 25 patients on each stratum is ongoing. Among 50 patients treated on Stratum 1 (PA with BRAF aberrations) or Stratum 3 (NF-associated LGG), 21 have progressed. Thirteen of 21 have progressed after stopping therapy. The median time to progression for these 13 patients is 119 days (10–928). The re-treatment study has enrolled 25 patients who received a median of 12 re-treatment courses (2–36). The most common attributable toxicities after re-treatment were grade 1 CPK elevation (44%), diarrhea (44%), hypoalbuminemia (40%), elevated AST (36%), rash (36%) and fatigue (32%). The most common grade 3/4 attributable toxicities were grade 3 paronychia (8%), CPK elevation (4%), AST elevation (4%), decreased ejection fraction (4%), neutropenia (4%), elevated triglycerides (4%), peripheral neuropathy (4%) and grade 4 CPK elevation (4%). There is not a significant difference between the toxicities observed during original therapy versus re-treatment. The most current response and patient demographic data will be presented.

https://ift.tt/2Ky3qtf

CRAN-34. TRANSCRIPTOMIC AND PROTEOMIC COMPARISON OF PEDIATRIC AND ADULT ADAMANTINOMATOUS CRANIOPHARYNGIOMA

Abstract

Adamantinomatous craniopharyngioma (ACP) is a biologically benign but clinically aggressive lesion that has a significant impact on quality of life. The incidence of the disease has a bimodal distribution with peaks occurring in children and adults. Our group previously published the results of a transcriptome analysis of pediatric ACPs that identified several genes that were consistently overexpressed relative to other brain tumors. We now present the results of a transcriptome analysis of both pediatric and adult ACP to identify biological differences between these groups that may provide novel therapeutic insights, or support the assertion that potential therapies identified through the study of pediatric ACP may also have a role in adult ACP. Following bulk RNA sequencing, we explored the differential expression of adult ACP versus pediatric ACPs via geneset enrichment analysis. Preliminary studies identified a decreased cytokine gene expression profile in adult ACP that may correspond to a reduced senescence-associated secretory phenotype (SASP), which has recently been described in pediatric ACP. Additionally, our results corroborate our previous work demonstrating an increase in IL-6 expression and overall inflammatory response in pediatric tumors. To further characterize age-associated transcriptomic differences, we performed immunohistochemistry, immunoblotting, and other proteomic studies. Our results demonstrate phenotypic similarities and differences between pediatric and adult ACP.

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IMMU-08. PHASE I TRIAL (NCT02457845) SAFETY, TOLERABILITY AND PRELIMINARY EFFICACY OF IMMUNOVIROTHERAPY WITH HSV G207 IN CHILDREN WITH PROGRESSIVE MALIGNANT SUPRATENTORIAL BRAIN TUMORS

Abstract

BACKGROUND

Outcomes for children with progressive malignant supratentorial brain tumors are dismal. Preclinical evidence indicates that pediatric brain tumors are highly sensitive to genetically engineered oncolytic HSV-1 G207, which lacks genes essential for replication in normal brain. We report on this first-in-children oncolytic virotherapy brain tumor trial of G207.

DESIGN/METHODS

A 3 + 3 design was used to evaluate the safety, tolerability and preliminary efficacy of G207 at two doses (10⁷ and 10⁸ plaque-forming units). After informed consent, patients underwent biopsy to confirm viable tumor followed by placement of up to four silastic intratumoral catheters. The following day, G207 was infused by convection enhanced delivery over 6 hours. Patients were assessed for viral shedding and viremia by PCR and response by serial MRIs.

RESULTS

Six subjects have been treated (5 glioblastoma; 1 anaplastic astrocytoma). No dose limiting toxicities, serious adverse events, or ≥ grade 2 toxicities related to G207 have occurred. No G207 shedding or viremia was detected in the saliva, conjunctiva or blood at any time. Evidence of radiographic responses to G207 were seen in 5 of 6 patients including a patient >12 months post-G207 with an ongoing response and improvement in performance score from 80 to 100.

CONCLUSION

G207 delivered intratumorally is safe and tolerable in children with progressive malignant supratentorial brain tumors. Preliminary evidence of efficacy is very promising to date. The next phase of the study (NCT02457845) will test the safety of G207 combined with a single 5 Gy dose of radiation within 24 hours of virus inoculation.

https://ift.tt/2KwMOSt

EMBR-14. RECLASSIFICATION OF CENTRAL NERVOUS SYSTEM PRIMITIVE NEUROECTODERMAL TUMOR (CNS-PNET) INTO ENTITIES REFLECTS OUTCOME: RESULTS FROM THE PROSPECTIVE SJYC07 AND SJMB03 TRIALS

Abstract

BACKGROUND

Central nervous system primitive neuroectodermal tumor (CNS-PNET) was removed from the WHO classification after DNA-methylation profiling unveiled its underlying heterogeneity. Here we describe the makeup and outcome of patients histopathologically diagnosed as CNS-PNET treated on 2 multi-center, prospective trials.

METHODS

Patients <3yr received chemotherapy with/without focal irradiation (SJYC07). Patients ≥3yr received risk-adapted craniospinal-irradiation (23.4Gy for localized disease, 36–39.6Gy for metastatic) and chemotherapy (SJMB03). DNA-methylation was performed using Infinium MethylationEPIC BeadChip and profiled on DKFZ molecularneuropathology2.0 classifier.

RESULTS

Fifty-six patients were enrolled (SJYC07=32; SJMB03=24) with median age 2.86yr (range: 0.64–19.47). Sixteen were stratified as high-risk including 10 with metastasis. Histopathological diagnosis upon central review was CNS-PNET (n=34), ETMR (n=17), CNS-neuroblastoma/ganglioneuroblastoma (n=3) and HGNET (n=2). 42/56 cases were methylation-profiled into ETMR (N=13), GBM (N=3), MB_group3 (N=2), CNS-NB-FOXR2 (N=3), CNS-EFT-CIC (N=1), EPN-RELA (N=1), choroid plexus tumor (pediatric B) (N=1), PB_groupB (N=1), normal tissue (N=3), and "no match" (calibrated scores <0.9) (N=14). Median duration of follow-up was 2.24yr (range: 0.06–12.7). 5yr-OS/PFS in SJMB03-AR and -HR patients were 46.7 ± 12.9%/46.7 ± 12.9% and 33.3 ± 15.7%/33.3 ± 15.7% (OS p=0.503; PFS p=0.494). 5yr-OS/PFS in SJYC07-IR and -HR patients were 46.8 ± 10.6%/44.7 ± 10.4% and 57.1 ± 18.7%/14.3 ± 13.2% respectively (OS p=0.973; PFS p=0.046). Patients methylation-profiled as ETMR/GBM/MB had 5yr-OS/PFS of 24.1 ± 10.4%/14.8 ± 8.9% compared to 90.0 ± 9.5%/80.0 ± 12.6% in the other entities (OS p=0.001; PFS p<0.001). Age, metastasis, extent of surgery and treatment protocol did not significantly impact outcome. Classification by DNA-methylation profiling (p=0.037), histopathological diagnosis (p=0.019) and radiation use (p<0.001) were predictive of PFS.

CONCLUSION

Outcome of pediatric CNS-PNET varied but better conformed to convention when assigned a new entity.

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ATRT-07. MURINE SOX2-POSITIVE EARLY PRECURSOR CELLS GIVE RISE TO RHABDOID TUMORS WITH FEATURES OF THE HUMAN ATRT-MYC GROUP

Abstract

PURPOSE

Atypical teratoid rhabdoid tumors (ATRT), characterized by SMARCB1 loss, have been classified by DNA methylation and gene expression profiling into three distinct molecular subgroups (ATRT-SHH, -MYC, -TYR). We hypothesize that ATRT from distinct subgroups have a different cell of origin.

METHODS

Multiple precursor cell specific, constitutive and inducible Smarcb1 knockout mouse strains were established by using a Cre-loxP system. Murine tumors were analyzed by histology and gene expression profiling. Unsupervised hierarchical clustering and differential expression analyses were performed.

RESULTS

Rhabdoid tumor (RT) development was detected only when Smarcb1 abrogation occurred in a very restricted time frame during embryonic development and only under the control of an ubiquitous (Rosa26) or Sox2 promoter. Unsupervised hierarchical clustering of Affymetrix gene expression profiles of these murine and of published human ATRT classified tumors of the Rosa26cre^ERT2::Smarcb1^Fl/Fl model either as ATRT-MYC or as ATRT-SHH. In contrast, ATRT of Sox2cre^ERT2::Smarcb1^Fl/Fl mice were assigned to the ATRT-MYC subgroup only. Mouse strains in which the Smarcb1 knockout was driven by Nestin-, hGFAP-, Math1-, Olig1- Cre recombinase presented other phenotypes but not RT.

CONCLUSION

Subgroup-specific RT genesis depends on the cell of origin. Here we identify early Sox2-positive progenitors as precursor cells of ATRT-MYC subgroup. We further demonstrate that Smarcb1 abrogation during a specific, short time period and in a specific targeted cell population is crucial for induction of ATRT-MYC.

https://ift.tt/2Kwhbsf

DIPG-41. IDENTIFICATION OF BIRC5 AS A NOVEL THERAPEUTIC TARGET FOR DIFFUSE INTRINSIC PONTINE GLIOMA

Abstract

Diffuse Intrinsic Pontine Glioma (DIPG) remains to be a lethal type of pediatric brain tumor to date, indicating an urgent need of finding novel therapeutic strategy. Through screening of a collection of anti-tumor agents against a patient-derived DIPG primary tumor cell line, we identified a few novel therapeutic candidates for treating DIPG, among which BIRC5 inhibitor YM155 was the top potent agent. Next, we confirmed that YM155 could selectively inhibit multiple DIPG primary cell lines with IC50 less than 10nM. Moreover, our gene expression analyses showed that BIRC5 was significantly upregulated in DIPG primary tumor tissues and paired normal cortex tissues from the same patient. Genetically targeting of BIRC5 with CRISPR-Cas9 or RNAi approach could also effectively disrupt the growth of multiple DIPG cell lines, confirming BIRC5 as a valid therapeutic target for treating DIPG. Mechanistically, BIRC5 inhibition could cause cell cycle arrest, shut off proliferation and induce massive apoptosis. Furthermore, we tested the combinatory inhibitory effects of YM155 plus chemotherapy or targeted therapy drugs with proven anti-DIPG activity, including THZ1, JQ1, Gemcitabine, Panobinostat, GSK-J4 and et al. The preliminary results demonstrated YM155 could work synergistically with a few of above-mentioned drugs in vitro. We are also testing the in vivo inhibitory effects of targeting BIRC5 against DIPG preclinical PDX models. Together, our study identified BIRC5 inhibition as a novel therapeutic strategy against DIPG.

https://ift.tt/2IHFjDb

GERM-15. A PHASE 2 TRIAL OF RESPONSE-BASED RADIATION THERAPY FOR PATIENTS WITH LOCALIZED CENTRAL NERVOUS SYSTEM GERM CELL TUMORS (CNS GCT): A CHILDREN’S ONCOLOGY GROUP (COG) STUDY

Abstract

Intracranial germ cell tumors represent 3-5% of pediatric CNS tumors. Non-germinomatous germ cell tumors (NGGCT) have worse outcomes compared to germinomas, however, improved survivals were achieved on COG ACNS0122 utilizing a combination of chemotherapy and craniospinal irradiation (CSI). Since CSI is associated with significant late effects, a Phase 2 study was undertaken to determine whether irradiation could be reduced without impacting survival in a subgroup of NGGCT patients. Patients with localized disease who achieved a complete (CR) or partial response (PR) to chemotherapy were eligible for reduced irradiation to 30.6Gy whole ventricular field (WVI) and 54Gy tumor-bed boost as compared to 36Gy CSI plus tumor-bed boost as used on ACNS0122. Between 5/2012 and 11/2016, 107 eligible patients were accrued. Median age was 11 years (range: 4-22) and 75% were male. Tumor location was pineal in 58, suprasellar in 37, ventricular in 6 and bifocal in 6 patients. Sixty-six patients achieved CR/PR post-induction and received reduced irradiation. The 2-year progression-free survival (PFS) was 89% (95% CI: 81%-97%) and overall survival was 92% (95% CI: 86%- 99%). Eight patients progressed; seven had a distant relapse (outside the irradiation field) and one patient had a local plus distant relapse. Alpha-fetoprotein and beta-human chorionic gonadotropin levels were not associated with PFS. There were no unexpected treatment-related adverse events or deaths. Although these survival data are encouraging, distant relapses noted in all of the patients who progressed are concerning. Longer follow-up of the ACNS1123 cohort may better inform our recommendations in the future.

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