Cancer by Sfakianakis Alexandros: 05/14/17

Κυριακή 14 Μαΐου 2017

T-cell Receptor Signaling Activates an ITK/NF-{kappa}B/GATA-3 axis in T-cell Lymphomas Facilitating Resistance to Chemotherapy

Purpose: T-cell lymphomas are a molecularly heterogeneous group of non-Hodgkin lymphomas (NHL) that account for a disproportionate number of NHL disease-related deaths due to their inherent and acquired resistance to standard multiagent chemotherapy regimens. Despite their molecular heterogeneity and frequent loss of various T cell–specific receptors, the T-cell antigen receptor is retained in the majority of these lymphomas. As T-cell receptor (TCR) engagement activates a number of signaling pathways and transcription factors that regulate T-cell growth and survival, we examined the TCR's role in mediating resistance to chemotherapy.

Experimental Design: Genetic and pharmacologic strategies were utilized to determine the contribution of tyrosine kinases and transcription factors activated in conventional T cells following TCR engagement in acquired chemotherapy resistance in primary T-cell lymphoma cells and patient-derived cell lines.

Results: Here, we report that TCR signaling activates a signaling axis that includes ITK, NF-B, and GATA-3 and promotes chemotherapy resistance.

Conclusions: These observations have significant therapeutic implications, as pharmacologic inhibition of ITK prevented the activation of this signaling axis and overcame chemotherapy resistance. Clin Cancer Res; 23(10); 2506–15. ©2016 AACR.

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FDA Approval Summary: Sonidegib for Locally Advanced Basal Cell Carcinoma

On July 24, 2015, the FDA approved sonidegib (ODOMZO; Novartis) for the treatment of patients with locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiotherapy. The approval was based on data from one randomized, double-blind, noncomparative trial of two doses of sonidegib administered to 230 hedgehog inhibitor–naïve patients with metastatic basal cell carcinoma (mBCC, n = 36) or laBCC (n = 194). Patients were randomized 2:1 to receive sonidegib 800 mg (n = 151) or 200 mg (n = 79) daily. The objective response rate (ORR) for patients with laBCC was 58% [95% confidence interval (CI), 45–70] in the 200 mg group and 44% (95% CI, 35–53) in the 800 mg group. The median duration of response for patients with laBCC was nonestimable (NE) in the 200 mg arm and 15.7 months (95% CI, NE) in the 800 mg arm. The ORR for patients with mBCC was 8% (95% CI, 0.2–36) and 17% (95% CI, 5–39) in patients treated with 200 and 800 mg, respectively. The most common adverse events occurring in ≥10% of patients were muscle spasms, alopecia, dysgeusia, nausea, fatigue, increased serum creatine kinase, decreased weight, and diarrhea. Clin Cancer Res; 23(10); 2377–81. ©2017 AACR.

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miRNA-487a Promotes Proliferation and Metastasis in Hepatocellular Carcinoma

Purpose: Hepatocellular carcinoma (HCC) harbors highly metastatic properties, accounting for postoperative recurrence and metastasis. However, the mechanisms for metastasis and recurrence remain incompletely clear. This study aimed to investigate the role of hsa-miR-487a (miR-487a) in promoting the proliferation and metastasis of HCC and to elucidate the underlying molecular mechanisms.

Experimental Design: 198 HCC samples were analyzed for association between miR-487a expression and patient clinicopathological features and prognosis. The roles of miR-487a in proliferation and metastasis were validated both in vivo and in vitro. The upstream regulator and downstream targets of miR-487a were determined using a dual luciferase reporter assay, chromatin immunoprecipitation and immunohistochemistry.

Results: Our results demonstrate that upregulated miR-487a correlates with a poor prognosis for HCC patients. miR-487a enhances proliferation and metastasis of HCC cells by directly binding to sprouty-related EVH1 domain containing 2 (SPRED2) or phosphoinositide-3-Kinase regulatory subunit 1 (PIK3R1). Interestingly, miR-487a mainly promotes metastasis via SPRED2 induced mitogen activated protein kinase signaling and promotes proliferation via PIK3R1 mediated AKT signaling. Transcription of miR-487a was found to be activated by up-regulated heat shock factor 1, which we previously demonstrated to be an important metastasis-associated transcription factor in a previous study. Phosphorodiamidate morpholino oligomers effectively silenced miR-487a and inhibited HCC tumor progression in mouse models.

Conclusions: Our findings show that miR-487a, mediated by heat shock factor 1, promotes proliferation and metastasis of HCC by PIK3R1 and SPRED2 binding, respectively. Our study provides a rationale for developing miR-487a as a potential prognostic marker or a potential therapeutic target against HCC. Clin Cancer Res; 23(10); 2593–604. ©2016 AACR.

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Molecular Pathways: Hypoxia-Activated Prodrugs in Cancer Therapy

Hypoxia is a known feature of aggressive solid tumors as well as a critical hallmark of the niche in aggressive hematologic malignances. Hypoxia is associated with insufficient response to standard therapy, resulting in disease progression and curtailed patients' survival through maintenance of noncycling cancer stem–like cells. A better understanding of the mechanisms and signaling pathways induced by hypoxia is essential to overcoming these effects. Recent findings demonstrate that bone marrow in the setting of hematologic malignancies is highly hypoxic, and that progression of the disease is associated with expansion of hypoxic niches and stabilization of the oncogenic hypoxia-inducible factor-1alpha (HIF1α). Solid tumors have also been shown to harbor hypoxic areas, maintaining survival of cancer cells via the HIF1α pathway. Developing new strategies for targeting hypoxia has become a crucial approach in modern cancer therapy. The number of preclinical and clinical trials targeting low-oxygen tumor compartments or the hypoxic bone marrow niche via hypoxia-activated prodrugs is increasing. This review discusses the development of the hypoxia-activated prodrugs and their applicability in treating both hematologic malignancies and solid tumors. Clin Cancer Res; 23(10); 2382–90. ©2017 AACR.

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Antibody Targeting GRP78 Enhances the Efficacy of Radiation Therapy in Human Glioblastoma and Non-Small Cell Lung Cancer Cell Lines and Tumor Models

Purpose: Non–small cell lung cancer (NSCLC) and glioblastoma multiforme (GBM) have poor median survival. NSCLC and GBM overexpress glucose regulated protein 78 (GRP78), which has a role in radioresistance and recurrence. In this study, we determined the effect of anti-GRP78 antibody and the combined effect of the anti-GRP78 antibody with ionizing radiation (XRT) on NSCLC and GBM cell lines both in vitro and in vivo.

Experimental Design: NSCLC and GBM cancer cell lines were treated with anti-GRP78 antibodies and evaluated for proliferation, colony formation, cell death, and PI3K/Akt/mTOR signaling. The efficacy of anti-GRP78 antibodies on tumor growth in combination with XRT was determined in vivo in mouse xenograft models.

Results: GBM and NSCLC cells treated with anti-GRP78 antibodies showed attenuated cell proliferation, colony formation, and enhanced apoptosis. GBM and NSCLC cells treated with anti-GRP78 antibodies also showed global suppression of PI3K/Akt/mTOR signaling. Combining antibody with XRT resulted in significant tumor growth delay in both NSCLC and GBM heterotopic tumor models.

Conclusions: Antibodies targeting GRP78 exhibited antitumor activity and enhanced the efficacy of radiation in NSCLC and GBM both in vitro and in vivo. GRP78 is a promising novel target, and anti-GRP78 antibodies could be used as an effective cancer therapy alone or in combination with XRT. Clin Cancer Res; 23(10); 2556–64. ©2016 AACR.

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Emerging Role of MicroRNAs as Liquid Biopsy Biomarkers in Gastrointestinal Cancers

Cancer has emerged as a leading cause of mortality worldwide, claiming more than 8 million lives annually. Gastrointestinal cancers account for about 35% of these mortalities. Recent advances in diagnostic and treatment strategies have reduced mortality among patients with gastrointestinal cancer, yet a significant number of patients still develop late-stage cancer, where treatment options are inadequate. Emerging interests in "liquid biopsies" have encouraged investigators to identify and develop clinically relevant noninvasive genomic and epigenomic signatures that can be exploited as biomarkers capable of detecting premalignant and early-stage cancers. In this context, microRNAs (miRNA), which are small, noncoding RNAs that are frequently dysregulated in cancers, have emerged as promising entities for such diagnostic purposes. Even though the future looks promising, current approaches for detecting miRNAs in blood and other biofluids remain inadequate. This review summarizes existing efforts to exploit circulating miRNAs as cancer biomarkers and evaluates their potential and challenges as liquid biopsy–based biomarkers for gastrointestinal cancers. Clin Cancer Res; 23(10); 2391–9. ©2017 AACR.

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Dual-specific Chimeric Antigen Receptor T Cells and an Indirect Vaccine Eradicate a Variety of Large Solid Tumors in an Immunocompetent, Self-antigen Setting

Purpose: While adoptive transfer of T cells bearing a chimeric antigen receptor (CAR) can eliminate substantial burdens of some leukemias, the ultimate challenge remains the eradication of large solid tumors for most cancers. We aimed to develop an immunotherapy approach effective against large tumors in an immunocompetent, self-antigen preclinical mouse model.

Experimental Design: In this study, we generated dual-specific T cells expressing both a CAR specific for Her2 and a TCR specific for the melanocyte protein (gp100). We used a regimen of adoptive cell transfer incorporating vaccination (ACTIV), with recombinant vaccinia virus expressing gp100, to treat a range of tumors including orthotopic breast tumors and large liver tumors.

Results: ACTIV therapy induced durable complete remission of a variety of Her2⁺ tumors, some in excess of 150 mm², in immunocompetent mice expressing Her2 in normal tissues, including the breast and brain. Vaccinia virus induced extensive proliferation of T cells, leading to massive infiltration of T cells into tumors. Durable tumor responses required the chemokine receptor CXCR3 and exogenous IL2, but were independent of IFN. Mice were resistant to tumor rechallenge, indicating immune memory involving epitope spreading. Evidence of limited neurologic toxicity was observed, associated with infiltration of cerebellum by T cells, but was only transient.

Conclusions: This study supports a view that it is possible to design a highly effective combination immunotherapy for solid cancers, with acceptable transient toxicity, even when the target antigen is also expressed in vital tissues. Clin Cancer Res; 23(10); 2478–90. ©2016 AACR.

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Prospective, Multicenter Clinical Trial of Everolimus as Primary Therapy in Waldenstrom Macroglobulinemia (WMCTG 09-214)

Purpose: Everolimus inhibits mTOR, a component of PI3K/AKT prosurvival signaling triggered by MYD88 and CXCR4-activating mutations in Waldenstrom macroglobulinemia.

Experimental design: We evaluated everolimus in a prospective, multicenter study of 33 symptomatic, previously untreated Waldenstrom macroglobulinemia patients. Intended therapy consisted of everolimus (10 mg/day) until progression or unacceptable toxicity. Dose deescalation was permitted. The study was registered at http://ift.tt/PmpYKN (NCT00976248).

Results: At best response, median serum IgM levels declined from 4,440 to 1,360 mg/dL (P < 0.0001), median hemoglobin rose from 10.8 to 12 g/dL (P = 0.001), and median bone marrow disease burden declined from 75% to 52.5% in serially biopsied patients. The ORR and major response rates were 72.7% and 60.6%, respectively. Among genotyped patients, nonresponders associated with wild-type MYD88 and mutated CXCR4 status. Median time to response was 4 weeks. Discordance between serum IgM levels and bone marrow disease burden was remarkable. With a median follow-up of 13.1 (range, 1.6–64.6 months), the median time to progression was 21 months for all patients and 33 months for major responders. Discontinuation of everolimus led to rapid serum IgM rebound in 7 patients and symptomatic hyperviscosity in 2 patients. Toxicity led to treatment discontinuation in 27% of patients, including 18% for pneumonitis.

Conclusions: Everolimus is active in previously untreated Waldenstrom macroglobulinemia. IgM discordance is common, and treatment cessation can often lead to rapid serum IgM rebound. Pneumonitis also appears more pronounced in untreated versus previously treated Waldenstrom macroglobulinemia patients. The risks and benefits of everolimus should be carefully weighed against other primary Waldenstrom macroglobulinemia therapy options. Clin Cancer Res; 23(10); 2400–4. ©2016 AACR.

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The Second-Generation Exportin-1 Inhibitor KPT-8602 Demonstrates Potent Activity against Acute Lymphoblastic Leukemia

Purpose: Human exportin-1 (XPO1) is the key nuclear-cytoplasmic transport protein that exports different cargo proteins out of the nucleus. Inducing nuclear accumulation of these proteins by inhibiting XPO1 causes cancer cell death. First clinical validation of pharmacological inhibition of XPO1 was obtained with the Selective Inhibitor of Nuclear Export (SINE) compound selinexor (KPT-330) demonstrating activity in phase-II/IIb clinical trials when dosed 1 to 3 times weekly. The second-generation SINE compound KPT-8602 shows improved tolerability and can be dosed daily. Here, we investigate and validate the drug–target interaction of KPT-8602 and explore its activity against acute lymphoblastic leukemia (ALL).

Experimental Design: We examined the effect of KPT-8602 on XPO1 function and XPO1-cargo as well as on a panel of leukemia cell lines. Mutant XPO1 leukemia cells were designed to validate KPT-8602's drug-target interaction. In vivo, anti-ALL activity was measured in a mouse ALL model and patient-derived ALL xenograft models.

Results: KPT-8602 induced caspase-dependent apoptosis in a panel of leukemic cell lines in vitro. Using CRISPR/Cas9 genome editing, we demonstrated the specificity of KPT-8602 for cysteine 528 in the cargo-binding groove of XPO1 and validated the drug target interaction. In vivo, KPT-8602 showed potent anti-leukemia activity in a mouse ALL model as well as in patient-derived T- and B-ALL xenograft models without affecting normal hematopoiesis.

Conclusions: KPT-8602 is highly specific for XPO1 inhibition and demonstrates potent anti-leukemic activity supporting clinical application of the second-generation SINE compound for the treatment of ALL. Clin Cancer Res; 23(10); 2528–41. ©2016 AACR.

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A Phase I/II Multicenter Study of Single-Agent Foretinib as First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma

Purpose: This phase I/II single-arm study evaluated the safety, pharmacokinetics, pharmacodynamics, and activity of foretinib, an oral multikinase inhibitor of MET, ROS, RON, AXL, TIE-2, and VEGFR2, in the first-line setting in advanced hepatocellular carcinoma patients.

Experimental Design: In the phase I part, advanced hepatocellular carcinoma patients were dose escalated on foretinib (30–60 mg) every day using the standard 3+3 design. Once the maximum tolerated dose (MTD) was determined, an additional 32 patients were dosed at the MTD in the phase II expansion cohort for assessment of efficacy and safety. Exploratory analyses were conducted to assess potential biomarkers that might correlate with clinical efficacy and survival.

Results: The MTD of foretinib was established as 30 mg every day. The most frequent adverse events were hypertension, decreased appetite, ascites, and pyrexia. When dosed at 30 mg every day in the first-line setting, foretinib demonstrated promising antitumor activity. According to the modified mRECIST, the objective response rate was 22.9%, the disease stabilization rate 82.9%, and the median duration of response 7.6 months. The median time to progression was 4.2 months and the median overall survival (OS) was 15.7 months. Fifteen candidate biomarkers whose levels in the circulation were significantly altered in response to foretinib treatment were elucidated. Multivariate analyses identified IL6 and IL8 as independent predictors of OS.

Conclusions: Foretinib demonstrated promising antitumor activity and good tolerability in the first-line setting in Asian advanced hepatocellular carcinoma patients. Baseline plasma levels of IL6 or IL8 might predict the response to foretinib. Clin Cancer Res; 23(10); 2405–13. ©2016 AACR.

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A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

Purpose: Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar.

Experimental Design: A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data in silico. Biomarkers were immunohistochemically assessed in 697 MBCs (n = 477, training; n = 220, validation set) and quantified in pre- and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor.

Results: Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank P = 0.013; HR = 1.77, 1.12–2.8 and P = 0.035; HR = 1.68, 1.03–2.74, respectively), or when coexpressed (P = 0.01; HR = 2.66, 1.26–5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4E P = 0.016; HR = 2.38 (1.18–4.8), eIF5 P = 0.022; HR = 2.55 (1.14–5.7); coexpression P = 0.001; HR = 7.04 (2.22–22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival.

Conclusions: Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required. Clin Cancer Res; 23(10); 2575–83. ©2016 AACR.

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Heterogeneity of Acquired Resistance to Anti-EGFR Monoclonal Antibodies in Patients with Metastatic Colorectal Cancer

Purpose: Even if RAS-BRAF wild-type and HER2/MET–negative metastatic colorectal cancer (mCRC) patients frequently respond to anti-EGFR mAbs, acquired resistance almost invariably occurs. Mechanisms of resistance to EGFR blockade include the emergence of KRAS, NRAS, and EGFR extracellular domain mutations as well as HER2/MET alterations. However, these findings derive from retrospective studies that analyzed one single resistance mechanism at a time; moreover, it is still unclear how molecular heterogeneity affects clonal evolution in patients. In this work, we aimed at extensively characterizing and correlating the molecular characteristics of tissue- and blood-based data in a prospective cohort of patients with mCRC who received anti-EGFR antibodies.

Experimental design: Twenty-two RAS-BRAF wild-type, HER2/MET–negative mCRC patients progressing on anti-EGFR therapy after initial response underwent rebiopsy. Next-generation sequencing and silver in situ hybridization (SISH)/IHC analyses were performed both on archival tumors and postprogression samples. Circulating tumor (ctDNA) molecular profiles were obtained in matched tissue–plasma samples.

Results: RAS mutations and HER2/MET amplification were the most frequently detected resistance mechanisms in both tissue and blood sample analysis. On the other hand, BRAF and EGFR ectodomain mutations were much rarer. Patients with acquired MET amplification showed worse PFS on anti-EGFRs. We detected both intralesion heterogeneity, as suggested by co-occurrence of different resistance mechanisms in the same sample, and interlesion heterogeneity. The combined analysis of tissue and blood (ctDNA) results highlights the complexity of clonal evolution triggered by EGFR blockade.

Conclusions: Our results indicate that it may be extremely challenging to target the complex landscape of molecular heterogeneity associated with emergence of resistance to targeted therapies in patients with mCRC. Clin Cancer Res; 23(10); 2414–22. ©2016 AACR.

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Highlights of This Issue

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Phase I Study of GDC-0425, a Checkpoint Kinase 1 Inhibitor, in Combination with Gemcitabine in Patients with Refractory Solid Tumors

Purpose: Chk1 inhibition potentiates DNA-damaging chemotherapy by overriding cell-cycle arrest and genome repair. This phase I study evaluated the Chk1 inhibitor GDC-0425 given in combination with gemcitabine to patients with advanced solid tumors.

Experimental Design: Patients received GDC-0425 alone for a 1-week lead-in followed by 21-day cycles of gemcitabine plus GDC-0425. Gemcitabine was initially administered at 750 mg/m² (Arm A), then increased to 1,000 mg/m² (Arm B), on days 1 and 8 in a 3 + 3 + 3 dose escalation to establish maximum tolerated dose (MTD). GDC-0425 was initially administered daily for three consecutive days; however, dosing was abbreviated to a single day on the basis of pharmacokinetics and tolerability. TP53 mutations were evaluated in archival tumor tissue. On-treatment tumor biopsies underwent pharmacodynamic biomarker analyses.

Results: Forty patients were treated with GDC-0425. The MTD of GDC-0425 was 60 mg when administered approximately 24 hours after gemcitabine 1,000 mg/m². Dose-limiting toxicities included thrombocytopenia (n = 5), neutropenia (n = 4), dyspnea, nausea, pyrexia, syncope, and increased alanine aminotransferase (n = 1 each). Common related adverse events were nausea (48%); anemia, neutropenia, vomiting (45% each); fatigue (43%); pyrexia (40%); and thrombocytopenia (35%). The GDC-0425 half-life was approximately 15 hours. There were two confirmed partial responses in patients with triple-negative breast cancer (TP53-mutated) and melanoma (n = 1 each) and one unconfirmed partial response in a patient with cancer of unknown primary origin.

Conclusions: Chk1 inhibition with GDC-0425 in combination with gemcitabine was tolerated with manageable bone marrow suppression. The observed preliminary clinical activity warrants further investigation of this chemopotentiation strategy. Clin Cancer Res; 23(10); 2423–32. ©2016 AACR.

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Isolation of T-Cell Receptors Specifically Reactive with Mutated Tumor-Associated Antigens from Tumor-Infiltrating Lymphocytes Based on CD137 Expression

Purpose: The adoptive transfer of lymphocytes genetically modified to express tumor reactive T-cell receptors (TCR) can mediate tumor regression. Some tumor-infiltrating lymphocytes (TIL) recognize somatic mutations expressed only in the patient's tumors, and evidence suggests that clinically effective TILs target tumor-specific neoantigens. Here we attempted to isolate neoantigen-reactive TCRs as a prelude to the treatment of patients with autologous T cells genetically modified to express such TCRs.

Experimental Design: Mutations expressed by tumors were identified using whole-exome and RNA sequencing. Tandem minigene (TMG) constructs encoding 12–24 mutated gene products were synthesized, each encoding the mutated amino acid flanked by 12 amino acids of the normal protein sequence. TILs were cultured with autologous dendritic cells (DC) transfected with in vitro transcribed (IVT) mRNAs encoding TMGs and were evaluated for IFN secretion and CD137 expression. Neoantigen-reactive T cells were enriched from TILs by sorting for CD137⁺ CD8⁺ T cells and expanded in vitro. Dominant TCR α and β chains were identified in the enriched populations using a combination of 5' rapid amplification of cDNA ends, deep sequencing of genomic DNA, PairSeq analysis, and single-cell RT-PCR analysis. Human PBL retrovirally transduced to express the TCRs were evaluated for recognition of relevant neoantigens.

Results: We identified 27 TCRs from 6 patients that recognized 14 neoantigens expressed by autologous tumor cells.

Conclusions: This strategy provides the means to generate T cells expressing neoantigen-reactive TCRs for use in future adoptive cell transfer immunotherapy trials for patients with cancer. Clin Cancer Res; 23(10); 2491–505. ©2016 AACR.

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A Phase I Study of the CDK4/6 Inhibitor Ribociclib (LEE011) in Pediatric Patients with Malignant Rhabdoid Tumors, Neuroblastoma, and Other Solid Tumors

Purpose: The cyclin-dependent kinase (CDK) 4/6 inhibitor, ribociclib (LEE011), displayed preclinical activity in neuroblastoma and malignant rhabdoid tumor (MRT) models. In this phase I study, the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of single-agent ribociclib were investigated in pediatric patients with neuroblastoma, MRT, or other cyclin D–CDK4/6–INK4–retinoblastoma pathway-altered tumors.

Experimental Design: Patients (aged 1–21 years) received escalating once-daily oral doses of ribociclib (3-weeks-on/1-week-off). Dose escalation was guided by a Bayesian logistic regression model with overdose control and real-time PK.

Results: Thirty-two patients (median age, 5.5 years) received ribociclib 280, 350, or 470 mg/m². Three patients had dose-limiting toxicities of grade 3 fatigue (280 mg/m²; n = 1) or grade 4 thrombocytopenia (470 mg/m²; n = 2). Most common treatment-related adverse events (AE) were hematologic: neutropenia (72% all-grade/63% grade 3/4), leukopenia (63%/38%), anemia (44%/3%), thrombocytopenia (44%/28%), and lymphopenia (38%/19%), followed by vomiting (38%/0%), fatigue (25%/3%), nausea (25%/0%), and QTc prolongation (22%/0%). Ribociclib exposure was dose-dependent at 350 and 470 mg/m² [equivalent to 600 (RP2D)–900 mg in adults], with high interpatient variability. Best overall response was stable disease (SD) in nine patients (seven with neuroblastoma, two with primary CNS MRT); five patients achieved SD for more than 6, 6, 8, 12, and 13 cycles, respectively.

Conclusions: Ribociclib demonstrated acceptable safety and PK in pediatric patients. MTD (470 mg/m²) and RP2D (350 mg/m²) were equivalent to those in adults. Observations of prolonged SD support further investigation of ribociclib combined with other agents in neuroblastoma and MRT. Clin Cancer Res; 23(10); 2433–41. ©2017 AACR.

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5T4-Targeted Therapy Ablates Cancer Stem Cells and Prevents Recurrence of Head and Neck Squamous Cell Carcinoma

Purpose: Locoregional recurrence is a frequent treatment outcome for patients with advanced head and neck squamous cell carcinoma (HNSCC). Emerging evidence suggests that tumor recurrence is mediated by a small subpopulation of uniquely tumorigenic cells, that is, cancer stem cells (CSC), that are resistant to conventional chemotherapy, endowed with self-renewal and multipotency.

Experimental Design: Here, we evaluated the efficacy of MEDI0641, a novel antibody–drug conjugate targeted to 5T4 and carrying a DNA-damaging "payload" (pyrrolobenzodiazepine) in preclinical models of HNSCC.

Results: Analysis of a tissue microarray containing 77 HNSCC with follow-up of up to 12 years revealed that patients with 5T4^high tumors displayed lower overall survival than those with 5T4^low tumors (P = 0.038). 5T4 is more highly expressed in head and neck CSC (ALDH^highCD44^high) than in control cells (non-CSC). Treatment with MEDI0641 caused a significant reduction in the CSC fraction in HNSCC cells (UM-SCC-11B, UM-SCC-22B) in vitro. Notably, a single intravenous dose of 1 mg/kg MEDI0641 caused long-lasting tumor regression in three patient-derived xenograft (PDX) models of HNSCC. MEDI0641 ablated CSC in the PDX-SCC-M0 model, reduced it by five-fold in the PDX-SCC-M1, and two-fold in the PDX-SCC-M11 model. Importantly, mice (n = 12) treated with neoadjuvant, single administration of MEDI0641 prior to surgical tumor removal showed no recurrence for more than 200 days, whereas the control group had 7 recurrences (in 12 mice; P = 0.0047).

Conclusions: Collectively, these findings demonstrate that an anti-5T4 antibody–drug conjugate reduces the fraction of CSCs and prevents local recurrence and suggest a novel therapeutic approach for patients with HNSCC. Clin Cancer Res; 23(10); 2516–27. ©2016 AACR.

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Phase Ib Trial of the Toll-like Receptor 8 Agonist, Motolimod (VTX-2337), Combined with Cetuximab in Patients with Recurrent or Metastatic SCCHN

Purpose: As Toll-like receptors (TLR) are key mediators of immune responses, TLR agonists may be important for augmenting the efficacy of therapies for squamous cell carcinoma of the head and neck (SCCHN). Motolimod (VTX-2337), a selective small-molecule agonist of TLR8, stimulates natural killer (NK) cells, dendritic cells, and monocytes. A phase Ib clinical trial assessed the safety and antitumor activity of motolimod in combination with cetuximab in patients with SCCHN. Correlative biomarkers of immune activity were explored.

Experimental Design: Thirteen patients with recurrent or metastatic SCCHN were enrolled in this open-label, dose–escalation study using a standard 3 + 3 design. Doses of motolimod (2.5, 3.0, or 3.5 mg/m²) were given on days 1, 8, and 15, in combination with fixed weekly doses of cetuximab in 28-day cycles.

Results: There were no protocol-defined dose-limiting toxicities, drug-related deaths, or evidence of synergistic toxicities between motolimod and cetuximab. Clinical tolerability at the 3.5 mg/m² dose level was not optimal for repeated dosing and 3.0 mg/m² was identified as the MTD. Two patients achieved partial responses for an overall response rate of 15%. Five patients had disease stabilization equating to a disease control rate of 54%. Statistically significant increases in plasma cytokines and in the frequency and activation of circulating NK cells were observed.

Conclusions: Motolimod can be safely administered in combination with cetuximab with an acceptable toxicity profile. Encouraging antitumor activity and robust pharmacodynamic responses were observed. Motolimod is being further investigated in a phase II trial in patients with SCCHN (ClinicalTrials.gov ID: NCT01836029). Clin Cancer Res; 23(10); 2442–50. ©2016 AACR.

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c-Myc Modulation and Acetylation Is a Key HDAC Inhibitor Target in Cancer

Purpose: Histone deacetylase inhibitors (HDACi) are promising anticancer drugs. Although some HDACi have entered the clinic, the mechanism(s) underlying their tumor selectivity are poorly understood.

Experimental Design and Results: Using gene expression analysis, we define a core set of six genes commonly regulated in acute myeloid leukemia (AML) blasts and cell lines. MYC, the most prominently modulated, is preferentially altered in leukemia. Upon HDACi treatment, c-Myc is acetylated at lysine 323 and its expression decreases, leading to TRAIL activation and apoptosis. c-Myc binds to the TRAIL promoter on the proximal GC box through SP1 or MIZ1, impairing TRAIL activation. HDACi exposure triggers TRAIL expression, altering c-Myc-TRAIL binding. These events do not occur in normal cells. Excitingly, this inverse correlation between TRAIL and c-Myc is supported by HDACi treatment ex vivo of AML blasts and primary human breast cancer cells. The predictive value of c-Myc to HDACi responsiveness is confirmed in vivo in AML patients undergoing HDACi-based clinical trials.

Conclusions: Collectively, our findings identify a key role for c-Myc in TRAIL deregulation and as a biomarker of the anticancer action of HDACi in AML. The potential improved patient stratification could pave the way toward personalized therapies. Clin Cancer Res; 23(10); 2542–55. ©2016 AACR.

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Sequencing of Sipuleucel-T and Androgen Deprivation Therapy in Men with Hormone-Sensitive Biochemically Recurrent Prostate Cancer: A Phase II Randomized Trial

Purpose: STAND, a randomized, phase II, open-label trial (NCT01431391), assessed sequencing of sipuleucel-T (an autologous cellular immunotherapy) with androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC) patients at high risk for metastasis.

Experimental Design: Men with BRPC following prostatectomy and/or radiotherapy, a PSA doubling time ≤12 months, and no metastasis were enrolled. Patients were randomized (34/arm) to sipuleucel-T followed by ADT (started 2 weeks after sipuleucel-T completion), or ADT followed by sipuleucel-T (started 12 weeks after ADT initiation); ADT continued for 12 months in both arms. The primary endpoint was PA2024-specific T-cell response [enzyme-linked immunospot (ELISPOT)] over time.

Results: PA2024-specific ELISPOT responses over time were similar between groups, except at week 6, where responses were higher with sipuleucel-T->ADT versus ADT->sipuleucel-T (P = 0.013). PA2024-specific T-cell proliferation responses, averaged across time points, were approximately 2-fold higher with sipuleucel-T->ADT versus ADT->sipuleucel-T (P = 0.001). PA2024-specific cellular and humoral responses and prostatic acid phosphatase–specific humoral responses increased significantly versus baseline (P < 0.001) and were maintained for 24 months (both arms). Median time-to-PSA recurrence was similar between arms (21.8 vs. 22.6 months, P = 0.357). Development of a PA2024-specific humoral response correlated with prolonged time-to-PSA progression (HR, 0.22; 95% CI, 0.08–0.67; P = 0.007). Sipuleucel-T with ADT was generally well tolerated.

Conclusions: Sipuleucel-T->ADT appears to induce greater antitumor immune responses than the reverse sequence. These results warrant further investigation to determine whether this sequence leads to improved clinical outcomes, as well as the independent contribution of ADT alone in terms of immune activation. Clin Cancer Res; 23(10); 2451–9. ©2016 AACR.

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FDA Approval Summary: Sonidegib for Locally Advanced Basal Cell Carcinoma

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T-cell Receptor Signaling Activates an ITK/NF-{kappa}B/GATA-3 axis in T-cell Lymphomas Facilitating Resistance to Chemotherapy

Results: Here, we report that TCR signaling activates a signaling axis that includes ITK, NF-B, and GATA-3 and promotes chemotherapy resistance.

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miRNA-487a Promotes Proliferation and Metastasis in Hepatocellular Carcinoma

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Molecular Pathways: Hypoxia-Activated Prodrugs in Cancer Therapy

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Antibody Targeting GRP78 Enhances the Efficacy of Radiation Therapy in Human Glioblastoma and Non-Small Cell Lung Cancer Cell Lines and Tumor Models

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Emerging Role of MicroRNAs as Liquid Biopsy Biomarkers in Gastrointestinal Cancers

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Dual-specific Chimeric Antigen Receptor T Cells and an Indirect Vaccine Eradicate a Variety of Large Solid Tumors in an Immunocompetent, Self-antigen Setting

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Prospective, Multicenter Clinical Trial of Everolimus as Primary Therapy in Waldenstrom Macroglobulinemia (WMCTG 09-214)

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A Phase I/II Multicenter Study of Single-Agent Foretinib as First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma

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Heterogeneity of Acquired Resistance to Anti-EGFR Monoclonal Antibodies in Patients with Metastatic Colorectal Cancer

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Highlights of This Issue

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Phase I Study of GDC-0425, a Checkpoint Kinase 1 Inhibitor, in Combination with Gemcitabine in Patients with Refractory Solid Tumors

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Isolation of T-Cell Receptors Specifically Reactive with Mutated Tumor-Associated Antigens from Tumor-Infiltrating Lymphocytes Based on CD137 Expression

Results: We identified 27 TCRs from 6 patients that recognized 14 neoantigens expressed by autologous tumor cells.

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Management of Massive Hemoptysis with Oren Friedman

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Alexandros Sfakianakis
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Mismatch repair cancer syndrome (MMRCS) : Multiple hyperpigmented and hypopigmented skin areas, brain malformations, pilomatricomas, a second childhood malignancy, a Lynch syndrome (LS)-associated tumour in a relative and parental consanguinity.

http://sfaki.blogspot.com/2017/05/mismatch-repair-cancer-syndrome-mmrcs.html

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Haematologica. 2010 May; 95(5): 699–701.

doi: 10.3324/haematol.2009.021626

PMCID: PMC2864372

Constitutional mismatch repair-deficiency syndrome

Katharina Wimmer1 and Christian P. Kratz2

1 Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

2 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20852, USA. E-mail: ta.ca.dem-i@remmiw.anirahtak

Katharina Wimmer, PhD, is Associate Professor at the Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University Innsbruck. She is supervising the onco-genetic laboratory for the diagnostics of cancer predisposition syndromes which are also her main research interest. Christian P. Kratz, M.D. is an investigator in the Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics at the National Cancer Institute, National Institutes of Health. His research focuses on individuals with inherited cancer predispositions.

Author information ▼ Copyright and License information ►

See "Constitutional mismatch repair deficiency and childhood leukemia/lymphoma – report on a novel biallelic MSH6 mutation" on page 841.

This article has been cited by other articles in PMC.

The mismatch repair (MMR) machinery contributes to genome integrity and the MLH1, MSH2, MSH6 and PMS2 genes play a crucial role in this process. MMR corrects single base-pair mismatches and small insertion-deletion loops that arise during replication. Moreover, the MMR system is involved in the cellular response to a variety of agents that damage DNA1 and in immunoglobulin class switch recombination.2 Heterozygous germline mutations in MLH1, MSH2, MSH6 and PMS2 cause Lynch syndrome (LS), an autosomal dominant cancer syndrome associated with hereditary non-polyposis colorectal cancer (HNPCC), endometrium carcinoma and other malignancies, occurring on average in the fourth and fifth decade of life. Notably, LS associated tumors display somatic loss of the remaining wild type MLH1, MSH2, MSH6 or PMS2 allele and evidence of microsatellite instability (for review see 3).

In contrast to individuals with LS who harbor a heterozygous mutant MMR gene allele, rare cases with biallelic deleterious germline mutations in MMR genes leading to constitutional mismatch repair-deficiency (CMMR-D) have been recognized since 1999.4,5 This cancer syndrome is characterized by a broad spectrum of early-onset malignancies and a phenotype that resembles neurofibromatosis type 1. In this issue of Haematologica, Ripperger and colleagues report on a patient with CMMR-D caused by a novel MSH6 mutation leading to a T-cell lymphoma and colonic adenocarcinoma at six and 13 years of age, respectively. In addition, they review 26 leukemia and/or lymphoma cases reported previously.6

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The clinical presentation and tumor spectrum of CMMR-D

Our knowledge of the CMMR-D syndrome originates primarily from the medical literature; consequently, potential publication bias must be kept in mind as we interpret these reports. Table 1 summarizes the malignancies observed in 89 reported6–11 and 3 unreported cases of CMMR-D. Neoplasms can be divided into four groups: (1) hematologic malignancies (reviewed in 6); (2) brain tumors; (3) LS-associated tumors; and (4) other malignancies. Notably, 31 out of the known 92 CMMR-D patients developed more than one malignancy, and in 19 cases the second or third neoplasm was an LS-associated tumor.

Table 1.

List of malignancies in 92 CMMR-D patients.

In some cases of CMMR-D, areas of skin hypo-pigmentation have been reported.12–15 However, signs reminiscent of neurofibromatosis type 1 (NF1), in particular café-aulait macules (CALMs), are much more common and were observed in the majority of the reported cases (63/92). There are only 2 patients explicitly reported to lack CALMs or other signs of NF1.9,13 Interestingly, several reports stress that CALMs in patients with CMMR-D differ from typical NF1-associated CALMs in that they vary in their degree of pigmentation, have irregular borders, and may display a segmental distribution. Other features of NF1 found in CMMR-D patients include skinfold freckling, Lisch nodules, neurofibromas and tibial pseudarthrosis. Hence, it is not surprising that a number of CMMR-D cases were initially diagnosed as having NF1. It has been speculated that the NF1-like clinical features in CMMR-D result from germline mosaicism arising early during embryonic development. The identification of a truncating NF1 mutation in the blood of one patient16 and data supporting the notion that the NF1 gene is a mutational target of MMR deficiency17 are in line with this assumption. However, extensive mutation analysis in other CMMR-D patients has not confirmed this theory (see 8,12,18 and papers cited therein).

Péron et al.2 have shown in 3 CMMR-D patients that constitutional PMS2 deficiency leads to impaired immunoglobulin class switch recombination characterized by increased serum IgM concomitant with decrease or absence of IgG2, IgG4, and IgA. Of note, one CMMR-D patient initially presented with a primary immunodeficiency,2 and patients with biallelic MSH2 and MSH6 mutations also show IgG2 and/or IgA deficiency 15,19,20. It remains to be seen whether defective IgA and IgG production is a common feature of CMMR-D. Fortunately, severe bacterial infections have not been reported to occur at high frequencies in persons with CMMR-D.

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Genotype-phenotype correlation of CMMR-D

A review of the literature suggests that the clinical features in patients with biallelic germline mutations of MLH1 or MSH2 differ from those with biallelic germline mutations of MSH6 or PMS2 (Table 2). Hematologic malignancies appear to occur more frequently in patients with MLH1 or MSH2 mutations than in patients with mutations of MSH6 or PMS2. In contrast, the latter group appears to have a higher prevalence of brain tumors. Furthermore, tumors tend to develop earlier in MLH1 or MSH2 mutation carriers than in patients with a mutation of MSH6 or PMS2. Patients with biallelic mutations in MSH6 or PMS2 are more likely to survive their first tumors and develop a second malignancy. Overall, the prevalence of LS-associated tumors is higher in patients with biallelic MSH6 or PMS2 mutations than in biallelic MLH1 or MSH2 mutation-positive individuals (Table 2). These factors facilitate the clinical diagnosis of CMMR-D in patients with mutations of MSH6 or PMS2 and may at least partly explain the preponderance of PMS2 mutations in published cases.

Table 2.

Differences in the overall tumor spectrum and age of malignancy onset between carriers of biallelic MLH1/MSH2 and MSH6/PMS2 mutations, respectively.

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Strategies for clinical and subsequent molecular diagnosis of CMMR-D

In view of the wide tumor spectrum that overlaps with Lynch and Turcot syndrome but also includes hematologic malignancies and embryonic tumors such as neuroblastoma, Wilms tumor and rhabdomyosarcoma (Table 1), CMMR-D should be considered in the differential diagnosis in all patients with malignancies (except clearly NF1-associated tumors) who show one or more of the following features: (1) CALMs and/or other signs of NF1 and/or hypo-pigmented skin lesions; (2) consanguineous parents; (3) family history of LS-associated tumors; (4) second malignancy; and (5) sibling with childhood cancer. It is important to note that especially in patients with PMS2 mutations, the family history will often not fulfill the Amsterdam or revised Bethesda criteria for LS.

Typically, confirmation of the diagnosis involves the analysis of microsatellite instability (MSI) and/or immunohistochemistry (IHC), followed by mutation analysis. MSI analysis follows current protocols used for LS-screening; however, this analysis may be unreliable in CMMR-D related brain tumors.7,11,21 IHC is a useful technique employed in patients with CMMR-D associated neoplasms including brain tumors and guides subsequent mutation analysis in the four MMR-genes. In general, a truncating mutation in PMS2 or MSH6 will result in isolated loss of these proteins, whereas a mutation in MLH1 or MSH2 will lead to concurrent loss of MLH1/PMS2 or MSH2/MSH6, respectively, since MLH1 and MSH2 are the obligatory partners in the formation of MLH1/PMS2 and MSH2/MSH6 heterodimers. Notably, in the case of an underlying missense mutation, IHC may show normal results. As CMMR-D patients constitutively lack the expression of one of the MMR genes, IHC detects loss in both neoplastic and non-neoplastic tissues. Conveniently, expression loss of one of the MMR genes can be demonstrated in blood lymphocytes (e.g. by Western blot 2). Similarly, it has been shown that MSI can be determined in normal non-neoplastic tissue of CMMR-D patients by analyzing DNA samples that are diluted to approximately 0–3 genome equivalents per PCR-reaction.22 Nonetheless, standardized procedures for the detection of MMR expression loss and MSI in non-neoplastic tissue from CMMR-D patients have not been developed to date. The diagnosis of CMMR-D should be confirmed by gene-specific mutation analysis. Reliable methods for all four MMR genes including PMS2 are now available.12 Mutation analysis will facilitate identification and surveillance of heterozygous and homozygous individuals in the wider family, and allow for informed decision-making about prenatal or pre-implantation genetic diagnosis.

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Treatment and surveillance of the patient and counseling of relatives

Genetic counseling should be offered to the parents prior to testing of the affected child, and should include information on the potential 25% recurrence risk and on the clinical consequences of a possible heterozygous mutation in both parents. Predictive testing following the established interdisciplinary counseling guidelines should be offered to all family members once a mutation has been identified. Heterozygous family members should be followed according to current LS-guidelines.23

Because of the wide spectrum of malignancies in CMMR-D patients, defining recommendations for surveillance of affected patients remains a challenge. Early diagnosis of CMMR-D and subsequent cancer screening at regular intervals may increase the likelihood of detecting associated cancers, such as colon cancer or brain tumors, at an operable stage. In theory, this screening could include regular exams such as: (1) clinical evaluation; (2) blood tests with full blood count and carcinoembryonic antigen (CEA); (3) magnetic resonance imaging of the brain; (4) endoscopic examination of the gastrointestinal tract; and (5) endometrial sampling and transvaginal ultrasound for endometrial and ovarian cancer. However, these recommendations rest only on clinical judgment and do not represent a standard of care. To date there is no available evidence to support any of these recommendations or to provide guidance on the optimal frequency of such tests. Likewise, there is currently no information available regarding the optimal treatment of CMMR-D patients. Several reports stress that careful attention should be given to the possibly increased cyto-toxicity and reduced efficacy of chemotherapeutic agents due to constitutionally impaired mutation repair, and the high risk of a second malignancy 6,8,14,15.

Reports such as the article by Ripperger and colleagues are valuable in increasing awareness and knowledge of the syndrome in the clinical community. Nevertheless, systematic studies are needed in order to better define the phenotype of MMR-D. Data related to cancer screening, treatment and outcome should be collected and evaluated systematically to provide a basis for recommendations on how to manage patients with CMMR-D.

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Footnotes

( Related Original Article on page 841)

We thank Drs. Anne Durandy and Johannes Zschocke for their helpful comments on the manuscript. Dr. Kratz's work was supported by the Intramural Research Program of the US National Cancer Institute.

No potential conflict of interest relevant to this article was reported.

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Articles from Haematologica are provided here courtesy of Ferrata Storti Foundation

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Locoregional Effects of Microbiota in a Preclinical Model of Colon Carcinogenesis

Inflammation and microbiota are critical components of intestinal tumorigenesis. To dissect how the microbiota contributes to tumor distribution, we generated germ-free (GF) ApcMin/+and ApcMin/+;Il10−/− mice and exposed them to specific-pathogen-free (SPF) or colorectal cancer-associated bacteria. We found that colon tumorigenesis significantly correlated with inflammation in SPF-housed ApcMin/+;Il10−/−, but not in ApcMin/+mice. In contrast, small intestinal neoplasia development significantly correlated with age in both ApcMin/+;Il10−/− and ApcMin/+ mice. GF ApcMin/+;Il10−/− mice conventionalized by an SPF microbiota had significantly more colon tumors compared with GF mice. Gnotobiotic studies revealed that while Fusobacterium nucleatum clinical isolates with FadA and Fap2 adhesins failed to induce inflammation and tumorigenesis, pks+Escherichia coli promoted tumorigenesis in the ApcMin/+;Il10−/− model in a colibactin-dependent manner, suggesting colibactin is a driver of carcinogenesis. Our results suggest a distinct etiology of cancers in different locations of the gut, where colon cancer is primarily driven by inflammation and the microbiome, while age is a driving force for small intestine cancer. Cancer Res; 77(10); 2620–32. ©2017 AACR.

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Models in Translational Oncology: A Public Resource Database for Preclinical Cancer Research

The devastating diseases of human cancer are mimicked in basic and translational cancer research by a steadily increasing number of tumor models, a situation requiring a platform with standardized reports to share model data. Models in Translational Oncology (MiTO) database was developed as a unique Web platform aiming for a comprehensive overview of preclinical models covering genetically engineered organisms, models of transplantation, chemical/physical induction, or spontaneous development, reviewed here. MiTO serves data entry for metastasis profiles and interventions. Moreover, cell lines and animal lines including tool strains can be recorded. Hyperlinks for connection with other databases and file uploads as supplementary information are supported. Several communication tools are offered to facilitate exchange of information. Notably, intellectual property can be protected prior to publication by inventor-defined accessibility of any given model. Data recall is via a highly configurable keyword search. Genome editing is expected to result in changes of the spectrum of model organisms, a reason to open MiTO for species-independent data. Registered users may deposit own model fact sheets (FS). MiTO experts check them for plausibility. Independently, manually curated FS are provided to principle investigators for revision and publication. Importantly, noneditable versions of reviewed FS can be cited in peer-reviewed journals. Cancer Res; 77(10); 2557–63. ©2017 AACR.

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Locoregional Effects of Microbiota in a Preclinical Model of Colon Carcinogenesis

HDAC Inhibitor Panobinostat Engages Host Innate Immune Defenses to Promote the Tumoricidal Effects of Trastuzumab in HER2+ Tumors

Histone deacetylase inhibitors (HDACi) may engage host immunity as one basis for their antitumor effects. Herein, we demonstrate an application of this concept using the HDACi panobinostat to augment the antitumor efficacy of trastuzumab (anti-HER2) therapy, through both tumor cell autonomous and nonautonomous mechanisms. In HER2+ tumors that are inherently sensitive to the cytostatic effects of trastuzumab, cotreatment with panobinostat abrogated AKT signaling and triggered tumor regression in mice that lacked innate and/or adaptive immune effector cells. However, the cooperative ability of panobinostat and trastuzumab to harness host anticancer immune defenses was essential for their curative activity in trastuzumab-refractory HER2+ tumors. In trastuzumab-resistant HER2+ AU565pv xenografts and BT474 tumors expressing constitutively active AKT, panobinostat enhanced the antibody-dependent cell-mediated cytotoxicity function of trastuzumab. IFNγ–mediated, CXCR3-dependent increases in tumor-associated NK cells underpinned the combined curative activity of panobinostat and trastuzumab in these tumors. These data highlight the immune-enhancing effects of panobinostat and provide compelling evidence that this HDACi can license trastuzumab to evoke NK-cell–mediated responses capable of eradicating trastuzumab-refractory HER2+ tumors. Cancer Res; 77(10); 2594–606. ©2017 AACR.

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Models in Translational Oncology: A Public Resource Database for Preclinical Cancer Research

Tumor Dormancy and Relapse: From a Natural Byproduct of Evolution to a Disease State

Species evolve by mutations and epigenetic changes acting on individuals in a population; tumors evolve by similar mechanisms at a cellular level in a tissue. This article reviews growing evidence about tumor dormancy and suggests that (i) cellular malignancy is a natural byproduct of evolutionary mechanisms, such as gene mutations and epigenetic modifications, which is manifested in the form of tumor dormancy in healthy individuals as well as in cancer survivors; (ii) cancer metastasis could be an early dissemination event that could occur during malignant dormancy even before primary cancer is clinically detectable; and (iii) chronic inflammation is a key factor in awakening dormant malignant cells at the primary site, leading to primary cancer development, and at distant sites, leading to advanced stage diseases. On the basis of this evidence, it is reasonable to propose that we are all cancer survivors rather than cancer-free individuals because of harboring dormant malignant cells in our organs. A better understanding of local and metastatic tumor dormancy could lead to novel cancer therapeutics for the prevention of cancer. Cancer Res; 77(10); 2564–9. ©2017 AACR.

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