Cancer by Sfakianakis Alexandros: 02/08/18

To investigate the association between pretreatment blood neutrophil-to-lymphocyte ratio (NLR) and clinical outcomes for advanced-stage cancer patients treated with immunotherapy.

Methods

We conducted a comprehensive literature search to assess the relationship between pretreatment blood NLR and overall survival (OS) or progression-free survival (PFS) in advanced-stage cancer patients treated with immunotherapy. Published data including hazard ratios (HRs) and related 95% confidence interval (CI) were extracted. Pooled estimates of treatment outcomes were calculated using RevMan 5.3.5.

Results

Twenty-seven studies with 4647 patients were included in the current study. The pooled results suggested that high pretreatment blood NLR was correlated with significant shorter OS (HR = 1.98, 95% CI 1.66–2.36, P < 0.001) and PFS (HR = 1.78, 95% CI 1.48–2.15, P < 0.001). Subgroup analysis stratified by study targets revealed that anti-VEGF/VEGFR therapy (HR = 2.04, 95% CI 1.61–2.60, P < 0.001) and immune checkpoints blockade (HR = 2.16, 95% CI 1.86–2.51, P < 0.001) were significantly associated with inferior OS while other targets (HR = 1.63, 95% CI 0.89–2.99, P = 0.120) were not associated with OS. There was no correlation between distinct NLR cutoff values and OS ( \({r^}}\) = 0.218, P = 0.329) or PFS benefit ( \({r^}}\) = − 0.386, P = 0.140). Of note, HRs of PFS showed significant correlation with HRs of OS ( \({r^}}\) = 0.656, P = 0.015).

Conclusion

Elevated pretreatment blood NLR was a promising prognostic and predictive biomarker for advanced-stage cancer patients treated with immunotherapy.

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The dynamics of medical care in skin cancers

No abstract available

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Development of encorafenib for BRAF-mutated advanced melanoma

Purpose of review To describe the pharmacological properties, preclinical and clinical data of the novel V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF)-inhibitor encorafenib (LGX818) and to compare these with established BRAF-inhibitors in the treatment of locally advanced or metastatic melanoma. Recent findings Encorafenib has shown improved efficacy in the treatment of metastatic melanoma in comparison with vemurafenib. Combination with the MEK inhibitor (MEKi) binimetinib allows for higher dose intensities of encorafenib further improving response rates (RRs). Summary Combination therapy with BRAF and MEKi has evolved as a standard of care in the treatment of locally advanced or metastatic BRAFV600-mutated melanoma. Despite compelling initial RRs, development of treatment resistance eventually leads to tumor progression in the majority of BRAF/MEK-inhibitor treated patients. Moreover, treatment-related adverse events are frequent, resulting in a substantial proportion of dose modifications and/or treatment discontinuations. The second-generation BRAF inhibitor encorafenib has been developed aiming at improved efficacy and tolerability through modifications in pharmacological properties. Clinical phase 3 data show improved progression-free survival both for encorafenib monotherapy and combination therapy with binimetinib compared with vemurafenib. Overall survival data and regulatory approval of this novel substance are eagerly awaited.

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Molecular pathology of lung cancer: current status and perspectives

Purpose of review In this article, we summarize the current knowledge on molecular alterations in lung cancer that are targets for therapy, and provide an outlook on the future development of molecular pathology in precision oncology. Recent findings Lung cancer has become a paradigm for the success of molecular targeted therapies in solid tumors. Tyrosine kinase inhibitors are effective treatment options in adenocarcinoma patients with an EGFR, ALK, ROS1 or B-Raf Proto-Oncogene, Serine/Threonine kinase mutation. Additional molecular targets that are addressed in clinical trials include ERBB2, MET, RET, NTRK1 and FGFR. Therapies with antibodies that block the interaction of PD-L1 with PD-1 and thereby liberate an antitumor immune response have introduced a new era in cancer therapy with impressive therapeutic benefits. The high financial burden, treatment failures and therapeutic side effects of immunotherapies have prompted a search for biomarkers beyond PD-L1 expression, for example, tumor mutation load or immune cell profiling, that might more reliably identify patients that are likely to respond. Summary The discoveries of cancer research have been translated into the clinical management of lung cancer patients. So far, the approach of targeted therapy that is directed towards certain molecular alterations in a given tumor has been successful for adenocarcinomas, but not yet for squamous or small cell carcinomas. Further clinical progress will require a better understanding of the molecular interactions within cancer cells that will subsequently enable innovative drug designs. Diagnostic molecular pathology will be a provider of information on a tumor's features and thus, navigate precision cancer therapy.

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Medical bioinformatics in melanoma

Purpose of review Bioinformatic insights from next-generation sequencing has been integral in understanding melanoma biology, resistance to treatment and provided new avenues for melanoma treatment. Whole-genome sequencing, whole-exome sequencing and RNA sequencing has redefined the molecular classification of melanoma, revealed distinct genetic aberrations that define clinical subtypes of melanoma and uncovered the diverse heterogeneity that resides in an individual tumor. Recent findings In this review, we will summarize the recent whole-genome study that catalogs the genomic landscape across many melanoma subtypes, the single-cell RNA sequencing studies that interrogates tumor heterogeneity and the personalized vaccine approaches to melanoma treatment. Summary Whole-genome sequencing of diverse subtypes of melanoma revealed acral and mucosal subtypes to have a different genomic landscape compared with cutaneous melanoma. Acral and mucosal melanomas are characterized by low mutation burden and high structural variants. Single-cell RNA sequencing revealed high intratumoral heterogeneity and the existence of rare intrinsic drug-resistant populations. Lastly, vaccination against tumor neoantigens could be a potential personalized medicine therapy for melanoma patients. In summary, bioinformatics research is deeply ingrained in all aspects of melanoma research and will continue to blossom together for many years to come.

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Advanced PET imaging in oncology: status and developments with current and future relevance to lung cancer care

Purpose of review This review highlights the status and developments of PET imaging in oncology, with particular emphasis on lung cancer. We discuss the significance of PET for diagnosis, staging, decision-making, monitoring of treatment response, and drug development. The PET key advantage, the noninvasive assessment of functional and molecular tumor characteristics including tumor heterogeneity, as well as PET trends relevant to cancer care are exemplified. Recent findings Advances of PET and radiotracer technology are encouraging for multiple fields of oncological research and clinical application, including in-depth assessment of PET images by texture analysis (radiomics). Whole body PET imaging and novel PET tracers allow assessing characteristics of most types of cancer. However, only few PET tracers in addition to 18F-fluorodeoxyglucose have sufficiently been validated, approved, and are reimbursed for a limited number of indications. Therefore, validation and standardization of PET parameters including tracer dosage, image acquisition, post processing, and reading are required to expand PET imaging as clinically applicable approach. Summary Considering the potential of PET imaging for precision medicine and drug development in lung and other types of cancer, increasing efforts are warranted to standardize PET technology and to provide evidence for PET imaging as a guiding biomarker in nearly all areas of cancer treatment.

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Editorial introductions

No abstract available

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Treatment of ALK-positive nonsmall cell lung cancer: recent advances

Purpose of review The review will highlight recent advances in development of ALK-TKIs and management of patients with ALK-positive nonsmall cell lung cancer. Recent findings There has been rapid progress in the use of targeted therapies for ALK-positive NSCLC. Since the discovery, development and approval of crizotinib in 2011, three second-generation ALK-TKIs, ceritinib, alectinib and brigatinib have been approved by the FDA. A range of newer generation ALK inhibitors with improved potency against ALK and against mutations that confer resistance to crizotinib are in clinical development. Summary Our review will discuss the recent phase III data with ceritinib and alectinib as well as clinical trials with other ALK inhibitors. We will also address two important issues in the management of ALK-positive NSCLC, prevention and treatment of brain metastases and management of emergent ALK-TKI resistance mechanisms.

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Cutaneous angiosarcoma: update on biology and latest treatment

Purpose of review The present review aims to provide readers with the latest updates on the biology and clinical management of cutaneous angiosarcoma (cAS). Recent findings The genomic alteration of cAS is heterogeneous. Mutations are enriched in the mitosis-activated kinase (MAPK) pathway. Functional analysis has identified molecules that may serve as potential markers and therapeutic targets of angiosarcoma. These molecules include survivin, HSP90, FOXM1, miR-497-5p, KCa3.1, and miR210. This body of knowledge has not yet transferred to clinical practice. The mainstay of treatment for cAS remains surgery followed by postoperative radiotherapy. The efficacy of paclitaxel as an adjuvant chemotherapy is suggested. For patients with advanced cAS, paclitaxel is the treatment of choice. There are also second-line treatment options that are supported by evidence of varying strength. A multikinase inhibitor, pazopanib, has been assessed in several studies, most of which support its efficacy for angiosarcoma. Bevacizumab monotherapy may be effective for angiosarcoma. The efficacy of eribulin mesylate and trabectedin for angiosarcoma is currently being assessed. Recent publications highlighted the role of the immune system in the biology of cAS. Summary Future research efforts should focus on the following aspects of cAS: drug development directed at recent molecular targets, clinical trials designed specifically for patients with cAS, and the role of immunotherapy for cAS.

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Master protocols in lung cancer: experience from Lung Master Protocol

Purpose of review Contemporary advances in the understanding of the molecular and immunologic basis of metastatic lung cancer have firmly changed its treatment paradigm to a personalized, biomarker-driven approach. However, the majority of lung-cancer patients [especially lung squamous cell carcinoma (LUSC)] still do not have effective targeted therapeutic options. Master protocols, such as Lung-MAP, represent an innovative clinical trial approach designed to accelerate evaluation of novel biomarker-driven therapies. Recent findings Lung-MAP is an umbrella trial for advanced LUSC and has been active since 2014. Cumulative experience from this overarching, multi-institution master protocol has demonstrated that centralized, real-time biomarker screening is feasible and substudy modularity is essential for protocol adaptability in a rapidly changing treatment landscape. In addition, screening and efficacy results from Lung-MAP affirm that LUSC has several putative drivers but remains difficult to effectively treat with targeted therapy. Summary Master protocols are a feasible and efficient approach for evaluating biomarker-driven therapies in lung cancer. As we begin to target less common genomic and immunotherapy subtypes, centrally coordinated clinical trial designs such as Lung-MAP are necessary to rapidly deliver effective therapies to patients, whereas also maximizing the quality of research data obtained.

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Update on adjuvant melanoma therapy

Purpose of review We review the results from relevant clinical trials and discuss current strategies in the melanoma adjuvant setting. Recent findings The favorable therapeutic efficacy and the significant less toxicity of nivolumab compared with ipilimumab, fully substitutes today's approval of ipilimumab, regardless mutation status, whereas in BRAF-mutated patients, dabrafenib and trametinib seem to confirm their high efficacy also in adjuvant setting. The use of interferon is restricted to patients with ulcerated melanoma and countries with no access to the new drugs. Summary Systemic adjuvant treatment after complete disease resection in high-risk melanoma patients aims to increase relapse-free survival (RFS) and overall survival (OS). According to the eighth edition of melanoma classification of American Joint Committee on Cancer (AJCC), the prognosis in stage III patients is heterogeneous and depends not only on N (nodal) but also on T (tumor thickness) category criteria. Recent data from randomized, phase-3 clinical trials analyzing the use of adjuvant anti-programmed death-1 and targeted therapies ultimately affect the standard of care and change the landscape of the adjuvant treatment.

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Supportive care in the era of immunotherapies for advanced non-small-cell lung cancer

Purpose of review The therapeutic armamentarium for advanced non-small-cell lung cancer has evolved considerably over the past years. Immune checkpoint inhibitors targeting programmed cell death-1 such as pembrolizumab and nivolumab or programmed cell death ligand 1 such as atezolizumab, durvalumab and avelumab have shown favorable efficacy results in this patient population in the first-line and second-line setting. These immunotherapies are associated with a distinct toxicity profile based on autoimmune organ toxicity which is a new challenge for supportive care during treatment with these drugs. Recent findings The differential diagnosis of events occurring during immune checkpoint inhibitor treatment is broad: they can be due to immune-related or nonimmune-related adverse events, atypical tumor responses (pseudoprogression or hyperprogression) or events related to comorbidities or other treatments. Summary The management of these patients includes a thorough baseline clinical, biological and radiologic evaluation, patient education, correct follow-up and management by a multidisciplinary team with a central role for the medical oncologist. Immune-related toxicities should be managed according to available guidelines.

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Novel therapeutic strategies and targets in advanced uveal melanoma

Purpose of review Currently, there are no U.S. Food and Drug Administration-approved or effective treatment options for advanced-stage uveal melanoma. In this article, we focus on therapeutic targets in pathways/mechanisms associated with common mutations in uveal melanoma. We review the challenges associated with targeting of these pathways and novel treatment strategies. Recent findings Common mutations that promote uveal melanoma initiation and progression include alterations in G protein subunit alpha q/11 (GNAQ/GNA11) and breast cancer gene 1-associated protein 1 (BAP1). Mutant GNAQ/GNA11 induces constitutive activation of tumorigenic pathways such as extracellular signal-regulated kinase (ERK)1/2 and yes-associated protein. Inhibition of mitogen-activated protein kinase kinase (MEK) downstream of ERK1/2, however, was shown in trials to have limited clinical benefit. Recent reports suggested that combination therapies of MEK inhibition and modulators of mechanisms of drug resistance may improve tumor responses to MEK inhibitors. BAP1 has been shown to be involved in modulating chromatin dynamics and deubiquitination of proteins. Hence, epigenetic inhibitors are being investigated in BAP1 mutant uveal melanoma. However, other functions of BAP1, such as in DNA damage repair and cell cycle regulation, indicate additional targets for treatment of BAP1 mutant uveal melanoma. In addition, the frequent delayed development of uveal melanoma macrometastases is likely due to cellular dormancy mechanisms. Nuclear receptor subfamily 2, group F, member 1 and transforming growth factor beta 2 were among factors that have been shown in other cancers to induce dormant phenotypes. Summary Findings from studies in uveal melanoma and in other cancers provide evidence for potential strategies that may be tested preclinically and clinically in advanced-stage uveal melanoma to improve treatment outcome and overall survival of patients.

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FDA Approves New Treatment for Certain Neuroendocrine Tumors

People with cancerous neuroendocrine tumors (NETs) that affect the digestive tract now have a new treatment option. On January 29, FDA approved the targeted treatment lutetium Lu 177 dotatate (Lutathera®) for adult patients with advanced NETs that affect the pancreas or gastrointestinal tract.

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FDA Approves New Treatment for Certain Neuroendocrine Tumors

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Early evaluation of radiation-induced parotid damage in patients with nasopharyngeal carcinoma by T2 mapping and mDIXON Quant imaging: initial findings

Radiation-induced parotid damage is a common complication in patients with nasopharyngeal carcinoma (NPC) treated with radiotherapy to head and neck region, which severely reduce the life quality of those pati...

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1x8 Gy versus 5x4 Gy for metastatic epidural spinal cord compression: a matched-pair study of three prognostic patient subgroups

This study provides separate comparisons of 1 × 8 Gy to 5 × 4 Gy for metastatic epidural spinal cord compression (MESCC) in patients with poor, intermediate and favorable survival prognoses.

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Early evaluation of radiation-induced parotid damage in patients with nasopharyngeal carcinoma by T2 mapping and mDIXON Quant imaging: initial findings

1x8 Gy versus 5x4 Gy for metastatic epidural spinal cord compression: a matched-pair study of three prognostic patient subgroups

New therapeutic approaches for brainstem tumors: a comparison of delivery routes using nanoliposomal irinotecan in an animal model

Abstract

Despite the advances in imaging, surgery and radiotherapy, the majority of patients with brainstem gliomas die within 2 years after initial diagnosis. Factors that contribute to the dismal prognosis of these patients include the infiltrative nature and anatomic location in an eloquent area of the brain, which prevents total surgical resection and the presence of the blood–brain barrier (BBB), which reduces the distribution of systemically administered agents. The development of new therapeutic approaches which can circumvent the BBB is a potential path to improve outcomes for these children. Convection-enhanced delivery (CED) and intranasal delivery (IND) are strategies that permit direct drug delivery into the central nervous system and are an alternative to intravenous injection (IV). We treated rats bearing human brainstem tumor xenografts with nanoliposomal irinotecan (CPT-11) using CED, IND, and IV. A single treatment of CED irinotecan had a similar effect on overall survival as multiple treatments by IV route. IND CPT-11 showed significantly increased survival of animals with brainstem tumors, and demonstrated the promise of this non-invasive approach of drug delivery bypassing the BBB when combined with nanoliposomal chemotherapy. Our results indicated that using CED and IND of nanoliposomal therapy increase likelihood of practical therapeutic approach for the treatment of brainstem gliomas.

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Bioinformatic analysis of gene expression and methylation regulation in glioblastoma

Abstract

Different gene expression and methylation profiles are identified in glioblastoma (GBM). To screen the differentially expressed genes affected by DNA methylation modification and further investigate their prognostic values for GBMs. We included The Cancer Genome Atlas (TCGA) RNA sequencing (676) and DNA methylation (Illumina Human Methylation 450K; 657) databases to detect the gene expression and methylation profiles. Chinese Glioma Genome Atlas (CGGA) RNA sequencing database and TCGA DNA methylation (Illumina Human Methylation 27K; 283) was included for validation. Gene expression and DNA methylation statues were identified using principal components analysis (PCA). A total of 3365 differentially expressed genes were identified. Among them, 2940 genes showed low methylation and high expression, while 425 genes showed high methylation and low expression in GBMs. An eight-gene (C9orf64, OSMR, MDK, MARVELD1, PTRF, MYD88, BIRC3, RPP25) signature was established to divide GBM patients into two groups based on the cut-off point (27.24). The high risk group had shorter overall survival (OS) than low risk group (median OS 15.77 vs. 10.61 months; P = 0.0002). Moreover, the different clinical and molecular features were shown between two groups. These findings could be validated in additional datasets. The differentially expressed genes affected by DNA methylation modification were detected. Our results showed that the eight-gene signature has independently prognostic value for GBM patients.

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New therapeutic approaches for brainstem tumors: a comparison of delivery routes using nanoliposomal irinotecan in an animal model

Abstract

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Toxic effects of phytol and retinol on human glioblastoma cells are associated with modulation of cholesterol and fatty acid biosynthetic pathways

Abstract

Glioblastoma (GBM) is the most common primary brain tumor. Genetic mutations may reprogram the metabolism of neoplastic cells. Particularly, alterations in cholesterol and fatty acid biosynthetic pathways may favor biomass synthesis and resistance to therapy. Therefore, compounds that interfere with those pathways, such as phytol (PHY) and retinol (RET), may be appropriate for cytotoxic approaches. We tested the effect of PHY or RET on the viability of human GBM cell lines (U87MG, A172 and T98G). Since the compounds showed a dose-dependent cytotoxic effect, additional analyses were performed with IC₅₀ values. Transcriptome analyses of A172 cells treated with PHY IC₅₀ or RET IC₅₀ revealed down-regulated genes involved in cholesterol and/or fatty acid biosynthetic pathways. Thus, we investigated the expression of proteins required for cholesterol and/or fatty acid synthesis after treating all lineages with PHY IC₅₀ or RET IC₅₀ and comparing them with controls. Sterol regulatory element-binding protein 1 (SREBP-1) expression was reduced by PHY in U87 and T98G cells. However, fatty acid synthase (FAS) protein expression, which is regulated by SREBP-1, was down-regulated in all lineages after both treatments. Moreover, farnesyl-diphosphate farnesyltransferase (FDFT1) levels, a protein associated with cholesterol synthesis, were reduced in all lineages by PHY and in U87MG and A172 cells by RET. Our results suggest that SREBP-1, FAS and FDFT1 are potential target(s) for future in vivo approaches against GBM and support the use of inhibitors of their synthesis, including PHY and RET, for such approaches.

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Bioinformatic analysis of gene expression and methylation regulation in glioblastoma

Abstract

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Impact of physiological hormonal fluctuations on 18 F-fluorodeoxyglucose uptake in breast cancer

Abstract

Purpose

Premenopausal physiologic steroid levels change cyclically, in contrast to steady state low levels seen in postmenopausal patients. The purpose of this study was to evaluate whether ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) uptake in breast cancer is influenced by physiological hormonal fluctuations.

Methods

A total of 160 primary invasive breast cancers from 155 females (54 premenopausal, 101 postmenopausal) who underwent ¹⁸F-FDG positron emission tomography/computed tomography before therapy were retrospectively analyzed. The maximal standardized uptake values (SUVmax) of tumors were compared with menstrual phases and menopausal status according to the following subgroups: 'luminal A-like,' 'luminal B-like,' and 'non-luminal.' Additionally, the effect of estradiol (E2) on ¹⁸F-FDG uptake in breast cancer cells was evaluated in vitro.

Results

Among premenopausal patients, SUVmax during the periovulatory-luteal phase was significantly higher than that during the follicular phase in luminal A-like tumors (n = 25, p = 0.004), while it did not differ between the follicular phase and the periovulatory-luteal phase in luminal B-like (n = 24) and non-luminal tumors (n = 7). Multiple regression analysis showed menstrual phase, tumor size, and Ki-67 index are independent predictors for SUVmax in premenopausal luminal A-like tumors. There were no significant differences in SUVmax between pre- and postmenopausal patients in any of the subgroups. In in vitro studies, uptake in estrogen receptor-positive cells was significantly augmented when E2 concentration was increased from 0.01 to ≥ 1 nM.

Conclusions

Our data suggest that ¹⁸F-FDG uptake may be impacted by physiological hormonal fluctuations during menstrual cycle in luminal A-like cancers, and that E2 could be partly responsible for these events.

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Myeloproliferative Neoplasms May Be Sensitive to Dual BET/JAK Inhibition [Myeloproliferative Disease]

In myeloproliferative neoplasms (MPN) chromatin changes promote NF-B signaling to drive inflammation.

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mTORC2-Driven Lipid Synthesis Promotes Liver Tumorigenesis [Liver Cancer]

mTORC2-induced lipid metabolism promotes hepatosteatosis progression to hepatocellular carcinoma.

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Ribociclib Extends Survival in HR+ Breast Cancer [News in Brief]

Adding the CDK4/6 inhibitor ribociclib to standard first-line endocrine therapy significantly prolonged survival in premenopausal and perimenopausal women with advanced HR-positive, HER2-negative breast cancer enrolled in the MONALEESA-7 trial. This is the first definitive evidence that CDK4/6 inhibitor–based therapy is effective for first-line treatment of premenopausal and perimenopausal women.

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HIF2{alpha} Antagonism Has Antitumor Activity in Advanced ccRCC [Clinical Trials]

The HIF2α antagonist PT2385 achieved responses in 14% of patients with heavily pretreated ccRCC.

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KAT2A Is a {alpha}-KGDH-Dependent Histone Succinyltransferase [Epigenetics]

Succinylation of histone H3K79 induces changes in gene expression that promote glioblastoma growth.

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Senescence-Associated Chromatin Remodeling Promotes Cancer Stemness [Senescence]

Treatment-induced senescence is associated with stem-cell reprogramming of non-stem cancer cells.

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Fusobacterium Travels with Colorectal Cancer Cells [News in Brief]

Fusobacterium is enriched in colorectal cancer, but until now it has been unclear whether these bacteria drive tumorigenesis. A recent study shows that colorectal cancer cells take their microbiomes with them as they metastasize—and that targeting Fusobacterium with antibiotics reduces tumor growth in mice xenografts.

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Talazoparib Bests Chemo for Breast Cancer [News in Brief]

Patients with advanced or metastatic HER2-negative breast cancer and germline BRCA1/2 mutations may benefit from talazoparib, according to data from a phase III trial. Compared with chemotherapy, the investigational PARP inhibitor induced some complete responses, prolonged progression-free survival, and improved patients' overall quality of life.

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Targeting JAG1 Sensitizes Bone Metastases to Chemotherapy [Metastasis]

Chemotherapy induces JAG1 expression in osteoblasts, promoting chemoresistance in bone metastases.

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CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation [Research Articles]

Immune checkpoint blockade, exemplified by antibodies targeting the PD-1 receptor, can induce durable tumor regressions in some patients. To enhance the efficacy of existing immunotherapies, we screened for small molecules capable of increasing the activity of T cells suppressed by PD-1. Here, we show that short-term exposure to small-molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) significantly enhances T-cell activation, contributing to antitumor effects in vivo, due in part to the derepression of NFAT family proteins and their target genes, critical regulators of T-cell function. Although CDK4/6 inhibitors decrease T-cell proliferation, they increase tumor infiltration and activation of effector T cells. Moreover, CDK4/6 inhibition augments the response to PD-1 blockade in a novel ex vivo organotypic tumor spheroid culture system and in multiple in vivo murine syngeneic models, thereby providing a rationale for combining CDK4/6 inhibitors and immunotherapies.

Significance: Our results define previously unrecognized immunomodulatory functions of CDK4/6 and suggest that combining CDK4/6 inhibitors with immune checkpoint blockade may increase treatment efficacy in patients. Furthermore, our study highlights the critical importance of identifying complementary strategies to improve the efficacy of immunotherapy for patients with cancer. Cancer Discov; 8(2); 216–33. ©2017 AACR.

See related commentary by Balko and Sosman, p. 143.

See related article by Jenkins et al., p. 196.

This article is highlighted in the In This Issue feature, p. 127

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CAR T-cell Therapy Impresses in Multiple Myeloma [News in Brief]

CAR T cells that target the B-cell maturation antigen produce remissions in patients with relapsed or refractory multiple myeloma. Updated results from a phase I study suggest that 94% of patients treated with the highest doses showed complete or partial remissions and high rates of progression-free survival.

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Glutaminolysis Drives Lung Cancer Metastasis via the PLAG1-GDH1 Axis [Metastasis]

PLAG1-mediated GDH1 upregulation promotes LKB1-deficient lung cancer anoikis resistance.

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T Cell Exhaustion Signatures Vary with Tumor Type and are Severe in Glioblastoma

Purpose: T cell dysfunction is a hallmark of GBM. While anergy and tolerance have been well characterized, T cell exhaustion remains relatively unexplored. Exhaustion, characterized in part by the upregulation of multiple immune checkpoints, is a known contributor to failures amidst immune checkpoint blockade, a strategy that has lacked success thus far in GBM. This study is among the first to examine, and credential as bona fide, exhaustion among T cells infiltrating human and murine GBM. Experimental Design: Tumor-infiltrating and peripheral blood lymphocytes (TIL, PBL) were isolated from patients with GBM. Levels of exhaustion-associated inhibitory receptors and post-stimulation levels of the cytokines IFN-g, TNF-a, and IL-2 were assessed by flow cytometry. T cell receptor (TCR) Vβ chain expansion was also assessed in TIL and PBL. Similar analysis was extended to TIL isolated from intracranial and subcutaneous immunocompetent murine models of glioma, breast, lung, and melanoma cancers. Results: Our data reveal that GBM elicits a particularly severe T cell exhaustion signature among infiltrating T cells characterized by: 1) prominent upregulation of multiple immune checkpoints; 2) stereotyped T cell transcriptional programs matching classical virus-induced exhaustion; and 3) notable T cell hypo-responsiveness in tumor-specific T cells. Exhaustion signatures differ predictably with tumor identity, but remain stable across manipulated tumor locations. Discussion: Distinct cancers possess similarly distinct mechanisms for exhausting T cells. The poor TIL function and severe exhaustion observed in GBM highlights the need to better understand this tumor-imposed mode of T cell dysfunction in order to formulate effective immunotherapeutic strategies targeting GBM.

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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 U.S. Food and Drug Administration 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, human epidermal growth factor receptor 2 (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, 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.

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Identification of novel pathways of osimertinib disposition and potential implications for the outcome of lung cancer therapy

Purpose: Osimertinib is a third-generation inhibitor of the epidermal growth factor receptor used in treatment of non-small cell lung cancer. A full understanding of its disposition and capacity for interaction with other medications will facilitate its effective use as a single agent and in combination therapy. Experimental Design: Recombinant cytochrome P450s and liver microsomal preparations were used to identify novel pathways of osimertinib metabolism in vitro. A panel of knockout and mouse lines humanized for pathways of drug metabolism were used to establish the relevance of these pathways in vivo. Results: Although some osimertinib metabolites were similar in mouse and human liver samples there were several significant differences, in particular a marked species difference in the P450s involved. The murine Cyp2d gene cluster played a predominant role in mouse, whereas CYP3A4 was the major human enzyme responsible for osimertinib metabolism. Induction of this enzyme in CYP3A4 humanized mice substantially decreased circulating osimertinib exposure. Importantly, we discovered a further novel pathway of osimertinib disposition involving CPY1A1. Modulation of CYP1A1/CYP1A2 levels markedly reduced parent drug concentrations, significantly altering metabolite pharmacokinetics (PK) in humanized mice in vivo. Conclusions: We demonstrate that a P450 enzyme expressed in smokers' lungs and lung tumors has the capacity to metabolise osimertinib. This could be a significant factor in defining the outcome of osimertinib treatment. This work also illustrates how P450-humanized mice can be used to identify and mitigate species differences in drug metabolism and thereby model the in vivo effect of critical metabolic pathways on anti-tumor response.

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REG{gamma} controls Hippo signaling and reciprocal NF-{kappa}B-YAP regulation to promote colon cancer

Purpose: Colorectal cancer (CRC) is one of the most commonly diagnosed cancers closely associated with inflammation and hyperactive growth. We have previously demonstrated a regulatory circuit between the proteasome activator REG and NF-kappaB (NF-B) during colon inflammation, known to be important in the development of colitis-associated cancer as well as sporadic CRC. How the inflammatory microenvironment affects the Hippo pathway during CRC development is largely unknown. Experimental Design: Here, we used REG deficient colon cancer cell lines, REG knockout mice and human CRC samples to identify the novel molecular mechanism by which REG functions as an oncoprotein in the development of colorectal cancer. Results: REG can directly interact with Lats1 and promote its degradation, which facilitates Yes-associated protein (YAP) activation in colon cancer cells. REG deficiency significantly attenuated colon cancer growth, associated with decreased YAP activity. Suppression of tumor growth due to REG depletion was overcome by constitutively active YAP. Surprisingly, reciprocal activation of YAP and NF-B pathways was observed in human colon cancer cells. REG Overexpression was found in over 60% of 172 CRC specimens, highly correlating with the elevation of YAP and p65. Post-operative follow-up revealed a significantly lower survival rate in patients with concomitantly high expression of REG, YAP and p-p65. Conclusions: REG could be a master regulator during CRC development to promote YAP signaling and reinforce cross-talks between inflammation and growth pathways, and that REG could be a new marker for prognosis of CRC patients.

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Prediction of chemotherapeutic efficacy in non-small cell lung cancer by serum metabolomic profiling

Purpose: No validated biomarkers that could identify the subset of patients with lung adenocarcinoma who might benefit from chemotherapy have yet been well established. This study aimed to explore potential biomarker model predictive of efficacy and survival outcomes after first-line pemetrexed plus platinum doublet based on metabolomics profiling. Experimental Design: Totally, 354 consecutive eligible patients were assigned to receive first-line chemotherapy of pemetrexed in combination with either cisplatin or carboplatin. Prospectively collected serum samples before initial treatment were utilized to perform metabolomics profiling analyses under the application of liquid chromatography-tandem mass spectrometry (LC-MS/MS). Binary logistic regression analysis was carried out to establish discrimination models. Results: There were 251 cases randomized sorted into discovery set, the rest of 103 cases into validation set. Seven metabolites including Hypotaurine, Uridine, Dodecanoylcarnitine, Choline, Dimethylglycine, Niacinamide, L-palmitoylcarnitine were identified associated with chemo-response. Based on the seven-metabolite panel, a discriminant model according to logistic regression values g(z) was established with the receiver operating characteristic curve (AUC) of 0.912 (Discovery set) and 0.909 (Validation set) in differentiating progressive disease (PD) groups from disease control (DC) groups. The median progression-free survival (PFS) after chemotherapy in patients with g(z) ≤0.155 was significantly longer than that in those with g(z) > 0.155 (10.3 vs.4.5 months, P < 0.001). Conclusions: This study developed an effective and convenient discriminant model that can accurately predict the efficacy and survival outcomes of pemetrexed plus platinum doublet chemotherapy prior to treatment delivery.

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Targeted BiTE expression by an oncolytic vector augments therapeutic efficacy against solid tumors

PURPOSE: Immunotherapy with bispecific T cell engagers has achieved striking success against hematological malignancies, but efficacy against solid tumors has been limited. We hypothesized that oncolytic measles viruses encoding bispecific T cell engagers (MV-BiTEs) represent a safe and effective treatment against solid tumors through local BiTE expression, direct tumor cell lysis and in situ tumor vaccination. EXPERIMENTAL DESIGN: To test this hypothesis, we generated MV-BiTEs from the Edmonston B vaccine strain to target two model antigens. Replicative and oncolytic potential were assessed by infection and cell viability assays, respectively. Functionality of virus-derived BiTEs was tested in vitro by complementary binding and cytotoxicity assays. In vivo efficacy of MV-BiTE was investigated using both syngeneic and xenograft mouse models of solid cancers. RESULTS: We verified secretion of functional BiTE antibodies by MV-BiTE-infected cells. Further, we demonstrated therapeutic efficacy of MV-BiTE against established tumors in fully immunocompetent mice. MV-BiTE efficacy was associated with increased intratumoral T cell infiltration and induction of protective anti-tumor immunity. Additionally, we showed therapeutic efficacy of MV-BiTE in xenograft models of patient-derived primary colorectal carcinoma spheroids with transfer of PBMCs. CONCLUSION: MV-BiTE treatment was effective in two distinct models of solid tumors without signs of toxicity. This provides strong evidence for therapeutic benefits of tumor-targeted BiTE expression by oncolytic MV. Thus, this study represents proof of concept for an effective strategy to treat solid tumors with BiTEs.

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HER3-Mediated Resistance to Hsp90 Inhibition Detected in Breast Cancer Xenografts by Affibody-based PET Imaging

Purpose: Recent studies have highlighted a role of human epidermal growth factor receptor 3 (HER3) in HER2-driven cancers (e.g. breast cancer) implicating the up-regulation of the receptor in resistance to HER-targeted therapies and Hsp90 inhibitors (e.g. AUY922). Therefore, we have developed an affibody-based PET radioconjugate that quantitatively assesses HER3 changes induced by Hsp90 inhibition in vivo. Experimental Design: Z_HER3:8698 affibody molecules were conjugated via the C-terminus cysteine to DFO-maleimide for ⁸⁹Zr radiolabeling. The probe was characterized in vitro and in vivo in a panel of human breast cell lines and xenograft models with varying HER3 receptor levels. Additionally, the radioconjugate was investigated as a tool to monitor the outcome of AUY922, an Hsp90 inhibitor in MCF-7 xenograft model. Results: We demonstrated that ⁸⁹Zr-DFO-Z_HER3:8698 can track changes in receptor expression in HER3-positive xenograft models and monitor the outcome of AUY922 treatment. Our in vitro findings showed that MCF-7 cells, which are phenotypically different from BT474, develop resistance to AUY922 through HER3/IGF-1Rb-mediated signaling. Of note, the lack of response in vitro due to HER3 recovery was confirmed in vivo using ⁸⁹Zr-DFO-Z_HER3:8698-based imaging. Upon AUY922 treatment, higher radioconjugate uptake was detected in treated MCF-7 xenografts, correlating with an AUY922-induced HER3 up-regulation concomitant with an increase in IGF-1Rb expression. Conclusion: These data underline the potential of HER3-basedPET imaging to noninvasively provide information about HER3 expression and to identify patients not-responding to targeted therapies due to HER3 recovery.

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A phase I study of CPI-613 in combination with high dose cytarabine and mitoxantrone for relapsed or refractory acute myeloid leukemia

Purpose: CPI-613, a lipoate analog that inhibits pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase (KGDH) has activity in patients with myeloid malignancies. This study explored the role of mitochondrial metabolism in chemotherapy response, determined the maximally tolerated dose, efficacy and safety of CPI-613 combined with high dose cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia. Methods: The role of mitochondrial response to chemotherapy was assessed in cell lines and animal models. A phase I study of CPI-613 plus cytarabine and mitoxantrone was conducted in patients with relapsed or refractory AML. Results: Exposure to chemotherapy induced mitochondrial oxygen consumption that depended on PDH. CPI-613 sensitized AML cells to chemotherapy indicating that mitochondrial metabolism is a source of resistance. Loss of p53 did not alter response to CPI-613. The phase I study enrolled 67 patients and 62 were evaluable for response. The overall response rate was 50% (26CR+5CRi/62). Median survival was 6.7 months. In patients over 60 years old, the CR/CRi rate was 47% (15/32) with a median survival of 6.9 months. The response rate for patients with poor risk cytogenetics also was encouraging with 46% (11 of 24 patients) achieving a CR or CRi. RNA sequence analysis of a subset of baseline bone marrow samples revealed a gene expression signature consistent with the presence of B cells in the pretreatment marrow of responders. Conclusion: The addition of CPI-613 to chemotherapy is a promising approach in older patients and those with poor risk cytogenetics.

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Mechanistic exploration of cancer stem cell marker voltage-dependent calcium channel {alpha}2{delta}1 subunit-mediated chemotherapy resistance in small cell lung cancer

Purpose: Chemo-resistance in small cell lung cancer (SCLC) is reportedly attributed to the existence of resistant cancer stem cells (CSCs). Studies involving CSC-specific markers and related mechanisms in SCLC remain limited. The current study explored the role of the voltage-dependent calcium channel α21 subunit as a CSC marker in chemo-resistant SCLC, and explored the potential mechanisms of α21-mediated chemo-resistance and strategies of overcoming the resistance. Experimental design: α21 positive cells were identified and isolated from SCLC cell lines and patient derived xenografts (PDXs) models, and CSC-like properties were subsequently verified. Transcriptome sequencing and Western Blotting were carried out to identify pathways involved in α21-mediated chemo-resistance in SCLC. Additionally, possible interventions to overcome a21 mediated chemo-resistance were examined. Results: Different proportions of α21+ cells were identified in SCLC cell lines and PDX models. a21 positive cells exhibited CSC-like properties (self-renewal, tumorigenic, differentiation potential and high-expression of genes related to CSCs and drug-resistance). Chemotherapy induced the enrichment of α21+ cells instead of CD133+ cells in PDXs, and an increased proportion of α21+ cells corresponded to increased chemo-resistance. Activation and over-expression of Erk in the a21 positive H1048 cell line was identified at the protein level. 1B50-1 mAb was observed to improve the efficacy of chemotherapy and delay relapse as maintenance therapy in PDX models. Conclusions: SCLC cells expressing α21 demonstrated CSC-like properties, and may contribute to chemo-resistance. Erk may play a key role in α21 mediated chemo-resistance. 1B50-1 inhibitors may serve as potential anti-SCLC drugs.

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Induction chemotherapy plus concurrent chemoradiotherapy in endemic nasopharyngeal carcinoma: individual patient data pooled analysis of four randomized trials

Purpose: Due to uneven geographical distribution and small number of randomized trials available, the value of additional induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) remains controversial. This study performed an individual patient data (IPD) pooled analysis to better assess the precise role of IC+CCRT in locoregionally advanced NPC. Experimental Design: Four randomized trials in endemic areas were identified, representing 1,193 patients; updated IPD were obtained. Progression-free survival (PFS) and overall survival (OS) were the primary and secondary end-points, respectively. Results: Median follow-up was 5.0 years. The hazard ratio (HR) for PFS was 0.70 (95% CI, 0.56-0.86; P = 0.0009; 9.3% absolute benefit at 5 years) in favor of IC+CCRT versus CCRT alone. IC+CCRT also improved OS (HR 0.75, 95% CI 0.57-0.99, P = 0.04) and reduced distant failure (HR 0.68, 95% CI 0.51-0.90; P = 0.008). IC+CCRT had a tendency to improve locoregional control compared with CCRT alone (HR, 0.70; 95% CI, 0.48-1.01; P = 0.06). There was no heterogeneity between trials in any analysis. No interactions between patient characteristics and treatment effects on PFS or OS were found. After adding two supplementary trials to provide a more comprehensive overview, the conclusions remained valid and were strengthened. In a supplementary Bayesian network analysis, no statistically significant differences in survival between different IC regimens were detected. Conclusion: This IPD pooled analysis demonstrate the superiority of additional IC over CCRT alone in locoregionally advanced NPC, with the survival benefit mainly associated with improved distant control.

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Adjuvant transarterial chemoembolization for HBV-related hepatocellular carcinoma after resection: a randomized controlled study

Purpose: The survival of patients with hepatocellular carcinoma (HCC) recurrence after curative resection are usually poor. We sought to evaluate the safety and efficacy of adjuvant transarterial chemoembolization (TACE) in HBV-related HCC patients with an intermediate (a single tumor larger than 5 cm without microvascular invasion) or high risk (a single tumor with microvascular invasion, or two or three tumors) of recurrence. Experimental Design: In this randomized phase 3 trial, 280 eligible patients were assigned to adjuvant TACE (n=140) or no adjuvant treatment (control; n = 140) groups. The primary endpoint was recurrence-free survival (RFS); secondary endpoints included overall survival (OS) and safety. Multivariable Cox-proportional hazards model was used to determine the independent impact of TACE on patients' outcomes. Results: Patients who received adjuvant TACE had a significantly longer RFS than those in the control group (56.0% vs. 42.1%, P=0.01; Hazard ratio [HR] 0.68; 95% CI 0.49-0.93). Patients in the adjuvant TACE group had 7.8% higher 3-year OS rate than the control group (85.2% vs. 77.4%; P=0.04; HR 0.59; 95% CI 0.36-0.97). The impact of adjuvant TACE on RFS and OS remained significant after controlling for other known prognostic factors (HR 0.67, P=0.01 for RFS; and HR 0.59, P=0.04 for OS). There was no grade 3 or 4 toxicity after adjuvant TACE. Conclusion: For patients with HBV-related HCC who had an intermediate or high risk of recurrence after curative hepatectomy, our study showed adjuvant TACE significantly reduced tumor recurrence, improved RFS and OS, and the procedure was well tolerated.

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PRECISION ONCOLOGY DECISION SUPPORT: CURRENT APPROACHES AND STRATEGIES FOR THE FUTURE

With the increasing availability of genomics, routine analysis of advanced cancers is now feasible. Treatment selection is frequently guided by the molecular characteristics of a patient's tumor, and an increasing number of trials are genomically-selected. Furthermore, multiple studies have demonstrated the benefit of therapies that are chosen based upon the molecular profile of a tumor. However, the rapid evolution of genomic testing platforms and emergence of new technologies makes interpreting molecular testing reports more challenging. More sophisticated precision oncology decision support services are essential. This review outlines existing tools available for health care providers and precision oncology teams, and highlights strategies for optimizing decision support. Specific attention is given to the assays currently available for molecular testing, as well as considerations for interpreting alteration information. This article also discusses strategies for identifying and matching patients to clinical trials, current challenges, and proposals for future development of precision oncology decision support.

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BQ323636.1, a Novel Splice Variant to NCOR2, as a Predictor for Tamoxifen Resistant Breast Cancer

Purpose: Adjuvant tamoxifen treatment revolutionized the management of estrogen receptor (ER) positive breast cancers to prevent cancer recurrence; however drug resistance compromises its clinical efficacy. The mechanisms underlying tamoxifen resistance are not fully understood and no robust biomarker is available to reliably predict those who will be resistant. Here we study BQ323636.1, a novel splice variant of the NCOR2 gene and evaluate its efficacy in predicting tamoxifen resistance in breast cancer patients. Experimental Design: A monoclonal anti-BQ323636.1 antibody that specifically recognizes the unique epitope of this splice variant was generated for in vitro mechanistic studies and for in vivo analysis by immunohistochemistry on tissue microarrays of two independent cohorts of 358 patients with more than 10 years clinical follow-up data, who had ER-positive primary breast cancer and received adjuvant tamoxifen treatment. Orthotopic mouse model was also used. Results: Overexpression of BQ323636.1 conferred resistance to tamoxifen in both in vitro and in orthotopic mouse model. Mechanistically, co-immunoprecipitation showed BQ323636.1 could bind to NCOR2 and inhibit the formation of co-repressor complex for the suppression of ER signaling. Nuclear BQ3232636.1 overexpression in patients samples was significantly associated with tamoxifen resistance (p= 1.79 x 10-6, sensitivity 52.9%, specificity 72.0%). In tamoxifen-treated patients, nuclear BQ323636.1 overexpression was significantly correlated with cancer metastasis and disease relapse. Nuclear BQ323636.1 was also significantly associated with poorer overall survival (p=1.13 x 10-4) and disease-specific survival (p=4.02 x 10-5). Conclusions: These findings demonstrate that BQ323636.1 can be a reliable biomarker to predict tamoxifen resistance in ER-positive breast cancer patients.

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PBX3 is part of an EMT regulatory network and indicates poor outcome in colorectal cancer

Purpose: Colorectal cancers are composed of phenotypically different tumor cell subpopulations within the same core genetic background. Here, we identify high expression of the TALE transcription factor PBX3 in tumor cells undergoing epithelial-mesenchymal transition (EMT), analyze PBX3 regulation, and determine clinical associations in colorectal cancer. Experimental Design: We used transcriptomic and in situ analyses to identify PBX3 expression in colorectal cancer, and cell biology approaches to determine its regulation and function. Clinical associations were analyzed in independent tissue collections and gene expression data sets of colorectal cancers with recorded follow-up data. Results: PBX3 was expressed in tumor cells with high WNT activity undergoing EMT at the leading tumor edge of colorectal cancers, while stromal cells were PBX3 negative. PBX3 expression was induced by WNT activation and by the EMT transcription factors SNAIL and ZEB1, while these effects were mediated indirectly through microRNA miR-200. PBX3 was required for a full EMT phenotype in colon cancer cells. On the protein level, PBX3 expression indicated poor cancer specific and disease free survival in a cohort of 244 UICC stage II colorectal cancers, and was associated with metastasis in a case-control collection consisting of 90 cases with or without distant metastasis. On the mRNA level high PBX3 expression was strongly linked to poor disease free survival. Conclusions: PBX3 is a novel indicator of EMT in colorectal cancer, part of an EMT regulatory network, and a promising prognostic predictor that may aid in therapeutic decision making for patients with colorectal cancer.

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T Cell Exhaustion Signatures Vary with Tumor Type and are Severe in Glioblastoma

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Drug resistance in HER2-positive breast cancer brain metastases: blame the barrier or the brain?

The brain is the most common site of first metastasis for patients with HER2-positive breast cancer treated with HER2-targeting drugs. However, the development of effective therapies for breast cancer brain metastases (BCBMs) is limited by an incomplete understanding of the mechanisms governing drug sensitivity in the central nervous system. Pharmacodynamic data from patients and in vivo models suggest that inadequate drug penetration across the 'blood-tumor' barrier is not the whole story. Using HER2-positive breast cancer brain metastases as a case study, we highlight recent data from orthotopic brain metastasis models that implicates brain-specific drug resistance mechanisms in BCBMs and suggests a translational research paradigm to guide drug development for treatment of BCBMs.

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Identification of novel pathways of osimertinib disposition and potential implications for the outcome of lung cancer therapy

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Harnessing the power of patient-reported outcomes in oncology

Patient-reported outcomes (PROs) represent an increasingly important mechanism for incorporating patients' experiences and perspectives into their care to enhance cancer care delivery and outcomes. In this article, we discuss the importance of integrating PROs into both the clinical and research settings in oncology, and highlight potential challenges.

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REG{gamma} controls Hippo signaling and reciprocal NF-{kappa}B-YAP regulation to promote colon cancer

http://ift.tt/2BjKGsb

HER3-Mediated Resistance to Hsp90 Inhibition Detected in Breast Cancer Xenografts by Affibody-based PET Imaging

http://ift.tt/2EvwMFB

A phase I study of CPI-613 in combination with high dose cytarabine and mitoxantrone for relapsed or refractory acute myeloid leukemia

http://ift.tt/2BioAGw

Mechanistic exploration of cancer stem cell marker voltage-dependent calcium channel {alpha}2{delta}1 subunit-mediated chemotherapy resistance in small cell lung cancer

http://ift.tt/2EvL9tk

Statins Synergize with Hedgehog Pathway Inhibitors for Treatment of Medulloblastoma

Purpose: The role of cholesterol biosynthesis in hedgehog pathway activity and progression of hedgehog pathway medulloblastoma (Hh-MB) were examined in vivo. Statins, commonly used cholesterol-lowering agents, were utilized to validate cholesterol biosynthesis as a therapeutic target for Hh-MB.

Experimental Design: Bioinformatic analysis was performed to evaluate the association between cholesterol biosynthesis with hedgehog group medulloblastoma in human biospecimens. Alterations in hedgehog signaling were evaluated in medulloblastoma cells after inhibition of cholesterol biosynthesis. The progression of endogenous medulloblastoma in mice was examined after genetic blockage of cholesterol biosynthesis in tumor cells. Statins alone, or in combination with vismodegib (an FDA-approved Smoothened antagonist), were utilized to inhibit medulloblastoma growth in vivo.

Results: Cholesterol biosynthesis was markedly enhanced in Hh-MB from both humans and mice. Inhibition of cholesterol biosynthesis dramatically decreased Hh pathway activity and reduced proliferation of medulloblastoma cells. Statins effectively inhibited medulloblastoma growth in vivo and functioned synergistically in combination with vismodegib.

Conclusions: Cholesterol biosynthesis is required for Smoothened activity in the hedgehog pathway, and it is indispensable for the growth of Hh-MB. Targeting cholesterol biosynthesis represents a promising strategy for treatment of Hh-MB. Clin Cancer Res; 1–14. ©2018 AACR.

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Induction chemotherapy plus concurrent chemoradiotherapy in endemic nasopharyngeal carcinoma: individual patient data pooled analysis of four randomized trials

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Adjuvant transarterial chemoembolization for HBV-related hepatocellular carcinoma after resection: a randomized controlled study

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Oxidative phosphorylation as an emerging target in cancer therapy

Cancer cells have upregulated glycolysis compared to normal cells, which has led many to the assumption that oxidative phosphorylation (OXPHOS) is downregulated in all cancers. However, recent studies have shown that OXPHOS can be also upregulated in certain cancers, including leukemias, lymphomas, pancreatic ductal adenocarcinoma, high OXPHOS subtype melanoma and endometrial carcinoma, and that this can occur even in the face of active glycolysis. OXPHOS inhibitors could therefore be used to target cancer subtypes in which OXPHOS is upregulated, and to alleviate therapeutically adverse tumor hypoxia. Several drugs including metformin, atovaquone and arsenic trioxide are used clinically for non-oncological indications, but emerging data demonstrates their potential use as OXPHOS inhibitors. We highlight novel applications of OXPHOS inhibitors with a suitable therapeutic index to target cancer cell metabolism.

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BQ323636.1, a Novel Splice Variant to NCOR2, as a Predictor for Tamoxifen Resistant Breast Cancer

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PBX3 is part of an EMT regulatory network and indicates poor outcome in colorectal cancer

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mTORC2-Driven Lipid Synthesis Promotes Liver Tumorigenesis [Liver Cancer]

mTORC2-induced lipid metabolism promotes hepatosteatosis progression to hepatocellular carcinoma.

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Ribociclib Extends Survival in HR+ Breast Cancer [News in Brief]

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HIF2{alpha} Antagonism Has Antitumor Activity in Advanced ccRCC [Clinical Trials]

The HIF2α antagonist PT2385 achieved responses in 14% of patients with heavily pretreated ccRCC.

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Fusobacterium Travels with Colorectal Cancer Cells [News in Brief]

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Talazoparib Bests Chemo for Breast Cancer [News in Brief]

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Targeting JAG1 Sensitizes Bone Metastases to Chemotherapy [Metastasis]

Chemotherapy induces JAG1 expression in osteoblasts, promoting chemoresistance in bone metastases.

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ERK Inhibition: A New Front in the War against MAPK Pathway-Driven Cancers? [In the Spotlight]

Summary: ERK inhibitors have enormous therapeutic potential against tumors that are BRAF mutant, BRAF–MEK inhibitor resistant, or RAS mutant. In this issue of Cancer Discovery, Sullivan and colleagues report on the first-in-human dose-escalation study of the ERK inhibitor ulixertinib, which they show to be well tolerated with clinical activity against a wide range of tumor types. Cancer Discov; 8(2); 140–2. ©2018 AACR.

See related article by Sullivan et al., p. 184.

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FGFR3-TACC3 Activates Mitochondrial Respiration via PIN4 Phosphorylation [Metabolism]

PIN4 is a FGFR3-TACC3 substrate required for ROS-mediated induction of PGCIα and tumor growth.

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CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation [Research Articles]

See related commentary by Balko and Sosman, p. 143.

See related article by Jenkins et al., p. 196.

This article is highlighted in the In This Issue feature, p. 127

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CAR T-cell Therapy Impresses in Multiple Myeloma [News in Brief]

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First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study [Research Articles]

Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. Dose escalation included 27 patients, dosed from 10 to 900 mg twice daily and established the recommended phase II dose (RP2D) of 600 mg twice daily. Ulixertinib exposure was dose proportional to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108-patient expansion cohort, 32% of patients required dose reduction. The most common treatment-related adverse events were diarrhea (48%), fatigue (42%), nausea (41%), and dermatitis acneiform (31%). Partial responses were seen in 3 of 18 (17%) patients dosed at or above maximum tolerated dose and in 11 of 81 (14%) evaluable patients in dose expansion. Responses occurred in patients with NRAS-, BRAF V600–, and non–V600 BRAF-mutant solid tumors.

Significance: Here, we describe the first-in-human dose-escalation study of an ERK1/2 inhibitor for the treatment of patients with advanced solid tumors. Ulixertinib has an acceptable safety profile with favorable pharmacokinetics and has shown early evidence of clinical activity in NRAS- and BRAF V600- and non-V600–mutant solid-tumor malignancies. Cancer Discov; 8(2); 184–95. ©2017 AACR.

See related commentary by Smalley and Smalley, p. 140.

This article is highlighted in the In This Issue feature, p. 127

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Glutaminolysis Drives Lung Cancer Metastasis via the PLAG1-GDH1 Axis [Metastasis]

PLAG1-mediated GDH1 upregulation promotes LKB1-deficient lung cancer anoikis resistance.

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Hepatotoxicity Associated With Vismodegib

An 82-year-old Caucasian woman with a history of basal cell carcinoma on vismodegib presented with nausea, vomiting and intermittent abdominal pain. Laboratory results were remarkable for the elevation of liver enzymes. Endoscopic retrograde cholangiopancreatography and percutaneous transhepatic cholangiogram (PTC) did not show evidence of intrahepatic or extrahepatic obstruction of the biliary tract. During PTC external biliary catheter was placed; however, bilirubin continued to rise. Further, laboratory work-up and imaging studies ruled out other possible aetiologies for hepatotoxicity such as infections, autoimmune hepatitis and other drugs known to be hepatotoxic thus leaving vismodegib the most likely cause of hepatotoxicity.

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Double invasive fungal infection due to dematiaceous moulds in a renal transplant patient

Alternaria and Verruconis are two dematiaceous moulds that occasionally cause disease in immunocompromised hosts. We present the case of a 58-year-old man with history of deceased donor renal transplantation 14 months prior, who presented with fevers and cough. He was found to have right upper lobe pneumonia and a non-healing eschar of his right knee. Dematiaceous fungi grew from bronchoalveolar lavage (BAL) and was sent to reference lab for identification. Meanwhile, the eschar on his right knee was biopsied and grew Alternaria spp. Pathology was consistent with invasive mould infection and he was treated as having disseminated Alternaria infection with voriconazole and amphotericin B lipid complex. Later on, the dematiaceous mould from a BAL specimen was identified as Verruconis gallopava. The patient was discharged on voriconazole awaiting minimal inhibitory concentrations for V. gallopava but was readmitted 2 days later with high fevers and died from acute respiratory failure.

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Pathological fracture of femoral neck in a middle-aged woman: a rare presentation of primary hydatid cyst disease in humans

Hydatid disease in humans is caused by Echinococcus granulosus. It most commonly involves the liver and, to a lesser extent, the lungs and spleen; however, it is known to involve other areas, too. Involvement of bone by hydatid cyst is rare. Here, we describe the case of a 37-year-old woman who presented with pain in the left groin and swelling in the left thigh. The radiological imaging showed a fracture of the femoral neck and cysts in the shaft of the femur. Diagnosis of hydatid cyst was confirmed on the basis of histopathology of biopsy specimens. The patient recovered after surgical excision of the cyst. This case illustrates the various sites and presentations of hydatid cyst disease, and the need to investigate for it if cystic bony lesions are encountered especially in endemic regions, as a delay in diagnosis can lead to long-term morbidity and even death.

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Autoimmune fasciitis triggered by the anti-programmed cell death-1 monoclonal antibody nivolumab

A 43-year-old woman with a history of recently diagnosed metastatic melanoma was commenced on systemic therapy with nivolumab, an anti-programmed cell death-1 monoclonal antibody and one of an increasing group of the so-called 'immune checkpoint inhibitors'. She experienced a dramatic complete response within 6 months of initiation. However, in addition to developing incident autoimmune hypothyroidism, she also developed progressive fatigue, proximal weakness, myalgia and dysphagia. Initial investigations with blood tests, electrophysiology and a muscle biopsy were non-specific or normal. Subsequent examination revealed 'woody' thickening of the subcutaneous tissues of the forearms, thighs and calves consistent with fasciitis. MRI and a full-thickness skin–muscle biopsy were ultimately diagnostic of a likely iatrogenic autoimmune myofasciitis. The clinical manifestations only responded partly to prednisolone 30 mg orally and treatment was escalated to include intravenous immunoglobulin. At 3 months, this has only resulted in a modest incremental improvement.

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Follicular dendritic cell sarcoma of the porta hepatis

Follicular dendritic cell (FDC) sarcoma is a very rare neoplasm which commonly involves the lymph nodes and less commonly involves extranodal organs such as the liver. Most cases of FDC sarcoma are idiopathic, however some cases are associated with other disease states. Management of FDC sarcoma is primarily focused on surgical resection of the mass, and secondarily focused on radiotherapy, chemotherapy and/or biologic pharmacotherapy. We report the case of a patient who was found to have FDC sarcoma presenting as an obstructing mass of the porta hepatis, a manifestation which does not appear to be reported in the literature.

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21st century obstetrics: a 50-year-old nullip--walk in the park?

We discuss the case of a 50-year-old nulliparous woman who conceived after in vitro fertilisation. She had multiple medical comorbidities and presented an obstetric and medical challenge. She was carefully managed through pregnancy and had a successful outcome. In this report, we explore the medical complexity, as well as ethical and logistic issues involved.

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Emphysematous gastritis secondary to Sarcina ventriculi

Description

An 87-year-old man with history of dementia, coronary artery disease on dual antiplatelet therapy and oesophagitis presented to the emergency department with acute-onset coffee ground emesis and left upper quadrant abdominal pain of 1-day duration. Vital signs were normal. Exam was notable for diffuse abdominal pain without peritoneal signs.

Medical work-up was remarkable for haemoglobin of 8.2 g/dL, lactate of 6.3 mmol/L and white blood cell count of 21.84x10⁹/L. CT with angiography of the abdomen and pelvis revealed extensive portal and mesenteric venous gas as well as gastric emphysema (figures 1 and 2). The bowel was normal.

Figure 1

Axial CT image of the upper abdomen with intravenous contrast demonstrates extensive portal venous gas (blue arrow). Multiple locules of gas (red arrows) are present in the wall of the stomach.

Figure 2

Coronal CT of the upper abdomen...

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Giant granadillas seeds phytobezoar rectal impactation: a very unusual case of intestinal obstruction

A 78-year-old Caucasian man presented to the emergency department with bloody diarrhoea, diffuse abdominal pain and fever with 1-week duration. He had just returned from Angola where he had been treated for a presumed Clostridium difficile infection without improvement. He had no relevant medical or familiar history except for hypertension and prostate benign hyperplasia. He was drowsy, feverish and eupnoeic. His oxygen saturation on pulse oximetry was 92%, blood pressure was 173/99 mm Hg and pulse rate 100 beats per minute. Except for a distended, silent and painful abdomen, particularly on lower quadrants, the rest of the examination was unremarkable. A CT showed a mesh-like mass inside the rectum conditioning colonic obstruction and distention. This turned to be a giant granadilla's seeds phytobezoar and was removed endoscopically. Five days later, the patient had a colonic perforation requiring total colectomy. He made a full recovery after rehabilitation for 3 months.

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Successful management of benign paroxysmal positional vertigo (BPPV) in a patient who was ventilated with a C3 complete spinal injury on a regional spinal unit intensive care

Benign paroxysmal positional vertigo (BPPV) occurs in 14.5% of patients with spinal cord injury (SCI) and may require intervention on intensive care unit (ICU). A 61-year-old man was admitted to a spinal injury ICU with a traumatic C3 complete SCI following a mountain bike accident. Ventilated but stable he complained of severe dizziness on rolling, during personal cares, which lasted for 40 s. Clinical examination was limited due to the injury and ventilation. Subjective questioning, visio-ocular control and a modified Dix-Hallpike and roll tests confirmed a right posterior canalithiasis BPPV. A modified right Epley was performed with assistance of four people, medical supervision, monitoring of tracheal ventilation and vital signs. No adverse reaction was observed. Resolution of dizziness on rolling was achieved with no recurrence at 1 year. BPPV can be successfully and safely managed on ICU.

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