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Tuesday, April 2, 2019

Cancer Research

Coordinately Targeting Cell-Cycle Checkpoint Functions in Integrated Models of Pancreatic Cancer
Purpose:Cancer cells often have deficiencies in cell-cycle control mechanisms and could be dependent on specific cell-cycle checkpoints to maintain viability. Because of the documented role of KRAS in driving replication stress, we targeted the checkpoint governing DNA replication using CHK1 kinase inhibitors in pancreatic ductal adenocarcinoma (PDAC) models and examined mechanisms of resistance. Experimental Design:Single-agent efficacy of CHK1 inhibition was investigated in established and primary...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Immune Exclusion-Wnt/CTNNB1 Class Predicts Resistance to Immunotherapies in HCC
Next-generation sequencing has provided information on actionable targets and biomarkers of response in oncology. In hepatocellular carcinoma (HCC), Wnt/CTNNB1 mutations characterize the immune-excluded class (cold tumors) and might represent the biomarkers predicting resistance to immune checkpoint inhibitors. Large-scale validation of these data is needed to customize immunotherapy in advanced HCC. See related article by Harding et al., p. 2116
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Single-Cell Transcriptomics of Pancreatic Cancer Precursors Demonstrates Epithelial and Microenvironmental Heterogeneity as an Early Event in Neoplastic Progression
Purpose:Early detection of pancreatic ductal adenocarcinoma (PDAC) remains elusive. Precursor lesions of PDAC, specifically intraductal papillary mucinous neoplasms (IPMNs), represent a bona fide pathway to invasive neoplasia, although the molecular correlates of progression remain to be fully elucidated. Single-cell transcriptomics provides a unique avenue for dissecting both the epithelial and microenvironmental heterogeneities that accompany multistep progression from noninvasive IPMNs to PDAC....
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Mapping Physical Tumor Microenvironment and Drug Delivery
The physical microenvironment of pancreatic tumors is highly abnormal, and this causes significant challenges for drug delivery through multiple mechanisms. Measurements of tissue elasticity could be used as a physical biomarker to assess aberrant drug delivery, and potentially guide stroma-targeting treatment strategies and patient stratification. See related article by Wang et al., p. 2136
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes
Purpose:Undifferentiated uterine sarcomas (UUS) are rare, extremely deadly, sarcomas with no effective treatment. The goal of this study was to identify novel intrinsic molecular UUS subtypes using integrated clinical, histopathologic, and molecular evaluation of a large, fully annotated, patient cohort. Experimental Design:Fifty cases of UUS with full clinicopathologic annotation were analyzed for gene expression (n = 50), copy-number variation (CNV, n = 40), cell morphometry (n = 39), and protein...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
No Cell Left Unturned: Intraductal Papillary Mucinous Neoplasm Heterogeneity
Intraductal papillary mucinous neoplasm (IPMN) is a pancreatic cancer precursor lesion with established genetic features, but the cellular ecosystem of these tumors remains to be fully characterized. This study utilizes single-cell RNA sequencing to describe the dynamic landscape of epithelial, immune, and stromal cells during IPMN progression to invasive cancer. See related article by Bernard et al., p. 2194
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Developing Allogeneic Double-Negative T Cells as a Novel Off-the-Shelf Adoptive Cellular Therapy for Cancer
Purpose:To expand clinical-grade healthy donor-derived double-negative T cells (DNT) to a therapeutically relevant number and characterize their potential to be used as an "off-the-shelf" adoptive cellular therapy (ACT) against cancers. Experimental Design:We developed methods to expand DNTs under GMP conditions and characterized their surface molecule expression pattern using flow cytometry–based high-throughput screening. We investigated the off-the-shelf potential of clinical-grade DNTs by assessing...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Circulating Tumor DNA in Advanced Anal Cancer: A Blood Biomarker Goes Viral
Circulating tumor DNA (ctDNA) as a blood-based biomarker for mutation detection is an exciting, highly sensitive approach in the clinical management of oncology patients. In human papillomavirus–associated malignancies like anal cancer, a viral-specific probe can be utilized for ctDNA detection in the majority of patients to predict clinical outcomes. See related article by Bernard-Tessier et al., p. 2109
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Human Breast Cancer Xenograft Model Implicates Peroxisome Proliferator-activated Receptor Signaling as Driver of Cancer-induced Muscle Fatigue
Purpose:This study tested the hypothesis that a patient-derived orthotopic xenograft (PDOX) model would recapitulate the common clinical phenomenon of breast cancer–induced skeletal muscle (SkM) fatigue in the absence of muscle wasting. This study additionally sought to identify drivers of this condition to facilitate the development of therapeutic agents for patients with breast cancer experiencing muscle fatigue. Experimental Design:Eight female BC-PDOX–bearing mice were produced via transplantation...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Advances in HER2-Targeted Therapy: Novel Agents and Opportunities Beyond Breast and Gastric Cancer
The introduction of HER2-targeted therapy for breast and gastric patients with ERBB2 (HER2) amplification/overexpression has led to dramatic improvements in oncologic outcomes. In the past 20 years, five HER2-targeted therapies have been FDA approved, with four approved in the past 8 years. HER2-targeted therapy similarly was found to improve outcomes in HER2-positive gastric cancer. Over the past decade, with the introduction of next-generation sequencing into clinical practice, our understanding...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
irRECIST for the Evaluation of Candidate Biomarkers of Response to Nivolumab in Metastatic Clear Cell Renal Cell Carcinoma: Analysis of a Phase II Prospective Clinical Trial
Purpose:Immune-related RECIST (irRECIST) were designed to capture atypical responses seen with immunotherapy. We hypothesized that, in patients with metastatic clear cell renal cell carcinoma (mccRCC), candidate biomarkers for nivolumab response would show improved association with clinical endpoints capturing atypical responders (irRECIST) compared with standard clinical endpoints (RECISTv1.1). Experimental Design:Endpoints based on RECISTv1.1 [objective response rate (ORR)/progression-free survival...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Immunotherapy for Glioblastoma: Adoptive T-cell Strategies
Glioblastoma (GBM) is a devastating disease with an extremely poor prognosis. Immunotherapy via adoptive cell transfer (ACT), especially with T cells engineered to express chimeric antigen receptors (CAR), represents a particularly promising approach. Despite the recent success of CAR T cells for blood cancers, the question remains whether this powerful anticancer therapy will ultimately work for brain tumors, and whether the primary immunologic challenges in this disease, which include antigenic...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Induction of Peripheral Effector CD8 T-cell Proliferation by Combination of Paclitaxel, Carboplatin, and Bevacizumab in Non-small Cell Lung Cancer Patients
Purpose:Chemotherapy has long been the standard treatment for advanced stage non–small cell lung cancer (NSCLC), but checkpoint inhibitors are now approved for use in several patient groups and combinations. To design optimal combination strategies, a better understanding of the immune-modulatory capacities of conventional treatments is needed. Therefore, we investigated the immune-modulatory effects of paclitaxel/carboplatin/bevacizumab (PCB), focusing on the immune populations associated with the...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Challenges with Novel Clinical Trial Designs: Master Protocols
The 2018 Accelerating Anticancer Agent Development (AAADV) Workshop assembled a panel of experts for an in-depth discussion session to present "Challenges with Novel Clinical Trial Designs." This panel offered assessments of the challenges faced by industry, the FDA, investigators, institutional review boards, and patients. The panel focused on master protocols, which include umbrella trials, platform trials, and basket trials. Umbrella trials and platform trials share many commonalities, whereas...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
YAP1-Mediated CDK6 Activation Confers Radiation Resistance in Esophageal Cancer - Rationale for the Combination of YAP1 and CDK4/6 Inhibitors in Esophageal Cancer
Purpose:Esophageal cancer is a lethal disease that is often resistant to therapy. Alterations of YAP1 and CDK6 are frequent in esophageal cancer. Deregulation of both molecules may be responsible for therapy resistance. Experimental Design:Expressions of YAP1 and CDK6 were examined in esophageal cancer cells and tissues using immunoblotting and immunohistochemistry. YAP1 expression was induced in esophageal cancer cells to examine YAP1-mediated CDK6 activation and its association with radiation...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Postprogression Outcomes for Osimertinib versus Standard-of-Care EGFR-TKI in Patients with Previously Untreated EGFR-mutated Advanced Non-Small Cell Lung Cancer
Purpose:In the phase III FLAURA study, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib significantly improved progression-free survival (PFS) versus standard-of-care (SoC) EGFR-TKI (gefitinib or erlotinib) in patients with previously untreated EGFR (exon 19 deletion or L858R) mutation-positive advanced non–small cell lung cancer (NSCLC). Interim overall survival (OS) data were encouraging, but not formally statistically significant at current maturity...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Dynamic Contrast-enhanced MRI Detects Responses to Stroma-directed Therapy in Mouse Models of Pancreatic Ductal Adenocarcinoma
Purpose:The dense stroma underlies the drug resistance of pancreatic ductal adenocarcinoma (PDA) and has motivated the development of stroma-directed drugs. Our objective is to test the concept that dynamic contrast–enhanced (DCE) MRI using FDA-approved contrast media, an imaging method sensitive to the tumor microenvironment, can detect early responses to stroma-directed drug. Experimental Design:Imaging studies were performed in three mouse models exhibiting high desmoplastic reactions: the autochthonous...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Immunologic Correlates of the Abscopal Effect in a SMARCB1/INI1-negative Poorly Differentiated Chordoma after EZH2 Inhibition and Radiotherapy
Purpose:We sought to determine the mechanism of an exceptional response in a patient diagnosed with a SMARCB1/INI1-negative chordoma treated with tazemetostat, an EZH2 inhibitor, and followed by radiotherapy. Patient and Methods: In an attempt to investigate the mechanism behind this apparent abscopal effect, we interrogated tumor tissues obtained over the clinical course. We utilized next-generation sequencing, standard IHC, and employed a novel methodology of multiplex immunofluorescence analysis....
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Highlights of This Issue
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Combination Paclitaxel and Palbociclib: Results of a Phase I Trial in Advanced Breast Cancer
Purpose:The CDK 4/6 inhibitor palbociclib rapidly and reversibly inhibits the cell cycle. The goal of this study was to exploit the cell cycle through intermittent, alternating dosing with palbociclib/paclitaxel to enhance efficacy. We determined the combination dose-limiting toxicity (DLT) in patients with Rb protein–expressing, advanced breast cancer. Patients and Methods:This open-label, phase I trial (NCT01320592) enrolled patients to sequential cohorts of palbociclib orally dosed intermittently...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Circulating miRNAs and PD-L1 Tumor Expression Are Associated with Survival in Advanced NSCLC Patients Treated with Immunotherapy: a Prospective Study
Purpose:Immune-checkpoint inhibitors (ICI) have improved the survival of patients with non–small cell lung cancer (NSCLC). However, only a subset of patients benefit from ICIs, and the role of PD-L1 as predictive biomarker is still debated. A plasma immune-related miRNA-signature classifier (MSC) was established in lung cancer screening settings to identify the lethal form of the disease in early stages. In this exploratory study, we tested the efficacy of the MSC as prognostic marker in patients...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Autophagy Inhibition to Augment mTOR Inhibition: a Phase I/II Trial of Everolimus and Hydroxychloroquine in Patients with Previously Treated Renal Cell Carcinoma
Purpose:Everolimus inhibits the mTOR, activating cytoprotective autophagy. Hydroxychloroquine inhibits autophagy. On the basis of preclinical data demonstrating synergistic cytotoxicity when mTOR inhibitors are combined with an autophagy inhibitor, we launched a clinical trial of combined everolimus and hydroxychloroquine, to determine its safety and activity in patients with clear-cell renal cell carcinoma (ccRCC). Patients and Methods:Three centers conducted a phase I/II trial of everolimus 10...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Genomic Landscape of Pancreatic Adenocarcinoma in Younger versus Older Patients: Does Age Matter?
Purpose:State-of-the-art genomic analyses of pancreatic adenocarcinoma (PDAC) have yielded insight into signaling pathways underlying carcinogenesis. PDAC is characterized by substantial genomic heterogeneity. We aimed to determine whether early-onset PDAC (EOPC; ≤55 years) displays a distinctive molecular landscape from average-age onset PDAC (AOPC; ≥70 years). Experimental Design:Three distinct datasets for PDAC were analyzed. In the first, patients undergoing treatment at Memorial Sloan Kettering...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Efficacy and Safety of the Biosimilar ABP 215 Compared with Bevacizumab in Patients with Advanced Nonsquamous Non-small Cell Lung Cancer (MAPLE): A Randomized, Double-blind, Phase III Study
Purpose:This phase III study compared clinical efficacy and safety of the biosimilar ABP 215 with bevacizumab reference product (RP) in patients with advanced nonsquamous non–small cell lung cancer (NSCLC). Patients and Methods:Patients were randomized 1:1 to ABP 215 or bevacizumab 15 mg/kg every three weeks for 6 cycles. All patients received carboplatin and paclitaxel every three weeks for ≥4 and ≤6 cycles. The primary efficacy endpoint was risk ratio of objective response rate (ORR); clinical...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Arylsulfonamide 64B Inhibits Hypoxia/HIF-Induced Expression of c-Met and CXCR4 and Reduces Primary Tumor Growth and Metastasis of Uveal Melanoma
Purpose:Uveal melanoma (UM) is the most prevalent and lethal intraocular malignancy in adults. Here, we examined the importance of hypoxia in UM growth and tested the antitumor effects of arylsulfonamide 64B, an inhibitor of the hypoxia-induced factor (HIF) pathway in animal models of UM and investigated the related mechanisms. Experimental Design:UM cells were implanted in the uvea of mice eyes and mice systemically treated with 64B. Drug effect on primary eye tumor growth, circulating tumor cells,...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
A Pilot Trial of the Combination of Transgenic NY-ESO-1-reactive Adoptive Cellular Therapy with Dendritic Cell Vaccination with or without Ipilimumab
Purpose:Transgenic adoptive cell therapy (ACT) targeting the tumor antigen NY-ESO-1 can be effective for the treatment of sarcoma and melanoma. Preclinical models have shown that this therapy can be improved with the addition of dendritic cell (DC) vaccination and immune checkpoint blockade. We studied the safety, feasibility, and antitumor efficacy of transgenic ACT with DC vaccination, with and without CTLA-4 blockade with ipilimumab. Patients and Methods:Freshly prepared autologous NY-ESO-1–specific...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Preclinical Efficacy of Endoglin-Targeting Antibody-Drug Conjugates for the Treatment of Ewing Sarcoma
Purpose:Endoglin (ENG; CD105) is a coreceptor of the TGFβ family that is highly expressed in proliferating endothelial cells. Often coopted by cancer cells, ENG can lead to neo-angiogenesis and vasculogenic mimicry in aggressive malignancies. It exists both as a transmembrane cell surface protein, where it primarily interacts with TGFβ, and as a soluble matricellular protein (sENG) when cleaved by matrix metalloproteinase 14 (MMP14). High ENG expression has been associated with poor prognosis in...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Clinical Validity of HPV Circulating Tumor DNA in Advanced Anal Carcinoma: An Ancillary Study to the Epitopes-HPV02 Trial
Purpose:Human papillomavirus (HPV) is found in 90% of squamous cell carcinomas of the anal canal (SCCA). We investigated the clinical validity of HPV circulating tumor DNA (ctDNA) detection in patients enrolled in the Epitopes-HPV02 trial that demonstrated the efficacy of docetaxel, cisplatin, and 5-FU as first-line chemotherapy in advanced SCCA. Experimental Design:According to the protocol, serum samples were collected before chemotherapy and on completion of chemotherapy. HPV16 ctDNA was quantified...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Low-pass Whole-genome Sequencing of Circulating Cell-free DNA Demonstrates Dynamic Changes in Genomic Copy Number in a Squamous Lung Cancer Clinical Cohort
Purpose:We developed a method to monitor copy number variations (CNV) in plasma cell-free DNA (cfDNA) from patients with metastatic squamous non–small cell lung cancer (NSCLC). We aimed to explore the association between tumor-derived cfDNA and clinical outcomes, and sought CNVs that may suggest potential resistance mechanisms. Experimental Design:Sensitivity and specificity of low-pass whole-genome sequencing (LP-WGS) were first determined using cell line DNA and cfDNA. LP-WGS was performed on...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Prospective Genotyping of Hepatocellular Carcinoma: Clinical Implications of Next-Generation Sequencing for Matching Patients to Targeted and Immune Therapies
Purpose:Prior molecular profiling of hepatocellular carcinoma (HCC) has identified actionable findings that may have a role in guiding therapeutic decision-making and clinical trial enrollment. We implemented prospective next-generation sequencing (NGS) in the clinic to determine whether such analyses provide predictive and/or prognostic information for HCC patients treated with contemporary systemic therapies. Experimental Design:Matched tumor/normal DNA from patients with HCC (N = 127) were analyzed...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Broad Spectrum Activity of the Checkpoint Kinase 1 Inhibitor Prexasertib as a Single Agent or Chemopotentiator Across a Range of Preclinical Pediatric Tumor Models
Purpose:Checkpoint kinase 1 (CHK1) inhibitors potentiate the DNA-damaging effects of cytotoxic therapies and/or promote elevated levels of replication stress, leading to tumor cell death. Prexasertib (LY2606368) is a CHK1 small-molecule inhibitor under clinical evaluation in multiple adult and pediatric cancers. In this study, prexasertib was tested in a large panel of preclinical models of pediatric solid malignancies alone or in combination with chemotherapy. Experimental Design:DNA damage and...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Methylation Biomarker Panel Performance in EsophaCap Cytology Samples for Diagnosing Barrett's Esophagus: A Prospective Validation Study
Purpose:Barrett's esophagus is the only known precursor of esophageal adenocarcinoma (EAC). Although endoscopy and biopsy are standard methods for Barrett's esophagus diagnosis, their high cost and risk limit their use as a screening modality. Here, we sought to develop a Barrett's esophagus detection method based on methylation status in cytology samples captured by EsophaCap using a streamlined sensitive technique, methylation on beads (MOB). Experimental Design:We conducted a prospective cohort...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Dopamine Receptor D5 is a Modulator of Tumor Response to Dopamine Receptor D2 Antagonism
Purpose:Dopamine receptor D2 (DRD2) is a G protein–coupled receptor antagonized by ONC201, an anticancer small molecule in clinical trials for high-grade gliomas and other malignancies. DRD5 is a dopamine receptor family member that opposes DRD2 signaling. We investigated the expression of these dopamine receptors in cancer and their influence on tumor cell sensitivity to ONC201. Experimental Design:The Cancer Genome Atlas was used to determine DRD2/DRD5 expression broadly across human cancers....
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Elastography Can Map the Local Inverse Relationship between Shear Modulus and Drug Delivery within the Pancreatic Ductal Adenocarcinoma Microenvironment
Purpose:High tissue pressure prevents chemotherapeutics from reaching the core of pancreatic tumors. Therefore, targeted therapies have been developed to reduce this pressure. While point probes have shown the effectiveness of these pressure-reducing therapies via single-location estimates, ultrasound elastography is now widely available as an imaging technique to provide real-time spatial maps of shear modulus (tissue stiffness). However, the relationship between shear modulus and the underlying...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
Nuclear-Cytoplasmic Transport Is a Therapeutic Target in Myelofibrosis
Purpose:Myelofibrosis is a hematopoietic stem cell neoplasm characterized by bone marrow reticulin fibrosis, extramedullary hematopoiesis, and frequent transformation to acute myeloid leukemia. Constitutive activation of JAK/STAT signaling through mutations in JAK2, CALR, or MPL is central to myelofibrosis pathogenesis. JAK inhibitors such as ruxolitinib reduce symptoms and improve quality of life, but are not curative and do not prevent leukemic transformation, defining a need to identify better...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
The First-week Proliferative Response of Peripheral Blood PD-1+CD8+ T Cells Predicts the Response to Anti-PD-1 Therapy in Solid Tumors
Purpose:To investigate blood-based dynamic biomarkers that predict responses to anti–programmed cell death protein 1 (PD-1) therapy in solid tumors. Experimental Design:Preplanned biomarker analysis was performed as part of a phase II clinical trial (NCT02607631) in patients with metastatic or refractory thymic epithelial tumors (TETs; n = 31) who received pembrolizumab. The biomarker was further tested in an independent cohort of prospectively recruited patients with metastatic non–small cell lung...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05
An Epithelial-to-Mesenchymal Transcriptional Switch Triggers Evolution of Pulmonary Sarcomatoid Carcinoma (PSC) and Identifies Dasatinib as New Therapeutic Option
Purpose:Pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive form of NSCLC. Rarity and poor characterization have limited the development of PSC-tailored treatment protocols, leaving patients with inadequate therapeutic options. In this study, we investigated the gene expression profile of PSCs, with the aim to characterize the molecular mechanisms responsible for their evolution and to identify new drugs for their treatment. Experimental Design:A training set of 17 biphasic PSCs was selected...
Clinical Cancer Research current issue
Mon Apr 01, 2019 10:05

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