Brian Wolpin - US grants

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer-related mortality in the United States, and 95% of patients who develop pancreatic cancer die from their disease. Unfortunately, relatively little is known about the pathogenesis and epidemiology of this under-studied malignancy. To address this problem, the current proposal focuses on the investigation of dietary, genetic and biochemical risk factors for pancreatic cancer. For Aim 1, I will examine a novel dietary index that estimates long-term systemic insulin exposure and two hormones altered in states of obesity and insulin resistance, adiponectin and leptin. For Aim 2, I will investigate plasma markers of inflammation, Helicobacter pylori infection, and telomere length, in an effort to better understand the link between chronic inflammation and, pancreatic cancer risk. For Aim 3, I will expand on recent observations linking heterogeneity at the ABO blood group locus with plasma inflammatory markers and the risk of pancreatic cancer. A major strength of this proposal is the ability to examine these factors prospectively, thereby avoiding the problems associated with retrospective analyses of pancreatic cancer epidemiology. Moreover, this proposal will assemble one of the largest prospective case-control sets to date, establishing a unique database of pancreatic cancer cases and matched controls, with repeated dietary and lifestyle assessments over several decades, archived blood specimens, and genomic DNA. This resource will allow me to rigorously examine multiple inter-related pathways with robust power. In addition, it will allow me to rapidly examine new hypotheses as they emerge. Finally, this award will enable me to develop advanced skills in biostatistics and epidemiology, pursue a focused program in pancreatic cancer research, and receive close, long-term mentorship from experienced and successful clinical researchers, promoting my transition to an independent investigator. RELEVANCE: Although pancreatic cancer is the 4th most common cause of cancer-related death in the U.S., we know little about predisposing factors for this disease. With the current proposal, I hope to advance our understanding of pancreatic cancer pathogenesis, generate an important resource to evaluate future hypotheses, and provide data to support recommendations for reducing mortality from this highly lethal malignancy.

PROJECT SUMMARY (no more than 30 lines of text): Pancreatic cancer is the fourth-leading cause of cancer death in the U.S. Over 80% of patients present with incurable disease, and the vast majority live for <12 months. The high mortality of pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is largely a consequence of diagnosis at an advanced stage when the tumor is no longer resectable for cure. However, symptoms rarely develop with early disease, and established risk factors for PDAC, such as tobacco smoking, obesity, chronic pancreatitis, diabetes, and family history of PDAC, are insufficient to risk stratify the population for disease screening. Experimental studies indicate that more than a decade elapses from formation of the founder malignant clone to a patient's diagnosis, suggesting a window of opportunity for early detection. Nevertheless, no early detection markers have advanced to clinical use, in part, because little infrastructure has been developed to facilitate rigorous investigation of promising candidates. To address the critical goal of PDAC early detection, we have brought together investigators with a long track-record of collaborative innovation to form the Pancreatic Cancer Circulating Biomarker (Pan-C2-Bio) Consortium. Within this Consortium, we join ongoing patient biospecimen collection at five large cancer centers with four highly promising early detection technologies and sophisticated computer modeling to define a non-invasive PDAC screening strategy. The Consortium will work to achieve three primary goals: (1) generation of a large, unified, thoroughly-annotated human and murine sample bank for testing of early detection markers, (2) definitive evaluation of four highly promising PDAC early detection markers for near-term clinical utility, including circulating cell-free DNA mutations and methylation patterns, cancer-derived exosomes, and metabolism markers, and (3) identification of biomarker-based screening strategies to facilitate early cancer diagnosis in high-risk groups and the general population. Thus, the work proposed by the Pan-C2-Bio Consortium will deliver much-needed biospecimen resources for early detection studies, provide evidence for (or against) the utility of four highly promising PDAC early detection technologies, and demonstrate how new biomarkers can be integrated with previously characterized risk factors to identify individuals for disease screening. With this work, we look to reduce mortality from pancreatic cancer by identifying those at highest risk and diagnosing subclinical disease when curative therapies can be applied.  

Project Summary Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States. Up to 20% of PDAC patients harbor germline or somatic mutations in genes involved in double-strand DNA damage repair (DDR), including the homologous recombination (HR) repair pathway genes BRCA1, BRCA2 and PALB2, as well as genes involved in the DNA damage response, such as ATM and CHEK2. A subset of PDAC patients with mutations in BRCA1 and BRCA2, as well as other DDR genes, may have durable tumor responses to poly(ADP-ribose) polymerase (PARP) inhibitors; however, the optimal biomarkers have not been identified to predict which patients will benefit from these therapies. Furthermore, combination treatment programs to move beyond single-agent PARP inhibition are not yet defined. This proposal brings together a team of distinguished laboratory, translational and clinical investigators to: (1) define optimal genomic and functional strategies for identifying PDAC patients with DDR deficiency; (2) conduct treatment trials to identify the patients with greatest benefit from PARP inhibition and to identify mechanisms of de novo and acquired resistance; and (3) to define novel combination treatment strategies for future clinical trials. In Aim 1 of this proposal, we will define scalable genomic and functional assays, including novel mutational signatures, a novel DNA replication fork stability assay, and immunohistochemical assays for RAD51 foci, that identify patients with PDAC harboring HR deficiency (HRD) or other DDR defects, so that clinicians can efficiently select PDAC patients most likely to benefit from targeted therapies. In Aim 2, we will perform an investigator-initiated, phase 2 clinical trial to determine the efficacy of the PARP inhibitor niraparib in DDR-mutant PDAC and will identify determinants of sensitivity and mechanisms of acquired resistance. In Aim 3, we will identify combination treatment strategies for patients with DDR-deficient PDAC using novel patient-derived organoid lines that model PARP inhibitor sensitivity and resistance in both DDR deficient and proficient contexts. Leveraging unique genomic analyses, innovative DDR deficiency assays, novel patient-derived models, a large clinical volume of PDAC patients, a multi-disciplinary team-science approach, and close collaboration with the Biospecimens and Pathology Core (Core B) and the Biostatistics and Bioinformatics Core (Core C), this proposal will deliver (1) clear biomarker strategies by which clinicians can identify patients with DDR-deficient PDAC, (2) data for the responsiveness of DDR-deficient PDAC to PARP inhibition, (3) new mechanistic insights into resistance mechanisms to PARP inhibition in PDAC, and (4) combination strategies for testing in the next generation of PDAC clinical trials. Through these studies, we aim to make meaningful improvements in treatment strategies for this important subset of PDAC patients who harbor DDR deficiency.

Project Summary This is a competitive renewal application for a SPORE in Gastrointestinal (GI) Cancers originating from the GI Malignancies Program of the Dana-Farber/Harvard Cancer Center (DF/HCC). Since its inception in 2007, the SPORE has established a thriving culture of inter-institutional collaboration that has united basic, clinical, and population scientists into a highly productive translational enterprise. The ability to attract and retain researchers from diverse disciplines has fostered fundamental discoveries in cancer biology, innovative translational hypotheses, and cutting-edge clinical trials. The SPORE has also maintained a central focus on developing a large cadre of new investigators, building on a successful model of interdisciplinary, cross- campus cooperation that serves as a nidus for inter-SPORE relationships and other collaborations. Moreover, the SPORE has created invaluable research resources, such as the Tissue, PDX and Organoid Repository and clinical, pathology, and genomics databases that collectively accelerate translational investigation. Each of the current projects has achieved or exceeded its translational goals, providing a foundation for programmatic studies, including independent large-scale collaborative initiatives. Building on this progress, the DF/HCC GI SPORE seeks to continue to translate biological and technological advances into improvements in the prevention and treatment of GI malignancies. The overarching objectives of a renewed SPORE are to: 1) Define optimal genomic and functional strategies, including integration of cell-free (cf)DNA profiling (Projects 1-4), to predict drug responsiveness and improve diagnostics, prognostics, and clinical decisions. 2) Elucidate the interplay between oncogenic mutations, targeted therapy, and anti-tumor immunity to inform cancer biology and improve the outcome of patients with GI cancers (Projects 1,3, 4). 3) Define mechanisms of resistance to novel targeted therapies and hence identify new approaches to overcome resistance and better select the patients most likely to respond to therapy (Projects 1-4). 4) Enhance study of deadly GI cancers that, despite rising incidence, remain under- studied (Project 2, 4). 5) Encourage collaboration and promote academic rigor by providing clinical specimens, fostering core technologies and resources, and hosting regular research meetings and seminars focused on GI cancers. 6) Provide mentorship and training for young GI cancer researchers and recruit leading translational investigators from other fields through Career Enhancement and Developmental Project Awards.