Adam Bass - US grants

[unreadable] DESCRIPTION (provided by applicant): As a physician trained in medical oncology, I aim to develop the skills necessary to allow me to become an independent translational physician-scientist. The goal of this proposal is to identity the genetic basis for carcinomas of the stomach and esophagus with the eventual hope to develop improved treatments for these disorders based on genetic insights into disease pathogenesis. The sponsor of this application, Matthew Meyerson, has developed techniques to study genomic aberrations in cancer using high-density SNP arrays and other novel sequencing and genotyping technologies. As a basis for genomic discovery and characterization we have built a collection of DNA samples derived from fresh-frozen gastric and esophageal carcinomas and will have access to >100 gastrointestinal carcinoma cell lines. Using these arrays, our early data shows frequent recurrent genomic aberrations in gastric and esophageal carcinomas. Many of these aberrations target tyrosine kinases, suggesting that subgroups of patients with these diseases may benefit from treatments with targeted inhibition of these kinases. We have also identified a novel amplification in squamous aerodigestive carcinomas and have initiated functional studies to validate this new potential oncogene. [unreadable] [unreadable] The Specific Aims are: [unreadable] 1. To generate and analyze high-density SNP array data from over 300 carcinomas and cell lines of the stomach and esophagus to identify regions of amplification and deletion. [unreadable] 2. To genotype a panel of over 300 gastric and esophageal carcinoma primary samples and cell lines for over 1000 annotated mutations in 83 cancer-associated genes and build a collection of genomically annotated cell lines for use in validation studies. [unreadable] 3. To validate a new putative oncogene in squamous aerodigestive carcinomas and subsequently validate other candidate genes in selected copy-number alterations in gastric and esophageal carcinomas. [unreadable] [unreadable] Relevance: This project will use genomic tools to identify critical genetic alterations in a large panel of gastric and esophageal cancer samples and will use more traditional laboratory techniques to follow-up candidate genes identified through genomic studies. Through this work, we have the potential to identify and validate critical drug targets in these diseases. Results of these studies could directly lead to development of improved therapeutic strategies for patients with these deadly malignancies. [unreadable] [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): Squamous cell carcinomas of the lung and head and neck are common and highly lethal cancers for which there are no approved targeted therapies associated with a genetic biomarker. Our previous studies have nominated Fibroblast Growth Factor Receptors (FGFRs) as candidate therapeutic targets in these diseases, though clinical activity of FGFR inhibitors has been modest to date despite a few cases of dramatic response. This goal of this proposal is to develop optimized strategies for the use of FGFR inhibitors in squamous cell carcinomas, in which amplification, mutation and translocation of FGFR genes are common. The long-term objective is to enable the successful clinical application of FGFR-targeted therapies in squamous cell cancers given the urgent need to introduce effective therapies for these diseases. This proposal is unique in that it leverages extensive and novel resources at the Dana-Farber Cancer Institute/Harvard Cancer Center and incorporates the study of cancer cell lines, transgenic mouse models, patient-derived xenografts, novel FGFR antagonists and patient specimens from ongoing clinical trials of FGFR inhibitors. The proposed Specific Aims are to: 1) Evaluate known and novel recurrent FGFR alterations for oncogenicity and FGFR inhibitor sensitivity using cell line and mouse models, 2) Develop strategies to overcome acquired resistance to FGFR kinase inhibition, and 3) Define the genomic context of FGFR kinase alterations and co-dependencies in cancer cell lines and patient specimens and evaluate strategies to target co-dependencies. These studies will define which somatic FGFR alterations identified in patients with squamous cell carcinomas are the most likely to be therapeutic targets through the development and characterization of cellular model systems, transgenic animals and patient-derived xenografts. For FGFR alterations validated to confer sensitivity to FGFR inhibitors we will use cellular and murine models and tumor specimens from subjects on clinical trials of FGFR inhibitors to identify mechanisms of acquired resistance and develop strategies to overcome resistance. In cases in which oncogenic FGFR alterations do not confer sensitivity to FGFR inhibition we will identify the genomic events accounting for primary resistance and utilize cellular and animal model systems to define approaches to overcome resistance by targeting co-dependencies. Through these Aims we intend to define the optimal ways in which to apply FGFR inhibitors clinically with the ultimate goal of improving outcomes for patients with squamous cell carcinomas.

PROJECT SUMMARY This project focuses upon Diffuse Gastric Cancer (DGC), a frequently lethal cancer, marked by its characteristic growth patterns with lack of cellular cohesion, highly invasive spread and marked propensity for metastasis. This proposal builds upon new progress in the study of DGC, bringing together a collaborative team of investigators with provocative new findings regarding the role of RHOA in the pathogenesis of this disease and several newly developed mouse model systems. These data and resources bring new opportunities to substantively advance the study of these deadly and understudied cancers. A first set of data underlying this application followed our recent identification of a novel stem cell population in gastric glands marked by Mist1 expression (Yokoyama et al, Cancer Cell 2015). These cells were demonstrated to give rise to DGC following engineered loss of tumor suppressor Cdh1. However, development of DGC required the secretion of Wnt5a by cells in the stem cell niche, with Wnt5a acting by activating GTPase RhoA in the Cdh1- null gastric cells. In parallel, we made a set of novel genomic discoveries, finding that ~20- 30% of DGCs harbor genomic aberrations impacting RHOA, either highly recurrent missense mutations of RHOA or a recurrent fusion gene including ARHGAP26, a RHOA regulator (TCGA, Nature, 2014). In this context, delineating the functions of RhoA in DGC pathogenesis, spanning both the role of Wild-type RHOA following Cdh1 loss and the oncogenic functions of RHOA mutations, emerge as critical paths towards the identification of therapeutic targets and understanding of basic pathophysiology of DGC formation. In our first Aim, we evaluate activation of wild-type RHOA in normal gastric corpus stem cells, and in early progression of Cdh1- deficient diffuse gastric cancer. We propose to test our hypothesis that RHOA is a mediator of Wnt5a effects upon corpus stem cells, especially following Cdh1 loss. These results will have immediate relevance to the definition of mechanisms of DGC initiation, clearly informing efforts to prevent and treat these deadly cancers. Our second aim evaluates RHOA somatic mutations in the initiation and progression of diffuse gastric cancer. In this aim we further characterize the biochemical and phenotypic effects of highly recurrent missense mutations of the RHOA GTPase identified in DGC. We will also functionally validate which RHOA effectors are essential for oncogenic activity of these mutants in both in vitro and in vivo systems, including our novel DGC mouse model driven by Cdh1 loss and RhoA mutation. Through these studies we hope to determine mechanisms of RHOA mediated transformation and identify specific pathways that are critical to the pathogenesis of DGC, findings with immediate potential relevance to the development of new therapeutic targets.

Project Summary The intent of this SPORE award is to create a flexible research program that responds rapidly to new advances in basic science by implementing changes in patient care. This challenge can only be undertaken if its governing body has the ability and authority to continuously monitor research plans and progress and make changes when necessary to ensure that research conducted by the SPORE maintains its translational focus. In addition, this program must be able to draw upon the resources of a large research infrastructure in order to achieve its ambitious goals. The purpose of the Administration, Evaluation and Planning Core is to coordinate the varied components of the DF/HCC GI SPORE necessary to provide oversight and leadership of the scientific, administrative and fiscal aspects of the SPORE. The Administration Core's specific aims are: Aim 1: Select projects, monitor research progress, and plan for the future Aim 2: Foster collaborative research within the SPORE and between SPOREs Aim 3: Integrate the GI Cancer SPORE into the structure of the DF/HCC Aim 4: Provide necessary resources and fiscal oversight Aim 5: Promote rapid dissemination of significant research findings and facilitate resource exchange between the DF/HCC SPORE and other institutions

Gastrointestinal Malignancies Program Project Summary / Abstract The overarching goals of the Program are to prevent, detect early, and manage more accurately and effectively the treatment of GI malignancies. The Program will take full advantage of cutting-edge genomic technologies to identify genetic and epigenetic changes that are important in initiation and progression of GI cancers, as well as their response to therapy. Given the complexity and heterogeneity of GI malignancies, the Program had historically emphasized pancreatic and colorectal cancers, two of the four leading causes of US cancer deaths. However, with the expanding expertise and accomplishments of the Program in the other GI cancers during the previous funding period, the Program has intensified efforts in hepatobiliary, esophagogastric, and neuroendocrine tumors. The program has 95 members, representing seven DF/HCC institutions and 12 academic departments. In 2014 peer-reviewed grant funding attributed to the Program was $5.9 million in total costs from the NCI and $5.3 million from other sponsors. During the current funding period, Gastrointestinal Malignancies Program members published 2,003 cancer-relevant papers. Of these 33% were inter-institutional, 24% were intra-programmatic, and 45% were inter-programmatic collaborations between two or more DF/HCC members. Overall, when counted once, 27% of DF/HCC publications were inter- programmatic collaborations.