Dana-Farber Harvard GI SPORE
Charles Fuchs, M.D., MPH — Director
Project 1: Improved Staging of Pancreatic Cancer
Ralph Weissleder, M.D., Ph.D.
Andrew L. Warshaw, M.D.
Pancreatic adenocarcinoma is a deadly disease with few effective therapeutic options. Surgical resection of early stage disease offers the only possibility of long-term survival. The overall care of patients with localized pancreatic cancers would be greatly aided by methods that accurately predict the clinical course of patients considered for surgery. In this way, extensive surgery could be avoided in those unlikely to benefit, and these patients can instead be considered for supportive care or experimental therapies. We propose to improve the pre-operative staging of patients with localized pancreatic cancers using novel imaging tools. This project describes a clinical protocol to determine whether magnetic resonance imaging with lymph node targeted magnetic nanoparticles (LN-MRI) will accurately predict the presence of lymph node metastases in patients with pancreatic cancer. In addition, each patient will have state-of-the-art imaging measuring other tumor parameters such as tumor volume (using contrast enhanced multi-detector CT, CE-MDCT), microvascularity (using steady state vascular volume fraction measurements by MRI, VVF-MRI) and glycolysis (positron emission tomography PET-CT with 18FDG). Outcome data at 3 years post-surgery will be collected on all study participants. Tumor specimens obtained at the time of surgery will be analyzed using gene expression microarrays to identify candidate biomarkers for the development of novel imaging targets for pancreatic intraepithelial neoplasia (PanINs) and pancreatic ductal adenocarcinoma (PDAC). Patients treated on this protocol will be recruited from the practices of participating surgeons at all DF/HCC adult institutions and undergo centralized imaging at MGH. Patient data management will be facilitated by the DF/HCC Clinical Research Information System (CRIS) , the Specimen Tracking Program (STIP) and the Harvard Molecular Imaging Portal (MIPortal). This project will utilize all four of the Cores described in this SPORE application. In addition to establishing new criteria for disease progression and survival, the data collected in these studies will provide valuable information necessary to develop new generations of novel diagnostic and potentially therapeutic agents for pancreatic cancer treatment.
Project 2: Molecular Fluorescent Imaging for the Early Detection of Colorectal Neoplasia
Raju Kucherlapati, Ph.D.
Umar Mahmood, M.D., Ph.D.
Daniel Chung, M.D.
Andrew Chan, M.D., MPH
When colorectal cancer (CRC) is detected at an early stage, the 5-year survival exceeds 95%. Although colonoscopy is an excellent screening tool and considered the current gold standard, there is a miss rate for polyps as high as 22%. In particular, "flat lesions" in the colon are more commonly missed and may be more likely to contain areas of dysplasia. The problem is further exacerbated in ulcerative colitis (UC), in which dysplasia can develop in macroscopically normal-appearing mucosa. Thus, there is a need to develop novel technologies that would permit the early detection and in situ characterization of early neoplastic colonic lesions with high sensitivity and specificity. The overall goal of this proposal is to clinically translate novel imaging agents and devices we have developed to address this unmet need. Specifically, we will utilize a class of "smart" agents that increase their near infrared (NIR) fluorescence after selective interaction with a target protease (cathepsin) that is overexpressed in colonic adenomas and adenocarcinomas. Utilizing this technology, our preliminary studies have demonstrated superior endoscopic detection of preneoplastic lesions in mouse models of colon cancer when compared to conventional white light examinations. Moreover, we have observed comparable sensitivity and specificity of this technique for neoplasia that arises in the background of chronic UC. We seek to optimize and characterize this agent in new mouse models that spontaneously develop focal colonic adenomas and adenocarcinomas of known age and location. Cathepsin protease expression will be correlated with lesion progression in these mouse models as well as in a broad spectrum of ex vivo human neoplastic lesions.. The culmination of this effort will be a pilot clinical trial in which the feasibility and diagnostic performance of this novel technology will be evaluated in patients with sporadic invasive CRC, patients with polyposis syndromes, and patients with dysplasia in the setting of UC.
Project 3: Defining Optimal Doses of Vitamin D for Chemoprevention in Blacks
Edward Giovannucci, M.D., Sc.D.
Karen Emmons, Ph.D.
Gary Bennett, Ph.D.
Charles Fuchs, M.D., MPH
An increasing body of evidence suggests that vitamin D may reduce the risk of colorectal cancer and other cancers of the digestive system, acting through various proposed methods, including a reduction of pro-inflammatory factors. Blacks and African-Americans have virtually half the levels of 25(OH)D, the generally accepted best indicator of vitamin D status, compared to Whites. Differences in levels of plasma 25(OH)D could account for the greater incidence of colorectal cancer and other digestive system cancers in Blacks, particularly in the northeastern U.S., where solar UV-B intensity is low. The optimal dose of supplemental vitamin D needed to achieve adequate levels of plasma 25(OH)D is unknown, but it is likely to be much higher than currently recommended doses (400 IU/day). A critical need exists, particularly in Blacks, to define doses of oral vitamin D supplementation that will achieve a sufficient level of plasma 25(OH)D before vitamin D chemoprevention studies are initiated. We therefore propose to examine plasma 25(OH)D in an underserved population of Blacks living in the Boston area and establish a dose of vitamin D supplementation that will achieve a presumed protective level of plasma 25(OH)D levels in this cohort. First, following assessment of baseline plasma 25(OH)D levels, 320 participants will be randomized to placebo, 1000 IU, 2000 IU, or 4000 IU of vitamin D3 (cholecalciferol) per day in a 1:1:1:1 ratio. Then, after 3 months of supplementation, plasma levels of 25(OH)D will be determined. Secondly, we will examine if oral vitamin D supplementation reduces plasma levels of pro-inflammatory factors C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-aR2 (TNFaR2), and increases anti-inflammatory interleukin-10 (IL-10) levels. Thirdly, participants will be genotyped for relevant vitamin D pathway genes, and genotype prevalence will be compared to results from participants of the Nurses’ Health Study and Health Professionals Follow-up Study, two cohorts for which we are separately funded to examine the influence of these genotypes on the risk of colorectal adenoma and cancer. We will also compare baseline 25(OH)D levels with Whites of these cohort members living in a similar latitude and who provided blood in the same season. We will also assess rise of 25(OH)D according to 25(OH)D-24-hydroxylase (CYP24) genotypes, as genetic variation in CYP24 as been proposed to contribute to lower 25(OH) in blacks. Results of this trial will help direct future randomized trials of vitamin D in the prevention of colorectal neoplasia and other cancers of the digestive system. In fact, once we define the optimal dose of vitamin D, our interdisciplinary team with expertise in disparities will be well positioned to lead an intervention trial that has major implications for efforts to address colorectal neoplasia disparities nationally.
Project 4: The role of PI3-Kinase signaling pathway in defining sensitivity and resistance to anti-EGFR therapy in colorectal cancer
Lewis C. Cantley, Ph.D.
Jeffrey A. Engelman, M.D., Ph.D.
Jeffrey A. Meyerhardt, M.D., MPH
David P. Ryan, M.D.
Clinical studies indicate that a humanized monoclonal antibody against the Epidermal Growth Factor Receptor (EGFR), cetuximab, confers an objective tumor response in a subset of patients with Metastatic colorectal cancer. However, most patients do not respond to cetuximab and therefore receive limited or no benefit from this drug. Currently, there is no test that can predict if a cancer will respond to cetuximab. Compelling evidence supports the view that targeting the receptor tyrosine kinases (RTK), particularly those that engage the Phosphoinositide 3-Kinase (PI3K) signaling pathways, is a highly effective strategy for killing for cancers. Accordingly, the therapeutic response to anti-RTK therapy has been shown to be modulated dramatically by the mutational status of key signaling components in the PI3K pathway. The PI3K/Akt signaling pathway drives many epithelial cancers, and its importance in colorectal cancers is underscored by the presence of PIK3CA mutations (the gene encoding for PI3K) in 20-30% of these cancers. PI3K can be activated by multiple different signaling pathways including EGFR, and there is accumulating evidence that EGFR regulates PI3K via distinct mechanisms in cancers sensitive to anti-EGFR therapies. We propose to study the PI3K signaling pathway, biochemically and genetically, in colorectal cancers with the translational goal of identifying markers that will predict sensitivity to cetuximab. This will enable the selection of patients that are most likely to benefit from cetuximab. Additionally, these studies may also reveal additional therapeutic targets to enhance cetuximab sensitivity. Our specific aims include: (1) Identify the mechanisms for activating the PI3K/AKT pathway in colorectal cancers; (2) To determine the differences in PI3K regulation between cetuximab sensitive and resistant colorectal cancers in xenograft tumor models; (3) To determine if we can use the information discovered in the first two aims to identify markers that will predict which colorectal cancers will respond to cetuximab. Brief Summary: Cetuximab, a monoclonal antibody against the Epidermal Growth Factor Receptor, is commonly used to treat patients with metastatic colorectal cancer. However, not all patients benefit from this therapy and currently there are no reliable molecular markers to select patients that will benefit. The goal of this project is to find such markers that can be used to select patients most likely to respond to cetuximab.
Project 5: Targeted Therapy Resistance Mechanisms in Gastrointestinal Stromal Tumor (GIST)
Jonathan Fletcher, M.D.
George Demetri, M.D.
This proposal seeks to make therapeutic advances by characterizing targeted therapy resistance mechanisms in gastrointestinal stromal tumors (GISTs). Most GISTs express mutant, constitutively activated, KIT or PDGFRA oncoproteins. We have shown that these formerly untreatable cancers can be palliated in 80% of patients by oral single-agent therapy with the KIT/PDGFRA inhibitor, imatinib. Patients who develop resistance to imatinib can benefit from second-line therapy with sunitinib, which is an alternate KIT/PDGFRA inhibitor. Ultimately, however, most GIST patients will progress on both of these FDA approved kinase inhibitors. Therefore, the aims of the research proposed here are to characterize imatinib/sunitinib resistance mechanisms in GISTs, and then identify therapeutic strategies that can circumvent the resistance mechanisms. Notably, our preliminary studies show that GIST imatinib resistance mechanisms vary from patient to patient, and also between metastatic lesions in a given patient. We have shown that even a single progressing GIST metastasis contains subsets of cells whose imatinib resistance mechanism differs from those in other cells from the same tumor focus. In the present effort, by revealing the scope — and particularly the heterogeneity — of the imatinib/sunitinib resistance problem in GIST, we will provide the understanding needed to design more effective clinical strategies. At the same time, these studies will enable the development of biomarkers, assays and cell lines to enable preclinical validation of novel therapeutic strategies to circumvent imatinib/sunitinib resistance. The goal in these studies is to translate the understanding of imatinib/sunitinib resistance into improved medical therapy for GIST patients who are progressing on imatinib or sunitinib. Initially, we will evaluate HSP90 inhibition as a strategy to inhibit the varied gain-of-function KIT mutations that manifest, in each patient, at the point of clinical progression on imatinib and sunitinib. This will be accomplished through a phase I/II clinical trial of the HSP90 inhibitor, IPI-504, combined with imatinib, in patients showing progression of metastatic GIST on imatinib or sunitinib. Through these studies, we will translate the basic science proposed in this SPORE through to clinical application.
Core 1: Administration, Evaluation, and Planning
Charles S. Fuchs, M.D., MPH
GI SPORE Steering Committee
Ronald DePinho, M.D.
Monica Bertagnolli, M.D.
Raju Kucherlapati, Ph.D.
Robert Mayer, M.D.
Ramesh Shivdasani, M.D., Ph.D.
Kenneth Tanabe, M.D.
Thomas O'Brien, M.D., Advisor
This application represents the creation of a Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancer originating from the Gastrointestinal (GI) Malignancies Program of the Dana-Farber/Harvard Cancer Center (DF/HCC). The main goal of the DF/HCC SPORE in GI Cancer is the translation of biological and technological advances into improvements in prevention, diagnostics, predictors of outcome, and advances in the treatment of gastrointestinal malignancies. The DF/HCC SPORE in GI Cancer includes researchers from all Harvard-affiliated hospitals: the Dana-Farber Cancer Institute, the Brigham and Women's Hospital, the Massachusetts General Hospital, the Beth Israel Deaconess Medical Center, Children's Hospital of Boston, and Harvard School of Public Health.
Five major projects are proposed including:
- Improved pre-operative staging of pancreatic cancer
- Molecular fluorescent imaging for the early detection of colorectal neoplasms
- Defining optimal doses of vitamin D for chemoprevention in Blacks
- The role of PI3-Kinase signaling pathway in defining sensitivity and resistance to anti-EGFR therapy in colorectal cancer
- Targeted therapy resistance mechanisms in gastrointestinal stromal tumor
These projects will be integrated by the creation of four cores:
- Administration, Evaluation & Planning
- Tissue and Pathology
- Genomics and Bioinformatics
The SPORE application outlines a Developmental Projects Program that includes a plan or selection of new projects as well as nine pilot projects that could be supported. We also include a Career Development Award Program that outlines a mechanism for the identification and support of talented young investigators in GI cancer. The projects and cores proposed in this application are highly integrated with present DF/HCC core resources, and involve key collaborations with investigators from other existing SPOREs. The creation of this GI SPORE at DF/HCC will combine leading Harvard researchers in basic, translational, and clinical sciences into a program that has the focus and coordination required to produce meaningful advances in the diagnosis, treatment, and prevention of GI cancers.
Core 2: Tissue and Pathology Resources
Massimo Loda, M.D.
Mark Redston, M.D.
Jonathan Fletcher, M.D.
The pathologic analysis and molecular characterization of human tissue samples is a fundamental and integral requirement for all portions of this SPORE application, including systematic pathologic evaluation of micrometastatic disease, collection and analysis of human tissue samples for oncogenomics and gene discovery, evaluation of genetically engineered mouse neoplasms with moleclular imaging correlates, analysis of cancer signaling pathways, and characterization of tumoral heterogeneity in the emergence of chemoresistance. The core is highly integrated with each of the 5 major projects. We will work in close collaboration with the Project Investigators for three specific purposes: i) to provide tissue specimens, histology services and standardized systematic morphologic consultative expertise in the pathologic evaluation of human gastrointestinal neoplasms; ii) to provide infrastructure and technical expertise for a variety of molecular pathologic assays, including high-efficiency screening and validation of genomic and proteomic targets in human gastrointestinal tissue specimens; and iii) to evaluate and implement new cellular imaging and analysis technologies that will greatly facilitate these research goals in future. Centralization of these Core activities builds upon the established infrastructure and intellectual expertise of the investigators, and provides a highly valuable component to the analysis of biological resources developed and utilized by project investigators. In addition, the core has strong integrations with the Biostatistics Core and Genomic Data and Bioinformatics Cores (Cores 3 and 4), thereby leveraging the greatest benefits from these resources, and providing a wealth of opportunities for significant advances in understanding of gastrointestinal carcinogenesis.
Our specific aims are as follows:
- to provide tissue specimens, histologic processing services and pathologic analysis of human gastrointestinal neoplasms;
- to characterize human gastrointestinal neoplasms using molecular pathology tools;
Core 3: Biostatistics
Dianne Finkelstein, Ph.D.
Beow Yong Yeap, Sc.D.
Hui Zheng, Ph.D.
The Biostatistics Core facility provides the statistical and computational support for all GI cancer SPORE investigators. The Core will support consultation and collaboration on all aspects of study design, database development and quality control, and analysis and interpretation of data. The specific aims of this core facility are to:
- Provide ready access to statistical expertise and computing consultation to the GI cancer SPORE program.
- Provide biostatistical expertise for the planning, conduct, analysis and reporting of laboratory experiments, epidemiology studies and clinical trials.
- Advise and support SPORE investigators and their data collectors (technicians, nurses, data managers, etc.) in the areas of data form design, data collection, record abstraction, computerization, database designing and management, and data quality control.
- Provide a scientific computing facility suitable to meet the statistical analysis of GI cancer SPORE investigators, including technical.
Core 4: Genomics and Bioinformatics
Lynda Chin, M.D.
John Quackenbush, Ph.D.
Centralization of genomics-bioinformatics will provide the SPORE investigators with access to the state-of-the-art genomic capability and bioinformatics expertise, by leveraging existing institutional infrastructure such as Harvard/Partners Center for Genomics and Genetics and the Belfer Cancer Genomics Center. An important benefit derived from centralization comes from improved data storage and sharing, allowing for better integration of ideas and information across the various projects within the SPORE. Moreover, given the pace of discovery in areas of genomics and bioinformatics, it is difficult to predict where the field will stand even one year in advance. This invariant feature of change provides justification for a core with strong technical implementation capability and intellectual leadership throughout the granting period, so that the best technology will be brought to bear on the biological questions of the SPORE. This Core will provide several levels of support to the SPORE. First, it will offer bioinformatics consultation, in collaboration with Biostatistics, to assist all projects in the design and preliminary analyses of genomic studies, including copy number and expression profiling as well as gene re-sequencing. In this process, the Core will serve the central coordinating role in data receipt/storage for genomic assays in all projects, so that integrated analyses can be performed more easily. Second, the Core will leverage existing institutional infrastructure for established capabilities such as expression profiling and candidate gene re-sequencing. In addition, the Core will bring to the SPORE unique capability in high-resolution copy number profiling by array-CGH. Third, the Core will provide custom-designed tools and bioinformatics expertise for mining copy number data with integrated expression analyses.
CAREER DEVELOPMENT AWARDS PROGRAM
Monica Bertagnolli, MD
Robert Mayer, MD
Career Development Awards Committee
Raju Kucherlapati, Ph.D.
Andrew Warshaw, M.D.
Lowell Schnipper, M.D.
Michael Zinner, M.D.
Daniel Podolsky, M.D.
Bruce Chabner, M.D.
David Livingston, M.D.
JudyAnn Bigby, M.D.
Career development is a particularly important activity for translational research programs. By its very nature, translational research is multidisciplinary. Because of the depth of knowledge required of each individual discipline, our present educational structure seldom allows trainees to function in a multidisciplinary environment. This Career Development Awards Program is designed to provide the incentive and structure necessary to bring junior investigators into the multidisciplinary translational research arena. The key to success of this endeavor is the availability and willingness of mentors throughout DF/HCC to meet the challenges of translational research. This Program will be led by Dr. Monica Bertagnolli, Program Director of the Feinberg Surgical Oncology Fellowship at Brigham and Women’s Hospital and Co-PI of the DF/HCC SPORE, and Dr. Robert Mayer, Vice-Chair for Academic Affairs at the Dana-Farber Cancer Institute (DFCI) and Director of the DF/PCC Medical Oncology Fellowship. They are joined by a committee including leaders in the fields of cancer therapeutics (Drs. Chabner and Schnipper), GI cancer surgery (Drs. Warshaw and Zinner), tumor biology and genetics (Drs. Livingston, Kucherlapati, and Podolsky), cancer epidemiology (Dr. Willett), and women’s health and health care disparities (Dr. Bigby). These outstanding senior mentors, representing BWH, MGH, DFCI, and BIDMC, will direct a program that ensure optimal selection, support, and oversight of the GI SPORE Career Development Awards Program.