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Dana Farber/Harvard Cancer Center Renal Cancer SPORE
Overall Abstract The Dana Farber/Harvard Cancer Center (DF/HCC) Renal Cancer SPORE originates from the Renal Cancer Program of the newly configured DF/HCC and the Beth Israel Deaconess Medical Center. The DF/HCC Renal Cancer SPORE includes investigators from all the Harvard affiliated hospitals - the Beth Israel Deaconess Medical Center, the Dana-Farber Cancer Institute, the Massachusetts General Hospital, the Brigham and Women's Hospital, and the Children's Hospital Medical Center, as well as the Harvard School of Public Health. The overall goal of the DF/HCC Renal Cancer SPORE is the translation of biological and technological advances into clinically meaningful advances for patients with renal cancer. This will be accomplished through a highly intergrated program of major research projects, cores and developmental activities focusing on early detection, minimally invasive therapy, angiogenesis inhibition, immune enhancement and identification of molecular prognostic and treatment selection criteria. Five major projects are supported through this SPORE including: 1) Identification of markers for early detection and monitoring of high-risk RCC populations; 2) Inhibition of VHL-regulated growth factor pathways for treatment of RCC; 3) Combination radiofrequency ablation and antivascular/antiangiogenesis therapy for RCC; 4) Identification of molecular and immunologic correlates of RCC prognosis and responsiveness to therapy, and 5) Dendritic cell/tumor fusions in conjunction with IL-12 as novel immunotherapy for RCC. These projects are integrated by four cores: 1) Administration, Evaluation and Planning; 2) Biostatistics; 3) Tissue Acquisition, Pathology and Clinical Data, and 4) Monitoring.
Project 1 Project 1 aims to identify and validate a set of molecular markers and to create a model to be used for detection of renal cell carcinoma (RCC) early onset and/or progression in populations at high risk for the disease. The VHL gene is mutated in all VHL patients and inactivated in the majority of sporadic RCC. This molecular link between the biology of sporadic disease and the biology of the familial cancer syndrome supports the identification of molecular markers predicting RCC activity in both settings. We propose a series of laboratory-initiated population-based studies in order to identify and validate markers of RCC early onset and progression. In the first part of this project we will identify candidate RCC-specific and RCC-associated molecular markers by two parallel and complementary approaches: a) in vitro techniques of proteomic and genomic analysis of human renal carcinoma cell lines and b) ex vivo proteomic profiling of serum obtained from sporadic RCC patients before and after nephrectomy for localized disease. In the second set of studies we will validate an optimal set of markers by studying sporadic RCC patients at high risk for relapse and we will create a model for early onset RCC prediction. In addition we will validate optimal candidate markers in a well-characterized VHL population and we will create a parallel model for prediction of impending RCC onset and progression in VHL patients. Once developed, this model will be tested in an independent patient set.
Project 2 Project 2 will evaluate whether combined inhibition of VHL-regulated growth factor pathways will lead to effective treatment for RCC. Specifically, we will assess whether the use of PK1166, an inhibitor of the activation of epidermal growth factor receptor (EGFR), which is the receptor for TGFa, will augment the anti-tumor effects previously seen with PTK787/ZK 222584, the inhibitor of PDGF and VEGF receptor tyrosine kinases. In order to test this hypothesis we propose a series of in vitro and in vivo studies. Using a panel of RCC cell lines we will complete characterizing the expression of growth factors and RTKs relevant to PTK787/ZK 222584 and PKI166. Using an anti-proliferative assay we will assess the additive effects of PTK787/ZK 222584 and PK1166 in these cell lines. Finally, we will evaluate phosphorylation status of these receptors and downstream targets as possible surrogate markers for their inhibition. In vivo, we will create a transgenic model that allows for non-invasive imaging of tumors that develop following pVHL loss. and test these inhibitors in both prevention and treatment studies. In addition, we will evaluate the effects of these agents on the growth of other tumors driven by loss of pVHL, including RCC tumors. In this setting we will evaluate KDR, PDGFR, and EGFR inhibition, using both molecular and radiographic surrogate markers. Finally we will use this preclinical data to support and design a Phase I clinical trial of KDR, PDGFR, and EGFR inhibition for treatment of patients with advanced RCC. In this study we will evaluate both pharmacokinetic and pharmacodynamic endpoints of KDR, PDGFR, and EGFR inhibition.
Project 3 In Project 3, we propose to test the hypothesis that: the inherent biophysical barriers to radiofrequency (RF) heating and resultant ablation in RCC can be overcome with modulation of tumor vascularity and microperfusion using antivascular/antiangiogenic therapies. We will accomplish the following Specific Aims to test this hypothesis and further develop and systematically translate this strategy for clinical use. 1) Test the activity of antivascular/antiangiogenic agents (including arsenic trioxide and the VEGF signaling inhibitor PTK787) in animal models of renal cancer (RCC in nude rats, and intrarenal rabbit VX2). 2) Characterize, optimize, and compare RF ablation combined with study agents in animal models. 3) Test the clinical efficacy of optimized combined RF and antivascular/antiangiogenic therapy in RCC patients (both with Stage IV disease undergoing debulking nephrectomy [trial 1] and inoperable patients undergoing RF [trial 2]) in randomized trials comparing RF alone to combination therapy. Tumor perfusion, blood angiogenic profiles, and changes in tumor pathology and microvascular density will be related to RF heating and tumor coagulation.
Project 4 In Project 4, we propose to serially assess patient TCR? chain expression dendritic cell phenotype, plasma VEGF levels, and circulating endothelial progenitors to determine the effects of nephrectomy on these parameters and the basis for the survival advantage conferred by the surgery. In addition, we propose to analyze nephrectomy specimens for patterns of gene expression and for levels of activity of various oncogenic signal transduction pathways associated with susceptibility to apoptosis in an effort to identify molecular correlates of disease-free and overall survival in patients undergoing curative surgery. We also propose to carry out similar microarray and signal transduction studies on tumor tissue from patients with advanced disease in order to identify molecular correlates of response to IL-2, the rapamycin analogue CCI-779, and other novel therapies undergoing clinical evaluation at DF/HCC institutions. The purpose of these correlative studies is to develop models that will serve to target specific therapies to individual patients based on the molecular characteristics of their tumor tissue in order to increase the likelihood of response and to avoid unnecessary exposure to toxic ineffective therapies.
Project 5 In Project 5, we propose to investigate the therapeutic efficacy of a Dendritic Cell Tumor Cell vaccine in combination with IL-12. Our hypothesis is that we can augment the immunologic and clinical effect of the vaccine by the 1) use of mature autologous DC as a fusion partner; 2) treatment of patients following debulking nephrectomy who have not received prior therapy for metastatic disease; and 3) combining the vaccine with recombinant human IL-12 (rhIL-12). In our first aim, we intend to study the feasibility, toxicity, and clinical impact of fusion cell vaccination generated with mature DC and administered with or without rhIL-12. Secondly, we will examine impact of vaccination on tumor specific immunity as determined by intracellular IFN expression and binding to tetramers bearing tumor peptides. Thirdly, we intend to correlate immunologic response following vaccination with measures of patient cellular immune function and phenotypic characteristics of the vaccine preparation.
Core 1 The purpose of the Administration, Evaluation and Planning Core is to assure the coordination of the Dana Farber/Harvard Cancer Center (DF/HCC) Renal Cancer SPORE components and to provide oversight and leadership of the scientific, administrative and fiscal aspects of the SPORE. We will take advantage of the Beth Israel Deaconess Medical Center's large and efficient administrative staff and its central Research Administration office. We will also work closely with the administrative office of the DF/HCC and work to integrate our Administrative activities with that of central Cancer Center. Within the DF/HCC Renal Cancer SPORE, there are several layers of oversight and evaluation. Dr. Atkins, as SPORE Director, will monitor the progress of the Projects and Cores, and oversee the Career Development and Developmental Projects Programs and oversee all other proposed activities. Our Governance Committee, made up of senior members of the DF/HCC Renal Cancer Program and patient advocates, will meet monthly to provide immediate decision-making. We have a strong Internal Advisory Board, comprised of prominent members of the Harvard Medical School community, and representing the participating institutions and major cancer research disciplines. Our External Advisory Board will meet as a group in New England area during years two and four of the five-year funding cycle and as individuals at DF/HCC institutions during the other years. The responsibilities of this core are to: 1) Monitor research progress and plan for the future; 2) Foster collaborative research within the SPORE and between SPOREs (both within the DF/HCC and without); 3) Integrate the Renal SPORE into the DF/HCC structure; 4) Provide necessary resources and fiscal oversight; 5) Promote rapid dissemination of significant research findings; 6) Promote participation of minorities in renal cancer research and treatment programs within the SPORE and the DF/HCC; 7) Encourage new investigator participation in renal cancer research.
Core 2 The Biostatistics Core supports all research activities within the SPORE, including Projects, Developmental Projects and other Cores. The Core provides collaboration and consultation on study design, data management/quality control, and data analysis and interpretation to SPORE researchers. Specific aims are to: 1) provide biostatistical collaboration for SPORE Projects, Developmental Projects, and Cores; 2) provide or recommend supporting computational infrastructure and 3) provide consulting and statistical mentoring to SPORE researchers.
CORE 3 The Tissue Acquisition, Pathology, and Clinical Data (TAPCD) Core has several purposes, the first and foremost of which is to maintain a tissue, blood, and urine repository for the various investigators participating in this SPORE. This task involves the collection, freezing and storage of renal cell carcinoma and paired normal kidney tissue as well as blood and urine from RCC patients. This Core serves as a central facility, coordinating the activities of the pathologists and Tissue Banks at all of the DF/HCC institutions. This Core is responsible for the dissection and provision of tumor tissue for gene microarray studies and for the fixation and sectioning of tissue for routine histology, immunohistochemistry, in situ hybridization, computer-assisted image analysis, laser capture microdissection and for the generation and interrogation of tissue microarrays as required by SPORE investigators. The TAPCD Core is also responsible for the maintenance of a clinical database on all consenting RCC patients. This database, as well as the specimen tracking and secured data management systems, provide an informatics link throughout the participating DF/HCC hospitals which allows for the sharing of clinical outcome data among SPORE investigators. The TAPCD collaborates with the Biostatistics Core in data analysis and auditing. This arrangement facilitates the analysis of clinical data from RCC patients enrolled in clinical trials at the various DF/HCC institutions and the correlation of clinical data with the various laboratory assays being carried out as part of individual SPORE projects.
Core 4 The Monitoring Core (MC) serves the translational needs of all 5 of the projects. It consists of three components: an Angiogenesis Monitoring Component (AMC), an Immunologic Monitoring Component (IMC) and an Imaging Component (IC). Vikas P. Sukhatme, M.D., Ph.D., as Director of the MC provides overall oversight and James Mier, M.D. and Neil Rofsky, M.D. are the Co-Directors. The MC was created with multiple components in order to provide maximal flexibility. It facilitates the translational goals of the SPORE. The AMC performs angiogenic cytokine measurements, endothelial proliferation, mitrigel tube formation and circulating endothelial cell assays. The IMC performs the PBMC isolation and flow cytometry studies to determine the array of adhesion molecules and chemokin receptors expressed. Other assays such as marker studies, gene expression profiling tests, etc. are being carried out in support of the Projects and the various approved Development Project. The IC is responsible for all imaging monitoring of patients participating in the clinical trials with MR (including arterial spin label MR) and PET, to maximize detection of sublte changes in tumor characteristics. The Core is a vibrant and robust entity that serves the translational needs of the SPORE in a flexible and imaginative manner.
Career Development Awards
Developmental Project Awards
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