Dana Farber/Harvard Cancer Center Kidney Cancer SPORE

Overall Abstract

The Dana Farber/Harvard Cancer Center (DF/HCC) Kidney Cancer SPORE originates from the DF/HCC Kidney Cancer Program 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 Kidney 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 integrated 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) Clinical Correlations of WTX Inactivation in Wilms Tumor; 3) Acquired Resistance to VEGF Receptor Blockade: Underlying Mechanism and Therapeutic Options 4) Targeting the PI3-Kinase/ Akt Pathway in RCC: Mechanism of Action and Opportunities for Rational Combination Therapy , and 5) Dendritic cell/tumor fusions in conjunction with IL-12 as novel immunotherapy for RCC. These projects are integrated by three cores: 1) Administration, Evaluation and Planning; 2) Biostatistics; 3) Tissue Acquisition, Pathology and Clinical Data.

Project 1: Identification of Markers for Early Detection and Monitoring of Populations at High Risk for Renal Cell Cancer

Project Leaders:
Othon Iliopoulos, MD
Steven Skates, MD
Douglas Dahl, MD (MGH)

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 B: Clinical Correlations of WTX Inactivation in Wilms Tumor

Project Leaders:
Daniel Haber, MD
Miguel Rivera, MD (MGH)

Investigators in Project B, as part of a SPORE supported Developmental Project, identified and cloned a novel tumor suppressor gene located on the X chromosome, WTX, which is inactivated in 30% of sporadic Wilms tumor cases. Remarkably, tumors with WTX mutations do not contain mutations of WT1 or b-catenin and thus may represent a distinct subset of Wilms tumors. In this Project the investigators initially propose to build on this discovery to define clinical and pathologic correlates of WTX inactivation and to test the potential application of WTX mutations as markers of prognosis in patients with Wilms tumors. Translational experiments will involve two unique clinical resources, an unselected cohort of 50 paraffin-embedded Wilms tumors from CHB and a second cohort of 100 frozen Wilms tumors obtained through a collaboration with the Children’s Oncology Group that is enriched for patients exhibiting relapse to standard therapy. Both cohorts are linked to clinical data. Prognostic studies will be enhanced by the development of monoclonal antibody recognizing WTX that can be used for immunohistochemical staining of paraffin specimens including a Tissue Microarray incorporating the CHB specimens being created in collaboration with Core 3. Subsequent elegant experiments are aimed at determining the molecular relationship between WTX loss and Wilms tumor development with the goal of identifying important tumorigenic pathways and WTX associated proteins that could serve as additional diagnostic and prognostic biomarkers. These experiments will be aided by the recent creation of an animal model of Wilms tumor involving conditional loss of WTX. Proteins discovered to be critical to Wilms tumor development in these experiments and validated as important the conditional WTX knockout mouse will be studied in the two tissue Cohorts described above to determine if they also have prognostic significance. These highly translational experiments will provide unique insights into the pathogenesis of Wilms tumor and will not only determine the prognostic significance of various molecular alterations, but will also likely identify potential targets for future therapeutic intervention in this important pediatric kidney cancer.

Project A. Acquired Resistance to VEGF Receptor Blockade: Underlying Mechanisms and Therapeutic Options

Project Leaders:
S. Nahum Goldberg, MD
James Mier, MD
Michael B. Atkins, MD (BIDMC)

Project A involves an ambitious effort focused on perhaps the most critical current issue in the treatment of kidney cancer; namely the identification of the underlying mechanism for acquired resistance to VEGF receptor blockade and the development of therapeutic strategies to circumvent it. The recent FDA approval of sorafenib and sunitinib, agents whose primary mode of action is the inhibition of VEGF receptor-2 signaling and the disruption of tumor angiogenesis, has had a profound impact on the management of patients with metastatic RCC. However, despite the ability of these agents to induce tumor responses in up to 40% of patients and prolong progression free survival, the majority of patients will develop treatment resistance within 6-12 months of initiating therapy. While tumor responses have been reported with sunitinib following resistance to bevacizumab therapy, and everolimus has been shown to prolong PFS by 2 months relative to placebo, at present there is no generally accepted effective therapy for patients exhibiting resistance to sunitinib therapy. Using RCC xenograft models and specialized perfusion imaging, investigators were able to show that acquired resistance was mediated by “angiogenic escape mechanisms” rather than mutational or other irreversible changes within the tumor. Subsequent experiments involving cDNA microarray, Western blots and phospoRTK assays on tumor tissue from collected from various xenograft models and measurements of circulating cytokines in patients led to the identification of several candidate genes and proteins with known roles in tumor progression and/or angiogenesis whose expression in tumors is altered with the development of resistance to sunitinib/sorafenib. Most notable were Cox2, angiopoietin 2, c-met, sphingosine kinase and CXCR4 all of which are amenable to pharmacologic inhibition. Armed with this information, this team of investigators has proposed a series of experiments aimed at further validating these findings in patients with kidney cancer and testing in both murine models and in a series of translational clinical trials approaches for overcoming resistance. Specific Aims include:1) Validation of already identified resistance-associated pathways in patient plasma and RCC tissue and assessment of the utility of ASL perfusion MRI as a surrogate marker for tissue blood flow and viability and potential predictive marker for response and impending relapse in patients receiving sunitinib; 2) Determination of the potential utility of pharmacologic inhibitors of various resistance pathways to delay or prevent resistance in xenograft models involving RCC cell lines and 3) subsequently in minimally passaged RCC explants implanted either subcutaneously or orthotopically under the renal capsule and 4) the design and execution of clinical trials combining sunitinib with other therapies, including the angiopoeitin inhibitor AMG386, selected to prevent escape from VEGF receptor blockade. The proposed experiments move seamlessly from the mouse to the human and from laboratory to clinic and back and draw upon many of the strengths and resources that the SPORE has developed over the past 5 years. They represent translational research at its utmost. Furthermore, in addition to identifying mechanisms by which RCCs develop resistance to VEGFR blockade and testing strategies for circumventing this problem, the research in this project will likely identify fundamental concepts related to tumor angiogenesis and establish tools for performing similar research in other cancers exhibiting initial sensitivity to anti-angiogenic therapy.

Project C. Targeting the PI3-Kinase/ Akt Pathway in RCC: Mechanism of Action and Opportunities for Rational Combination Therapy

Project Leaders:
James Mier, MD
David McDermott, MD (BIDMC)

Recent clinical investigations have established therapeutic benefit for inhibitors of mTOR in patients with RCC. Benefit has been most firmly established in patients with poor clinical prognostic features and in tumors with predominantly non-clear cell histology suggesting that mTOR inhibitors might work as true tumor targeted agents and produce their antitumor effects, at least in part, through mechanisms distinct from their impact on HIF and angiogenesis. This observation has prompted Project C investigators to look upstream of mTOR and attempt to develop inhibitors of the PI3-K pathway as treatment for RCC. PI3-K inhibitors have numerous theoretical advantages over conventional mTOR inhibitors, not the least of which is the tendency of the latter to activate PI3-K through a feedback loop involving the mTOR substrate p70rsk. These investigators studied the effects of the dual PI3-K/mTOR inhibitor BEZ-235 on intracellular signaling and tumor growth and observed single agent antitumor activity in 786-0 xenografts apparently superior to mTOR inhibition alone. They have thus proposed to extend these studies by comparing the antitumor activities of BEZ-235 with those of the mTOR inhibitor rapamycin in xenografts generated from RCC short term cultures (STCs) that have not been propagated as monolayer cultures and therefore may be more representative of RCC in situ. These studies will also compare the effects of treatment with BEZ-235 in paired tumor cell lines that differ only with respect to VHL status or constitutive Akt activity, both of which are known to affect the response to mTOR inhibitors. One of our proposed Aims involves a Phase II trial with BEZ-235 in RCC patients. This trial will include a search for predictive biomarkers and a comprehensive pharmacodynamic analysis of the drug’s effect on Akt, FOXO3a, p53 and mTOR signaling in tumor tissue. BEZ-235 induces growth arrest in RCC cell lines and its antiproliferative effects can be enhanced by the concurrent inhibition of other kinases associated with cell survival (MEK, GSK-3β). One of the objectives of this application is to determine if the in vitro synergy between BEZ-235 and inhibitors of MEK or GSK-3β can be duplicated in vivo in RCC xenograft models. These proposed studies will determine if BEZ-235 has pro-angiogenic effects similar to that reported for the PI3-K inhibitor Ly294002 and whether this effect can be blocked with the concurrent administration of the VEGF receptor antagonist sunitinib. Finally, they eventually propose to initiate a clinical trial of BEZ-235 in combination with the drug that showed the greatest potential as an adjunct to BEZ-235 in the aforementioned xenograft studies. Collectively, these studies will assess the antitumor activity of BEZ-235 both as a single agent and in combination with other drugs as well as define the patient population most likely to respond this novel agent.

Project 5: Dendritic Cell/Tumor Fusions in Conjunction with IL-12 as a Novel Immunotherapy for Renal Cancer

Project Leaders:
David Avigan, MD
David F. McDermott, MD (BIDMC)
Donald Kufe, MD (DFCI)

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: Administration, Evaluation and Planning Core

Core Directors:
Michael B. Atkins, MD (BIDMC)
Othon Iliopoulos, MD (MGH)

Administrator:
Aline D. Nandelstadt (BIDMC)

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: Biostatistics

Core Director:
Meredith Regan, ScD DFCI

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: Tissue Acquisition, Pathology and Clinical Data

Core Director:
Sabina Signoretti, MD BWH

Associate Directors:
David McDermott, MD BIDMC
William Oh, MD DFCI

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.

SPORE Career Development AwaRD REcipIENTS

PI- SPORE funding year(s)	Institution/ Mentor	Project Title
Billy Kim, M.D.- 1,2	DFCI/ Kaelin	Determining the Role of HIF1 and HIF2 in VHL associated tumorigenesis
Pankaj Seth, Ph.D.- 1,2	BIDMC/ Sukhatme	Gene Profiling of Renal Cancer Cell Endothelium
Won Han, M.D. 3	BWH/ Bonventre	Human Kidney Cancer Injury Molecule-1 in RCC
Robert Ross, M.D. 3*, 4, 5	MGH-DFCI/ Weisleder	Evaluation of the response and resistance of kidney cancer to VEGF and/or mTor-pathway inhibitor with MION-enhanced MRI
Daniel Cho, M.D. 4, 5	BIDMC/ Atkins- Mier	Enhancing the efficacy of sorafenib and sunitinib in the treatment of advanced RCC by concurrent inhibition of additional kinases
Lianjie Li, Ph.D 4, 5	DFCI/ Kaelin	The biochemichal analysis of the differential risk of RCC associated with Type 2A and Type 2B vHL disease
Kevin Courtney, M.D, Ph.D Extension#	DFCI/BIDMC Cantley	Evaluation of phosphoinositide 3-kinase (PI3K) and CXCR4 activation in renal cell carcinoma

Developmental Projects funded from 2003 – present

PI	Institution	Project Title
Year 1 (2003-04)
Iliopoulos, Othon	MGH	Functional Analysis of the BHD Tumor-Suppressor Protein
Libermann, Towia Jones, Jon	BIDMC	Genetic Classification of Clear Cell RCC
Michaelson, Dror	MGH	The Role of Bone-Targeted Therapy with Zoledronic Acid in Metastatic RCC
Panka, David Mier, James	BIDMC	Potential synergy between sorafenib and AKT inhibitors against RCC*
Year 2 (2004-05)
Haber, Dan Rivera, Miguel	MGH	Identification of Novel Genes in Sporadic Wilms Tumor* #
Artavonis-Tsakonas, Spyros	MGH	A Genetic Model for Target identification in VHL-HIF Signaling
Signoretti, Sabina Moch, Holger	BWH	Molecular Analysis of RCC Using Single Nucleotide Polymorphisms (SNP) Arrays#
Alper, Seth	BIDMC	Role of Carbonic Anhydrase IX in Proliferation and Metastasis of RCC
Dabora, Sandra	BWH	A Phase II Multi-Center Study of Rapamycin for Treating Kidney Angiomyolipomas
Olumi, Aria	BIDMC	Pro-apoptotic TRAIL-directed Therapies for the Treatment of Advanced RCC
Ross, Robert Weissleder, Ralph	DFCI MGH	Comparison of pathologic microvessel density and monocrystalline iron oxide nanoparticle-enhanced MRI in evaluationg tumor vascularity in pts undergoing Nx for RCC
Year 3 (2005-06)
Alsop, David Rofsky, Neil	BIDMC	ASL MRI Blood Flow for Monitoring Response to Anti-angiogenic Therapy*
Avigan, David Rosenblatt, Jacalyn	BIDMC	Phenotypic and Functional Characteristics of Human T cells Stimulated ex vivo with DC/tumor Fusion Cells and Expanded with CD3, CD28 Ab*
Libermann, Towia Zerbini, Luiz	BIDMC	The Tyrosine Kinase Receptor Axl, a Novel Therapeutic Target in RCC#
Seth, Pankaj	BIDMC	Role of Angiopoietin like 4 (ANGPTL4) as a VEGF Independent Pro-angiogenesis Factor
Year 4 (2006-07)
Marasco, Wayne Wu, Anna	DFCI UCLA	PET Evaluation of RCC Metastases using High-affinity Human Anti-CAIX Monoclonal Antibody with Optimized Pharmacokinetic Properties
Signoretti, Sabina	BWH	Development of Mouse Orthotopic Xenografts of Human RCC# *
Frank, David	DFCI	STAT-Mediated Modulation of HIF Signaling: Molecular Strategies for the Treatment of RCC#
Lenahan (Zarwan), Corine Rosenblatt, Jacalyn Avigan, David	BIDMC	The effect of Anti-angiogenic Drugs on Tumor Mediated Immune Suppression and Response to the DC/RCC Fusion Vaccine*
Iliopoulos, Othon	MGH	A Drosophila Genetic Screen for Target Identification in VHL-HIF Signaling
Goldberg, Nahum Mier, James	BIDMC	Mechanism of RCC Resistance to VEGFR Blockade with Sorafenib*
Year 5 (2007-08)
Panka, David Cho, Daniel Mier, James	BIDMC	Potential Synergy Between Triterpenoids and NADPH Oxidase Inhibitors in the Treatment of RCC
Sukhatme, Vikas	BIDMC	LDH-A Inhibitors for the Treatment of Fumarate Hydratase (FH) Associated Hereditary Leiomyomatosis and RCC (HLRCC)
Zimmer, Michael	MGH	Identification of Novel Proteins that inhibit HIF mRNA Translation
Libermann, Towia Sukhatme, Vikas	BIDMC	Identification of new drugs for treatment of RCC patients using Gene Signatures and the Connectivity Map Database
Extension Year (2008-09)
Cho, Eunyoung Choueiri, Toni	HSPH DFCI	Analgesic Use and the Risk of RCC
Bhatt, Rupal	BIDMC	Role of defects in IFNg signaling in escape from VEGFR inhibition

http://www.dfhcc.harvard.edu/spores/renal/

Back to Massachusetts SPOREs

^ Back to Top