SPOREs
Kidney
Projects
Projects
Project 1: Clinical Correlations of WTX Inactivation in Wilms Tumor
Leaders: Daniel Haber, MD, PhD (MGH) and Miguel Rivera, MD (MGH)
Project 1 involves the interrogation of the clinical significance and biologic nature of a newly discovered tumor suppressor gene, WTX, whose expression is lost in 30% of patients with Wilms tumor. The Project has its origins in a Developmental Project in year 2 and 3 of the SPORE whose results were recently published in Science. In this Project, Drs. Daniel Haber, a renowned geneticist, Wilms tumor scientist, Leader of the DF/HCC Cancer Genetics Program, and the Director of the MGH Cancer Center; Miguel Rivera, a young pediatric pathologist; and Allison Friedman, a pediatric oncologist with an interest in Wilms tumors, link forces to study the prognostic and clinical significance of WTX loss in two cohorts of Wilms tumor patients—one obtained from Children's Hospital and the other from a collaboration with the Children's Oncology Group. In addition, they plan elegant experiments using a recently created conditional WTX knockout mouse to unravel the function of WTX and identify potential mediators of this function in WTX WT tumors that can then be used to further interrogate tissue specimens from the previously mentioned cohorts.
Project 2: Treatment of VHL-/- clear cell renal carcinoma with HIF2a siRNA.
Leaders: William Kaelin, MD (DFCI); Sabina Signoretti, MD (BWH); and Michael Atkins, MD (BIDMC)
Project 2 represents a permutation on research efforts from the initial SPORE, namely the targeting of key factors in clear cell renal cancer upregulated by the loss of pVHL. This initial work involving both genotype-phenotype correlations and preclinical models suggested that downregulation of HIF2a was both necessary and sufficient for pVHL to suppress renal carcinoma growth and thus validated HIF2a as a potential therapeutic target in this disease. Unfortunately, transcription factors such as HIF2a are historically difficult to inhibit with drug-like small organic molecules. As an alternative, these investigators have proposed to investigate the potential to inhibit HIF2a using siRNA. Recent studies suggest that siRNA can be effectively delivered in vivo when encapsulated in nanoparticles targeted to the transferrin receptor. In specific aims 1 and 2 we will test whether this technology can be used to downregulate HIF2a in VHL-/- renal carcinoma lines grown orthotopically in nude mice and we will attempt to develop pharmacodynamic markers suitable for preclinical and clinical studies. In Aim 3 we will measure HIF2a and transferrin receptor levels in human kidney cancer samples to assess their relationship to each other and VHL loss, the influence of acquired resistance to VEGFR blockade on their expression, as well as their prognostic significance and ability to predict benefit to standard therapies. Finally, in Aim 4 we will conduct a “first in man” Phase I/IB trial of HIF2a siRNA nanoparticles for the treatment of patients with RCC. Initial components of this trial will establish the toxicity and MTD of this approach. A subsequent expansion phase will be performed in a selected patient population informed by experiments in Aims 2 and 3 and will include correlative pharmacodynamic endpoints modeled after those developed in Aim 2. Taken together, this work, which clearly goes from bench-to-bedside, should establish the safety and therapeutic potential for targeting this critical etiologic factor in VHL -/- clear cell RCC using transferrin decorated nanoparticle containing siRNA technology and lay the groundwork for future clinical development of this potentially exciring approach in patients with this disease.
Project 3: Acquired resistance to VEGF receptor blockade: Underlying mechanism and therapeutic options.
Leaders: Nahum Goldberg, MD (BIDMC); James Mier, MD (BIDMC); and Michael Atkins, MD (BIDMC)
Project 3 brings together a multidisciplinary team of scientists and clinical investigators with complementary skills in an effort to address perhaps the most critical clinical question facing the treatment of patients with kidney cancer, namely determining the mechanism of disease resistance to VEGFR inhibitor therapy and a means of delaying or preventing it. Led by Drs. Nahum Goldberg, James Mier, and Michael Atkins, this project has emerged from Year 2 and Year 4 Developmental Projects to Drs. Alsop and Goldberg/Mier, respectively, work within existing Projects 2 and 3 and Core 4, and a recent NCCN grant to Dr. Mier. These investigators have established murine xenograft models that exhibit initial response followed by resistance to VEGFR antagonists similar to what is observed in human RCC. In these models they have established the mechanism of resistance to be angiogenic escape; and have identified several molecular factors that might contribute to restoration of angiogenesis in the face of continued VEGFR blockade. The goals of this project are to use paired patient RCC biopsy material, serial plasma collections and serial ASL perfusion imaging to validate these xenograft findings in patients with RCC and to use a variety of increasingly representative animal models and finally clinical trials to test inhibitors of purported resistance mechanisms.
Project 4: Targeting the PI3-Kinase/AKT pathway in RCC: Mechanism of action and opportunities for rational combination therapy.
Leaders: James Mier, MD (BIDMC) and David McDermott, MD (BIDMC)
Project 4 combines the efforts of Drs. James Mier; David McDermott, Chair of the DF/HCC Kidney Cancer Clinical Research Subcommittee; and Daniel Cho to explore the clinical utility of dual inhibition of the PI3K-mTOR pathway relative to mTOR inhibition alone. This project is based on preliminary studies performed within a Developmental Project to Dr. Mier and a Career Development Award to Dr. Cho showing that the dual PI3K/mTOR inhibitor Bez-235 exhibits preferential killing of RCC in a murine xenograft model relative to the mTOR inhibitor rapamycin. They have identified potential biological mechanisms behind this apparent therapeutic benefit and plan to explore this further in a series of xenograft models and then in a biomarker driven phase II trial of Bez-235. Furthermore they have developed hypotheses regarding how the PI3K/AKT/mTOR pathway could be better inhibited via combination targeted therapy approaches and will use the data from their preclinical experiments and phase II trial to rationally develop and test combination treatment strategies that involve optimal inhibition of PI3/AKT/mTOR and any consequent or persistent pro-survival pathways. This investigation of combinations will likely form the basis of future phase I/II clinical trials involving the most promising combinations in patients with advanced RCC.
Project 5: Adoptive Immunotherapy for Renal Carcinoma Using Dendritic Cell/Tumor Fusions
Leaders: David Avigan, MD (BIDMC) and Donald Kufe, MD (DFCI)
Project 5 represents an extension of previous Project 5 within the initial SPORE. In the original project, investigators conducted clinical trials in which DC/RCC (dendritic cell/renal cell carcinoma) fusions induced anti-tumor immunity in a majority of patients but clinical responses were observed in only a handful of patients. These findings implicated the now well characterized immunosuppressive milieu by which tumor cells evade host immunity as a factor limiting vaccine efficacy. Key components of tumor induced immune suppression relevant to kidney cancer are the tendency of vaccines to generate regulatory T cells and the expression by the tumor of immune inhibitory molecules such as B7H1 (PD-L1). In particular, expression of PD-L1 by kidney tumor cells has been shown to be associated with poor prognosis. Project 5 investigators have developed a series of strategies for overcoming these inhibitory influences that prevent in vivo generation of effective anti-tumor immunity. One approach is the stimulation of tumor reactive cells ex vivo for use as adoptive immunotherapy. They have shown that stimulation of autologous T cells with DC/RCC fusions followed by CD3/CD28 antibody coated beads generates an expanded pool of potent, tumor reactive T cells for adoptive immunotherapy while limiting the influence of regulatory T cells. In addition, they have also shown that exposure to sunitinib in vivo depletes regulatory T cell numbers and suppresses PDL1 expression on tumor cells. These observations lay the groundwork for a series of exciting translational studies. They initially propose a “window of opportunity” Phase I trial involving DC/RCC fusion vaccine in combination with adoptive immunotherapy using escalating doses of DC/RCC educated, CD3/CD28 expanded T cells. The goal of the dose escalation and expansion phase of this trial will be to determine the safety, maximum tolerated dose and immunologic and clinical activity of this treatment approach. Subsequent to this, they propose to build on their preliminary data establishing several potentially beneficial effects of sunitinib on immune function by incorporating this agent into their clinical trial design. Specifically they propose to perform a Phase II trial of sunitinib therapy supplemented by CD/RCC fusion vaccine and adoptive immunotherapy with sunitinib exposed, DC/RCC fusion educated, anti-CD3/CD28 antibody expanded T cells. While the primary endpoint of this combination study will be comparison of tumor specific immunity with or without sunitinib, the ultimate goal is to develop a treatment approach that combines antiangiogenic therapy with sunitinib and sophisticated immunotherapy that can induce higher quality antitumor responses that can be maintained off of sunitinib therapy.
