Full Projects

Current SPORE projects are described below. The grant also funds four Career Enhancement Projects and five Development Research Projects. Five previous CEPs and four previous DRPs have been funded since the SPORE grant was awarded to DF/HCC. Annual requests for proposals are issued for additional CEP & DRPs, usually in the spring. 

Small Molecule HIFα Inhibitors for Treatment of Renal Cell Carcinoma

Project Summary

There are several forms of kidney cancer. The most common form is referred to as clear cell renal carcinoma. The initiating event in most clear cell renal carcinomas is the inactivation of a protein called the VHL tumor suppressor protein. Loss of the VHL protein leads to increased activity of several proteins that belong to the HIF protein family. We showed before that increased activity of one of the HIFs, called HIF2, promotes the growth of clear cell renal carcinomas. HIF2 is a so-called transcription factor and controls the activity of over 100 genes in clear cell renal carcinomas, including the gene that governs the production of vascular endothelial growth factor (VEGF). It has been well established that drugs that block VEGF are helpful for treating clear cell renal carcinomas but they are not curative. We believe that targeting HIF2 itself will be far more effective than simply blocking one of the many genes it activates (such as VEGF). We are working closely with Peloton Therapeutics, which has developed a drug that blocks HIF2 function in laboratory models. In aim 1 and 2 we will conduct a clinical trial to determine if this drug can, indeed, block HIF2 activity in man and, if so, whether this leads to clinical benefit for patients with clear cell renal carcinoma. In aim 2 we will also develop new ways of monitoring HIF2 activity in clinical samples. In aim 3 we will ask whether blocking HIF2 function can, as expected, enhance the antitumor effects of VEGF inhibitors against clear cell renal carcinomas in mouse models of this disease. We recently made the unanticipated discovery that thalidomide, which has become an important drug for the treatment of a cancer called multiple myeloma, works by earmarking two transcription factors (called IKZF1 and IKZF3) for destruction. This gives us hope that we could, in time, discover drugs that likewise mark the HIF2 transcription factor for destruction. We will attempt to identify such drugs in aim 4. If successful, such drugs should markedly enhance the actions of drugs, such as the Peloton drug, that block HIF2 function. In addition, combining two drugs that inhibit HIF2 in two different ways should decrease the emergence of clear cell renal carcinoma cells that are resistant to therapy (since they would now have to circumvent two forms of attack on the same target).

HDM2 as a Therapeutic Target in RCC

Project Investigators

Project Summary

Treatment with any of several VEGF receptor-targeted tyrosine kinase inhibitors (TKIs) results in prolonged disease stability or even regression in the majority of patients with metastatic renal cell carcinoma (RCC). This antitumor effect is generally transient and incomplete, however, due to the rapid development of drug resistance. This project emerged from our earlier work in RCC xenografts on the mechanisms of acquired TKI resistance. We observed that p53 activation was essential for a robust response to sunitinib. We also noted that the expression of p53-dependent genes was transient and down modulated with the onset of TKI resistance. Finally, we demonstrated that the concurrent administration of a drug that blocks HDM2- dependent p53 ubiquitylation and degradation prevented the development of TKI resistance. At least two potential mechanisms for this effect were documented, one of which involved in the induction of the E3 ligase Fbw7 and the degradation of the oncoprotein HIF-2alpha. Another potential mechanism by which HDM2 antagonists prevent TKI resistance is their ability to block the expression of hypoxia-driven chemokines such as SDF-1 (CXCL-12) and to prevent the influx of CD11b+/Gr-1+ myeloid-derived tumor suppressor cells (MDSC). In this project, we propose to carry out a Phase I/Ib clinical trial examining a combination of sunitinib with the HDM2 antagonist CGM097 (Novartis). This trial will have a 20 patient expansion cohort in which the administration of the HDM2 antagonist will be delayed in half of the patients. Tumor biopsies will be performed on these patients (half of which will be receiving sunitinib alone and half the drug combination at the time of biopsy) to assess the effects of treatment on p53 activation and MDSC and Treg trafficking. We will examine the effects of MDSC depletion on treatment outcome in murine RCC models and will determine if targeting the SDF-1 receptor (CXCR4) with the CXCR4 inhibitor AMD11070 prevents MDSC recruitment and the onset of TKI resistance as effectively as HDM2 blockade. Finally, we will assess the effects of HDM2 blockade on the expression of IL-8, FGF, and other factors previously implicated in the development of TKI resistance

Targeting mTOR Dependment Mechanism in Clear Cell Renal Carcinoma

Project Summary

The mechanistic target of Rapamycin (mTOR) complex 1 (mTORC1) is a master regulator of cellular growth and metabolism. Two allosteric inhibitors of mTORC1, the rapalogs temsirolimus and everolimus, are FDA approved for renal cell carcinoma (RCC). However, despite the fact that mTORC1 appears to be activated in the majority of RCC, only a subset of patients derives significant clinical benefit from these agents. Currently there are no predictive biomarkers of treatment response to mTORC1 inhibitors in RCC. The recent TCGA analysis of RCC identified multiple genetic alterations that potentially result in constitutive activation of the mTOR pathway (seen in 8-17%, e.g. MTOR). This leads to our first hypothesis, that mutations in genes encoding critical proteins in the PI3K-mTOR pathway will be associated with clinical response to rapalog therapy in RCC. Recently several drugs have been developed that are ATP-competitive mTOR kinase inhibitors. This leads to our second hypothesis, that ATP-competitive mTOR kinase inhibitors will have benefit for patients who progress on rapalog therapy. CRISPR gene editing technology has recently been developed, and enables genome wide screens for enhancers of rapalog effects on cell growth. This leads to our third hypothesis, that a genome-wide CRISPR/Cas9 screen will identify genes that are essential for kidney cancer growth and/or confer synthetic lethality when combined with mTOR inhibition, thereby leading to an improved therapeutic strategy. Hence, our specific aims are: 1A: To identify genetic predictors of response to agents targeting the mTOR pathway in advanced RCC. 1B: To study mechanisms of resistance to mTOR inhibitors occurring in vivo in patients. 2: To conduct an mTOR-kinase inhibitor (MLN0128) trial in metastatic RCC patients who progressed on rapalog therapy, including genetic analysis and cell line development. 3A: To conduct genome-wide CRISPR/Cas9 screens to identify genes essential or conditionally essential upon mTOR inhibition in kidney cancer cells in vitro; to validate and prioritize these genes; and to determine the contribution of hit genes to tumor cell growth in vivo.

Optimal Targeting of the PD-1/PDL-1 Pathway in Metastatic Renal Cell Carcinoma

Project Summary

Advances in tumor immunology have led to a better understanding of the immunoinhibitory mechanisms (e.g. inhibitory ligands/receptors and regulatory T cells) that create a major barrier to effective anti-tumor immunity. One of the most critical pathways responsible for mediating tumor-induced immune suppression is the programmed death-1 (PD-1) pathway. While the early results seen with PD-1 pathway blocking antibodies (Abs) in cancer have been encouraging, further study is required to optimize their use in RCC patients. Preliminary correlative studies suggest that while tumor PD-L1 expression may increase the likelihood of benefit with anti-PD-1, it fails to identify all responders. Predictive biomarker development and validation will help to guide this approach to the proper patients (Aims 1 and 2). The application of PD-1 blockade in the treatment naïve setting may yield even better results and obviate the need for subsequent lines of therapy (Aim 2). Using a multi-faceted approach, this project will provide a better understanding of the mechanisms of action and resistance to PD-1 pathway blockade, thereby facilitating the development of effective combination regimens (Aims 2 and 3). We will study the impact of intra-tumoral heterogeneity on biomarker development through our unique collection of matched primary tumor and metastasis specimens in our SPORE Tissue Bank and samples obtained from two prospective clinical trials of patients receiving anti-PD-1 antibodies. Laboratory experiments will integrate novel Abs, engineered proteins and genetic tools including: 1) anti-PD-1, PD-L1, and PD-L2 monoclonal Abs for IHC of human tissues and long term treatment of mice; 2) whole-exome and transcriptome sequencing of both tumor and infiltrating T cells (TILs), which can be used to explore mechanisms of innate resistance, and 3) innovative murine models such as mice that conditionally lack PD-1 on specific cell types and reporter mice that enable FoxP3 visualization. This highly collaborative team of basic and clinical scientists brings together an exceptional collective expertise in RCC immunotherapy trials, the PD-1 pathway and tumor immunoregulation, which should facilitate the generation of clinically meaningful results.