Unlocking the Human Relevance of a New Genetic Papillary Renal Cell Carcinoma Mouse Model
Abstract
Background: The goal of this proposal is to provide critical knowledge on the genetic events driving the development of the relatively rare kidney cancer subtype – papillary renal cell carcinoma (pRCC) and to help identify targeted therapies for this disease. Patients with metastatic renal cell carcinoma have a grim 12% 5-year survival rate. Without this knowledge, our ultimate goal to develop curative treatment options for patients with advanced pRCC will remain unachievable. Most kidney tumors are renal cell carcinoma, a mixture of different kidney-derived cancer subtypes (clear cell, papillary, and chromophobe). Most clinical trials have been performed on patients with the clear cell subtype, and successful treatments have been extended for use in patients with all types of renal cell carcinoma despite little evidence that these treatments are effective for patients with pRCC. This approach has been used due to (1) the lack of laboratory models to study pRCC and (2) the challenge of patient accrual for clinical trials as pRCC is not the predominant subtype. We also know that pRCC is a diverse disease and that different patients have significantly different molecular subtypes of cancer, which significantly complicates effective treatment. We have recently developed a powerful genetic model of pRCC in mice that develops multiple solid pRCC tumors within 9 months. In this proposal, we will (a) molecularly characterize tumor clones derived from this mouse model using RNA and protein expression techniques and (b) determine how these mouse tumors relate to the molecular subtypes of pRCC that afflict human patients. Hypothesis: Determining which molecular subtype(s) of human pRCC this new mouse model recapitulates will be critical to unlocking the model’s potential to provide insight into treatment for pRCC patients. Gap to Be Addressed: No molecularly characterized human-relevant mouse models for pRCC currently exist. One of the major hurdles in bringing new treatments to patients is the ability to test promising hypothesis in preclinical models (e.g., a mouse), which currently do not exist for pRCC. We will deliver a powerful new platform for innovators and pharmaceutical companies to test novel treatments, which we anticipate will reduce the uncertainty (i.e., risk) and cost of bringing these potentially curative options to patients. Innovation: This work is highly innovative on several fronts. First, we are utilizing a new and previously undescribed in vivo model of pRCC. These mice, here described for the first time, develop spontaneous tumors with histologic features that closely mimic human papillary renal cell carcinoma. Molecular subtyping of these tumors is a key step to unlocking the human relevance potential of this model. pRCC is a diverse set of molecular subtypes in humans. Defining the molecular signatures of our mouse tumors will be critical for exploiting this exciting model to apply it to human disease. Impact: Successful completion of this project will provide critical resources in the form of a molecularly subtyped genetic mouse model for papillary renal cell carcinoma. Currently, this resource does not exist, significantly limiting our ability to understand potential vulnerabilities for the disease in individual patients. Such a model could allow testing of hypotheses before moving on to costly and time-consuming human clinical trials for new strategies. Laboratory models (mouse and cell culture) have been the key to identifying and testing durable treatment options in other forms of cancer. In this project, we expect to deliver both mouse and cell culture-based models for molecular subtype-specific forms of pRCC relevant to human patients. We anticipate that the research community will exploit these models to identify tumor vulnerabilities and develop and test targeted therapeutics against each tumor molecular subtype that can one day provide more effective treatment for
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910822
Entities
People
- Richard Link
Organizations
- Baylor College of Medicine
- United States Army