PI: Partha Roy
Co-PI: Michael Lotze
Title: Profilin 1 as a Novel Target in Patients with Renal Cancer
Description: Malignant tumors of the kidney account in 2018 for 63,000 new cases and 15,000 deaths in the U.S. The most common subtype, clear cell renal cell carcinoma (ccRCC), is found in >75% of cases. Approximately 20%-30% of patients have metastasis at the time of diagnosis. About one-third of patients following initial treatment will develop either local recurrence and/or distant metastasis. The five-year survival of patients with advanced ccRCC is still only 10%. Drugs targeted to block expansion of vascular network in the tumor (anti-angiogenic therapy, a common treatment for ccRCC patients) is only effective initially, but in most patients the disease continues to progress due to drug resistance. Immunotherapy, a mode of treatment that hijacks the patient’s immune system to fight back the cancer, has shown significant promise, at least in some patients. Therefore, a more in-depth molecular understanding of the pathogenesis and progression of the exuberant vascularization of ccRCC, coupled with understanding of the immunologic sequelae, will lead to new integrated therapies. In this proposed study, we will address several major FY18 KCRP areas of emphasis including targeted therapies, microenvironment and immunology, and prognosis of RCC. Specifically, we will investigate whether and how profilin1 (Pfn1), a molecule elevated primarily in blood vessels in ccRCC and that correlates with advanced stage of tumor and poor prognosis of patients (a) contributes to altering tumor microenvironment and disease progression, and (b) predicts the response of RCC patients to immunotherapy. We will then explore whether efforts to target Pfn1 function through novel small molecules are effective in retarding disease progression in preclinical models. From these studies we will identify Pfn1 as a regulator of disease progression as well as a prognostic marker for predicting therapeutic response of RCC patients. A successful proof-of-concept demonstration of the efficacy of Pfn1-targeting chemical tools in retarding angiogenesis-dependent disease progression will establish the conceptual basis for a path forward toward a new direction of Pfn1-targeted therapy for patients with ccRCC. If successful, these small molecules can be further advanced through medicinal chemistry to generate next-generation drugs for RCC, demonstrating that our studies have translational potential in the future.