IQGAP1 Scaffold-Kinase Interaction Blockade in Renal Cell Carcinoma: A Novel Biomarker and Therapeutic Strategy
Abstract
Kidney cancer is one of the most common cancers diagnosed in the United States and among Veterans and military beneficiaries. Surgery to remove a kidney mass or the entire kidney is an effective way to treat kidney cancer located inside the kidney. However, kidney cancer that has spread outside of the kidney is most often treated with targeted therapies -- drugs that block specific protein signals within kidney cancer cells. Unfortunately, these targeted therapies do not work for all kidney cancers, and all kidney cancers eventually develop resistance and the ability to grow despite medical therapy. The median survival for patients diagnosed with metastatic kidney cancer is less than 2 years. There is an urgent need for a better understanding of the molecular basis of kidney cancer, of the mechanisms of resistance to these targeted therapies, and to develop new treatment strategies to improve outcomes for patients with kidney cancer. IQGAP1 is a scaffold protein that has been shown to bind the kinase ERK. Blocking the IQGAP1-ERK scaffold kinase interaction has shown promise as a new approach to treat skin, pancreas, and lung cancers. The broad objective of this study is to (1) apply cutting-edge methods to determine the expression of IQGAP1 in kidney cancer and (2) test the effect of inhibiting IQGAP1-ERK scaffold-kinase interactions in models of human kidney cancer. The goal of this award period is for Dr. Leppert to achieve complete independence as a surgeon-scientist and investigator, and gain expertise in proteomics and xenograft models of kidney cancer. He will receive extensive training through the Stanford Program in Epithelial Biology and the Stanford Center for Systems Biology. Dr. Leppert will benefit from the frequent interaction with collaborators, which represent leaders in each of the specific subdisciplines focused on in this proposal. Through this project, Dr. Leppert will position his lab to be a leader in the evaluation of signaling and new treatments for kidney cancer. Studying the IQGAP1-ERK scaffold-kinase interaction holds promise as a biomarker of kidney cancer, which can be used to help diagnose kidney cancer in patients undergoing a biopsy, or help determine a patient s prognosis. Targeting IQGAP1-ERK may also prove to be a new treatment strategy for patients with metastatic kidney cancer on its own or in combination with current therapies. These efforts may lead to early clinical trials within the 3-year award or to help prioritize enrolling kidney cancer patients in already planned trials testing IQGAP1 inhibition. Ultimately, improving our understanding of kidney cancer and developing new treatments for metastatic kidney cancer could dramatically improve the care of Veterans and military beneficiaries diagnosed with kidney cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610553
Entities
People
- John Leppert
Organizations
- United States Army
- VA Palo Alto Health Care System