Harnessing Epigenomics to Detect and Target Sarcomatoid Differentiation in Renal Cell Carcinoma
Abstract
Renal cell carcinoma (kidney cancer) is particularly common among the U.S. Veteran population and causes 15,000 deaths in the United States each year. Approximately 15%-20% of kidney cancers that spread outside of the kidneys transform into an aggressive form of cancer called sarcomatoid renal cell carcinoma (sRCC). This project aims to develop a less invasive, more accurate method of detecting sRCC. Easy, accurate diagnosis of sRCC is important because this type of cancer responds well to immunotherapy but poorly to other treatments. Diagnosing sRCC currently requires biopsy or surgical removal of a tumor, which is burdensome for patients and often fails to identify sRCC. To overcome these hurdles, the proposed research will develop a blood test, or liquid biopsy for detecting sRCC. Liquid biopsies identify DNA that is shed into the blood by cancer cells. A recent breakthrough in detecting cancer DNA in the blood has generated enormous excitement about the potential of liquid biopsies to help guide cancer treatment. It is now possible to detect cancer DNA in the blood with exquisite sensitivity by taking advantage of a chemical tag, known as methylation, that is attached to DNA. Because sRCC has characteristic DNA methylation patterns, we expect it will be possible to tell whether DNA in the blood comes from a kidney cancer that has transformed into sRCC. This project will take advantage of a large collection of tumor and blood samples that have been donated by patients at Dana-Farber Cancer Institute over the last two decades. We will analyze patterns of DNA methylation in blood from kidney cancer patients, identifying those with sarcomatoid differentiation. The accuracy of these findings will then be verified by comparing them to biopsy results. In addition, we will determine if our blood test can identify patients who responded to medicines called VEGF inhibitors, a common therapy for advanced kidney cancer that is not effective for sRCC. An additional aim of this project is to understand how sRCC arises from kidney cancer. sRCC is thought to represent a change in the identity of kidney cancer cells that allows them to invade other body tissues and grow unconstrained. Studies have shown that this behavior involves alterations in gene expression -- turning certain genes on or off. We will investigate how this process unfolds by analyzing the DNA modifications that control the activity of these genes in sRCC. This information may pave the way for developing new treatments for this aggressive cancer. By focusing on sRCC, this research aims to benefit patients at highest risk of dying from kidney cancer. We hope that the blood test we propose will identify patients who are most likely to benefit from immunotherapy. If successful, this blood test could be integrated into patient care within the next few years. The insights we gain into sRCC from studying gene regulation in tumor tissues will hopefully identify new ways to treat this aggressive disease. If so, such treatments could be tested in patients within the next several years. Researcher Development Plan: Sylvan Baca, M.D., Ph.D., will conduct the research under the mentorship of Dr. Toni Choueiri and Dr. Matthew Freedman. Dr. Baca is a young investigator with training in genitourinary oncology and functional epigenomics who is launching his career as an independent kidney cancer researcher. Dr. Choueiri is a renowned expert in the treatment and biology of kidney cancer. Dr. Freedman is a lab-based investigator who has pioneered epigenomic profiling of human specimens to study genitourinary cancers. With his mentors, Dr. Baca has formulated a rigorous plan for structured mentoring, didactic coursework, seminar attendance, and presentation of this work at national conferences. Dr. Choueiri and Dr. Freedman are invested in Dr. Baca s career goal of leading a kidney cancer research program at a major academic cancer center. Comp
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110299
Entities
People
- Sylvan C. Baca
Organizations
- Dana–Farber Cancer Institute
- United States Army