Utilizing Cell-Free Methylomes to Inform Clinical Scenarios in Renal Cell Carcinoma
Abstract
The ability to detect cancer from a blood draw or urine sounds like science fiction. The first report of detecting DNA in our bloodstream was in 1948. Since then, technology has advanced substantially and DNA sequencing costs have plummeted. Liquid biopsies have the potential to transform care for patients, and the cancer field of oncology is at a tipping point. This proposal has identified three areas of unmet need to improve care for patients diagnosed with kidney cancer. Our group has perfected a cutting-edge technique that captures, measures, and reads methylated tumor DNA that is shed by cancer cells into the bloodstream. This technique is called cfMeDIP-seq (cell-free methylated DNA immunoprecipitation). Methylation is a chemical tag placed on DNA. Importantly, DNA methylation has distinct patterns in tumors that distinguish them from normal tissue. In tumors (compared to normal tissue), thousands of sites become methylated while thousands of sites lose methylation. Because there are thousands of sites that differ between cancer and normal tissue, this method is significantly more sensitive than techniques that have come before it. Our proposal is deliberately designed to impact and inform clinical decision-making with the ultimate goal of decreasing morbidity (injury and suffering) and mortality (death) for kidney cancer patients. Kidney masses are incidentally found on approximately 15% of imaging tests that are ordered for other reasons. In Aim 1, we propose applying our liquid biopsy technique to accurately identify patients with benign (non-cancerous) kidney lesions who can safely avoid potentially harmful interventions, like surgery or biopsy, from those with kidney cancer who would benefit from early and aggressive curative treatment. In Aim 2, we will use cfMeDIP-seq to distinguish between the different forms of kidney cancer, which is important as these different forms of kidney cancer are treated with different drugs. A cfDNA methylation-based test that accurately diagnoses the various types of kidney cancer would help ensure that patients receive the best treatment for their particular type of kidney cancer while eliminating the need for an invasive biopsy. In Aim 3, we will use cfMeDIP-seq to detect patients who may suffer from severe side-effects of immunotherapy. While immunotherapy has revolutionized the treatment of kidney cancer, over 50% of patients suffer side effects. Early detection of these side-effects followed by the appropriate treatment could reduce morbidity and mortality and greatly improve quality of life for patients with kidney cancer. These aims address five of the KCRP Areas of Emphasis, including liquid biopsy, biomarker development, noninvasive interventions, understanding and managing toxicity, and screening and early detection. We have assembled a multi-disciplinary team with the appropriate expertise to successfully execute the aims in this proposal. Notably, we have access to blood and urine samples from patients with kidney cancer that have been uniformly collected and processed through the Gelb Center biobank. This biobank is an Institutional Review Board-approved biorepository that has collected blood, urine, tissue, and clinical data from patients with genitourinary cancers since 2001 and has a long history of providing resources for research projects. It is critical to note that the samples required for this technology can be collected at any hospital, VA, community, or academic center, thus democratizing the availability of this powerful method to all patients. It is no longer science fiction that a blood draw or urine can provide important information about cancer. The Dana-Farber Cancer Institute presents the ideal environment in which to perform this work. We have assembled a team of dedicated clinicians, researchers, and computational biologists to drive this work forward. We are excited about the potential of cfMeDIP-seq to meaningful
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110339
Entities
People
- Matthew L Freedman
Organizations
- Dana–Farber Cancer Institute
- United States Army