2021 Mentored Investigator Grant Recipient — Melanie Weigert, PhD

Melanie Weigert, PhD

University of Chicago

Genome-Wide Profiling of 5-hydroxymethylcytosine on Cell-Free DNA

Project Summary

Ovarian cancer (OvCa) is the fifth most common cause of cancer related deaths among women in the United States with estimates predicting that in 2020 about 21,750 women will be diagnosed with the disease. While most women will be diagnosed with advanced stage disease, only 52.8% have a chance of surviving one year, with the 5 year survival rate being only 30%. Although overall survival rates for OvCa have improved with the introduction of platinum-based chemotherapy, survival rates have stagnated for the past twenty years. This is due to our inability to catch early disease and because most advanced stage patients will relapse and develop resistance to platinum-based chemotherapy. While there are a range of alternative treatment options for these patients, recurrent OvCa is rarely curable, and there are currently no biomarkers available to guide further treatment options. Without biomarkers predictive of platinum resistance, clinicians rely on patient fitness and the assessment of platinum free intervals to guide further treatment. This project aims to address this problem by identifying biomarkers that can be used to monitor the development of platinum resistance. To achieve our goal, we will analyze DNA that is shed into the bloodstream by the tumor. Analyzing tumor DNA that is shed into the blood stream can be easily done without surgery and only requires a simple blood draw. Once a blood draw has been performed, we can isolate cell-free DNA and analyze it for changes in itself (mutations) and markings on the DNA (epigenetic modifications). We know that these marks can: 1) reveal the origin of the DNA within the body (e.g. DNA found in the brain has different marks than DNA found in the liver) and 2) help establish and maintain organ and cell identity (e.g. Why are the heart and kidney different though they share the same genetic code?). In preliminary experiments, we have found that these marks also differ in patients with platinum-sensitive and platinum-resistant OvCa. Analyzing the locations of marks on DNA from chemo-sensitive and chemo-resistant patients will enable us to identify biomarkers to distinguish the two groups. This will help clinicians to identify patients that will benefit from platinum-based therapy and allow them to provide alternative treatments to those likely to develop treatment resistance. This will also reduce the amount of patients receiving inefficient treatments with toxic drugs and improve overall quality of life. Furthermore, since these marks are important for regulating our genetic code (e.g. Different parts of our genetic code are active in the skin, and differ from the ones active in the lungs), we hypothesize that they can uncover mechanisms that are involved in platinum resistance and reveal targets that can help us overcome treatment resistance.

This grant was made possible in part by a generous donation from Jennifer Willett in  memory of Lynne Willett.

Bio

Dr. Melanie Weigert is currently a postdoctoral scholar in the ovarian cancer research laboratory at the University of Chicago. Dr. Weigert received her undergraduate degree in Biotechnology from Furtwangen University. During her undergraduate studies, she worked at the Max Planck Institute of Immunobiology and Epigenetics and helped investigate the effects of paternal diet on offspring chromatin state and intergenerational obesity. She obtained her PhD from the University of Glasgow, under the supervision of Dr. Iain McNeish, investigating the role of programmed necrosis in oncolytic adenovirus-induced cell death in ovarian cancer. This work resulted in several awards, such as the AACR Bristol Meyer Squibb Scholar in Training Award. After completing her doctoral degree, Dr. Weigert continued her research on ovarian cancer by joining the laboratory of Dr. Ernst Lengyel in 2017. Her research at the University of Chicago focuses on identifying hydroxyl-methylation based biomarkers using liquid biopsies.