Targeting Epigenomic Adaptations to Overcome Drug Resistance in Ovarian Cancer
Abstract
Rationale: Angiogenesis is well recognized as an important step in the growth and progression of many tumor types. Over the last 15 years, anti-angiogenic therapy has become an effective modality for cancer therapy. The primary proangiogenic driver of this process is VEGF. As VEGF is constitutively overexpressed in many cancers, therapies targeting this pathway were highly anticipated additions to standard chemotherapeutic drugs. Bevacizumab (Avastin)—a humanized monoclonal anti VEGF-A antibody—is now used as an anti-angiogenic drug in several forms of cancers and has been approved by the U.S. Food and Drug Administration for various solid tumors, including metastatic colorectal cancer, metastatic renal cell cancer, metastatic gastric cancer, non-small-cell lung cancer, recurrent/metastatic cervical cancer, recurrent ovarian cancer, and glioblastoma multiforme. Unfortunately, the benefit in overall survival is modest, and the rapid emergence of drug resistance is a significant clinical problem. Over the last decade, several mechanisms have been identified to decipher the emergence of resistance. There is a multitude of changes within the tumor microenvironment in response to anti-angiogenic therapy that offers new therapeutic opportunities. Our previous data demonstrated that macrophages play a critical role in the emergence of resistance to anti-VEGF therapy. Increasing evidence has shown that epigenetic changes can be a crucial driving force behind the acquisition of drug resistance. Therefore, therapy that overcomes adaptive resistance to anti-VEGF antibody by targeting macrophages and epigenetic modification could potentially improve clinical outcomes of cancer patients. In this proposal, we will explore the mechanisms by which macrophages promote adaptive resistance to anti-VEGF treatment and test the efficacy of simultaneously targeting DNMT (DNA methyltransferase) as resistance to anti-VEGF therapy emerges. Based on our preliminary data, we hypothesize that macrophages promote adaptive resistance to AVA treatment, which can be reversed by epigenetic modifications to increase the treatment efficiency. Ovarian Cancer Advocacy Plans: A highly experienced ovarian cancer advocate, Ms. Sachia Powell, will participate as the ovarian cancer advocate in this research. Ms. Powell is an active participant and team captain in the Rivkin center SummeRun. Ms. Powell will bring the approaches she has used successfully in ovarian cancer advocacy to this grant. She will provide the patient perspective when research projects are designed and implemented and has been involved in all phases of the development of this proposal. Ms. Powell will be actively involved in all aspects of the proposed research program, including planning and oversight, program evaluation, and/or dissemination of information to the public through her advocacy programs. Expected Outcome: In short, the significance of this grant is that resistance is a big problem in ovarian cancer, particularly with bevacizumab treatment. Our data, along with others, suggest that macrophages are playing a major role in the emergence of anti-VEGF therapy resistance. Our team, with complementary expertise in the proposed approaches, will identify the “resistance mechanism,” associated with anti-VEGF therapy in ovarian cancer treatment. Our long-term goal is to translate this into the clinic. Therapy that overcomes adaptive resistance to anti-VEGF antibody by targeting macrophages and epigenetic modification could potentially improve clinical outcomes of cancer patients. Thus, the proposed study is readily translatable to overcome resistance to anti-VEGF therapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110361
Entities
People
- Sunila Pradeep
Organizations
- Medical College of Wisconsin
- United States Army