Epigenetic Reprogramming to Target Senescent Ovarian Cancer Cells and Overcome Therapeutic Resistance
Abstract
Scientific Rationale and Objectives: Ovarian cancer is the deadliest gynecological cancer with over 19,880 new diagnoses and 12,810 deaths in 2022 alone. The standard-of-care therapies for ovarian cancer are platinum-based drugs and poly(ADP-ribose) polymerase (PARP) inhibitors. Resistance to both therapies remains a major clinical issue. Therefore, new therapies are needed to discover a long-term cure for these women. This proposal seeks to address this critical problem in ovarian cancer. Studies have shown that, if ovarian cancer cells are not killed by therapy, they may undergo a process called cellular senescence. Cellular senescence has both good and bad effects on tumor progression, and recent work has indicated that decreasing the bad effects of senescence can alleviate therapy resistance. Two of the most important bad parts of senescence are (1) increased inflammation and (2) increased anti-cell death signaling. We discovered that a protein called DOT1L is increased in senescent ovarian cancer cells after therapy treatment, and high DOT1L activity subsequently increases both the inflammation and anti-cell death signaling. Therefore, inhibition of DOT1L could be a one-two punch to fully eliminate these bad effects of senescence and overcome therapy resistance. In this proposal, we aim to determine how to kill the resistant ovarian cancer cells using inhibition of DOT1L that hits two resistance mechanisms, namely increased inflammation and anti-cell death signaling. The DOT1L inhibitor pinometostat is currently in clinical trials for acute myeloid leukemia, providing the opportunity to repurpose pinometostat for ovarian cancer. Areas of Emphasis: This proposal is directly related to (1) understanding the basic biology of ovarian cancer progression and response to therapy and (2) developing novel therapeutic strategies for treatment. The proposed studies are highly relevant to the vision and mission of the OCRP. These studies will study resistance of ovarian cancer, one of the ongoing missions of the OCRP, in disease-relevant ovarian cancer models. The proposed animal studies will identify whether inhibition of DOT1L after treatment with either platinum-based or PARP inhibitor therapy leads to a durable, long-term cure for therapy-resistant ovarian cancer. What Individuals Will This Research Help? These studies have the potential to help ovarian cancer patients with initial or acquired resistance to therapy, which is the majority of women. While the current studies focus on high-grade serous ovarian cancer, future work based on these studies will determine the applicability of the combination of clinically relevant DOT1L inhibitors after standard-of-care treatment in all subtypes of ovarian cancer. Clinical Applications, Benefits, and Risks: The potential clinical applications are implementation of a clinically relevant DOT1L inhibitor after treatment of ovarian cancer patients with either platinum-based on PARP inhibitor therapies. DOT1L inhibitors are already being tested in phase 1/2 clinical trials. If successful, the proposed studies could provide proof of principle to use these DOT1L inhibitors for ovarian cancer. Preclinical studies like the ones proposed here will be critical towards minimizing the risk (for instance, side effects) of the drug in solid tumor models. Overall, these studies have the potential to lead to an investigator-initiated clinical trial of clinically relevant DOT1L inhibitors after treatment with standard-of-care therapy. Ultimate Applicability and Impact for Military Service Members, Their Families, and Other Military Beneficiaries: The physical and mental cost of ovarian cancer on military health is clear. A staggering number of female Service Members and wives and adult daughters of active-duty military will be diagnosed with ovarian cancer (~11,900 of 850,000 women). Additionally, women continue to die, with a very grim ~30% 5-year survival rate f
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310436
Entities
People
- Katherine M Aird
Organizations
- United States Army