Understanding and Harnessing Therapy-Induced Senescence to Treat Ovarian Cancer
Abstract
High-grade serous carcinoma (HGSC) accounts for 70% of ovarian cancers and is the most lethal type, killing 120,000 women worldwide each year. It is almost always diagnosed at late stage due to the lack of symptoms, when the cancer has already spread throughout the abdomen. To treat HGSC, doctors first remove the tumors, then treat patients with chemotherapy to kill the rapidly growing cancer cells by damaging their DNA. However, chemotherapy invariably fails to eliminate all of these cells as many are simply put to sleep and stop growing, entering a state known as therapy-induced senescence (TIS). What is concerning about these sleeping cells? (1) TIS cancer cells are not killed by standard chemotherapy. (2) TIS cancer cells can escape TIS and reawaken to start growing again. (3) The immune system does not recognize all TIS cancer cells. We believe that TIS is a largely overlooked cause of resistance to therapy, which means 85% of HGSC patients will have their cancer return within 2 years. There are few effective therapies to treat recurrent HGSC and the majority of these women will die from their disease within 5 years. This highlights the urgent need to develop new therapies to target TIS to treat HGSC. To unlock the potential of targeting TIS to treat HGSC, we need to first properly understand how TIS works so we can identify new ways of manipulating it. Some key questions we need to consider are: When HGSC cells are exposed to different cancer therapies, are all TIS cells put to sleep in the same way? Can we design senolytic drugs to kill these sleeping TIS cancer cells before they reawaken? In cancer cells that are already resistant to being killed by standard treatments, can we find a way to put them back to sleep, then kill them off? We hypothesize that by understanding TIS, we will identify new opportunities to harness TIS to our advantage to provide breakthrough treatments for ovarian cancer. We will address this hypothesis in the following aims: Aim 1: Understand the TIS sleep state in cells exposed to standard of care chemotherapy or a novel therapy we developed that does not damage DNA. Aim 2: Discover new senolytic drugs that are more effective at killing sleeping TIS cells and less toxic than those in current use. Aim 3: Identify new ways to put resistant cancer cells back to sleep, then (i) kill them off with senolytic drugs or (ii) activate the immune system to attack them. Cancer cells that are sleeping and not growing require a radically different approach to treatment than the standard approach of combining standard of care drugs to damage the DNA of rapidly growing cancer cells catastrophically to kill them. Our proposal seeks to better understand TIS so that we can identify the optimal strategies harnessing it and urgently deliver an alternative treatment paradigm for HGSC. Our studies are in line with the mission of the Ovarian Cancer Research Program to treat ovarian cancer. The clear beneficiaries of these studies are women with ovarian cancer, particularly HGSC. The identification of new ways to target TIS including those that use one’s own immune system to kill the cancer will improve health outcomes for women with ovarian cancer by preventing their disease from returning. We will also identify ways to stop the uncontrolled growth of ovarian cancers that have stopped responding to conventional treatments. Together, these new strategies aim to provide a longer-lasting treatment response. Ultimately, the outcomes of the preclinical studies from this proposal will lead to the rational development of clinical trials targeting TIS and provide new hope for women with ovarian cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210501
Entities
People
- Keefe Chan
Organizations
- United States Army
- University of Melbourne