Mercapturic Acid Pathway Inhibitors as a Novel Treatment for Ovarian Cancer
Abstract
Objective and Rationale: Ovarian cancer (OC) is known to be one of the most lethal gynecological cancers worldwide. It is the eighth most frequently detected cancer and the fifth leading cause of death in the female population around the globe. The incidence of OC is very high, with more than 235,000 women diagnosed for this type of cancer each year. Despite several therapeutic strategies, such as radiation and chemotherapy (gemcitabine or cisplatin), the overall 5-year survival rate is less than 40%. Several epidemiological studies revealed that diabetes increases the risk of several cancers, including colorectal, endometrial, breast, and OC. While therapy that reduces new blood vessel formation (anti-angiogenic therapy) is efficacious in patients with OC, most patients eventually develop cancer resistant to this treatment. The precise molecular mechanisms underlying this drug resistance are not well understood. RLIP (a 76 kDa mercapturic acid pathway MAP transporter) is a stress-responsive membrane protein implicated in the regulation of multiple cellular signaling pathways. One of the important findings in RLIP knockout (RLIP-/-) mice was low basal levels of glucose while the animals are active and normally functional. RLIP expression is increased by oxidative stress, which plays a vital role in the pathogenesis of cancers. Hypoglycemia, hypotriglyceridemia, hypocholesterolemia, lower body mass, and fat, as well as pronounced insulin-sensitivity, are the characteristics of RLIP-/- mice, which suggested to us the possibility that elevation of RLIP in response to stress could itself elicit metabolic syndrome. Overall, RLIP links cancer, obesity, metabolic syndrome, and diabetes into a single disease-causing gene. When you get rid of this gene in a mouse, the mouse cannot get obese; it cannot get diabetes; it cannot get high cholesterol; and it cannot get cancer. RLIP-/- mice are highly resistant to cancer. Thus, RLIP has emerged as an essential requirement for tumor survival and metastasis. Treatment of localized OC with surgery, radiotherapy, chemotherapy, and hormonal therapy is insufficient to eradicate OC, as evident from development of metastatic ovarian cancer (MOC). Response rates to first-line platinum-based therapy are >80%, but the overall 5-year survival rate for patients with advanced OC is only ~20% because of acquired drug resistance and adverse side effects. Therefore, overcoming drug-resistance is the key to successful treatment of OC, and the development of novel therapeutic approaches is urgently needed. Our objective is to develop improved prevention strategies to alleviate the pain and suffering caused by MOC. RLIP is a stress-responsive membrane protein implicated in the regulation of multiple cellular signaling pathways, and its expression was found to be significantly greater in malignant cells compared to nonmalignant cells. It represents the predominant glutathione-electrophile conjugate (GS-E) transporter in cells, and its inhibition/or depletion causes apoptosis in OC. Our overall objective is to test whether total systemic depletion of RLIP by antisense and inhibition by antibody will suppress ovarian carcinogenesis or inhibit metastatic disease in rodent models of carcinogenesis and metastases. Here, we propose that chronic partial suppression of MAP transporter RLIP, a stress-defense protein, will prevent MOC by restoring the function of p53, a tumor suppressor gene that is deficient or dysfunctional in over 1/3 of OC. The rationale for this proposal stems from our recent studies showing that chronic RLIP depletion completely eliminates the uniform occurrence of malignancy that characterizes p53 gene-knockout (p53-/-) mice. This degree of cancer suppression in p53-/-- mice is unprecedented and has not achieved by any previous genetic or pharmacological intervention. Our discovery has fundamental implications in cancer prevention, and the studies proposed herein a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210331
Entities
People
- Sharad S Singhal
Organizations
- Beckman Research Institute of City of Hope
- United States Army