A novel combination therapy for recurrent ovarian cancer

About This Grant

PROJECT SUMMARY Ovarian cancer is the most lethal gynecologic malignancy and ranks as the fifth leading cause of cancer-related mortality among women in the United States. Standard treatment consists of cytoreductive surgery followed by chemotherapy with carboplatin and paclitaxel. However, recurrence occurs in approximately 70% of patients within 18 to 24 months, primarily due to the development of platinum resistance. The prognosis for platinum- resistant ovarian cancer remains dismal, necessitating the development of alternative therapeutic approaches. Doxorubicin (DOX), a broad-spectrum anthracycline, is extensively utilized in oncology, including the treatment of ovarian cancer. Despite its efficacy, the clinical application of DOX is restricted by dose-limiting toxicities, particularly myocardial toxicity that can progress to chronic heart failure, as well as the emergence of multidrug resistance upon repeated administration. To mitigate these limitations, liposomal doxorubicin (DOXIL) has been adopted as a standard treatment for recurrent ovarian cancer. While DOXIL is associated with reduced cardiotoxicity, its response rate remains suboptimal (<20%) in platinum-resistant cases. To address these challenges, we investigated a novel therapeutic strategy combining DOXIL with withaferin A (WFA), a bioactive steroidal lactone derived from Withania somnifera (commonly known as ashwagandha). WFA exhibits potent anti-cancer properties, including inhibition of tumor proliferation, angiogenesis, and metastasis. In preclinical models, the combination of WFA with DOXIL demonstrated synergistic anti-tumor activity, significantly suppressing ovarian cancer growth. Furthermore, ovarian cancer- bearing animal models exhibited cachexia, characterized by skeletal muscle atrophy and cardiac dysfunction, leading to reductions in ejection fraction, fractional shortening, and cardiac output. Treatment with WFA markedly ameliorated both skeletal muscle and cardiac cachexia in these models. Based on our preclinical findings, we have initiated a Phase I clinical trials to evaluate the safety, tolerability, and maximum tolerable dose (MTD) of WFA (in the form of ashwagandha) in combination with DOXIL. The Phase I trials will recruit 18 patients with recurrent ovarian cancer who have developed platinum resistant. Patients will receive a standard dose of DOXIL (40 mg/m²) administered intravenously in conjunction with escalating doses of ashwagandha (2.0 g, 4.0 g, and 8.0 g) administered as oral capsules twice daily with water. Cardiac function will be closely monitored in all participants during the trials. This therapeutic approach has received FDA approval (IND #159645, NCT #05610735). The anticipated outcomes include enhanced therapeutic efficacy of DOXIL and significant reductions in DOXIL-associated cardiotoxicity. Data from the Phase I trial will be applicable in designing and implementation of subsequent Phase II studies, with the overarching goal of improving clinical outcomes for patients with recurrent ovarian cancer.