Photodynamic Alteration of Cell Membrane Lipids to Enhance Chemotherapy Efficacy in Metastatic Ovarian Cancer

PROJECT SUMMARY High-grade serous ovarian carcinoma (HGSOC) manifests with peritoneal metastases in over 75% of patients. Despite aggressive treatment, including cytoreductive surgery and platinum-taxane chemotherapy, the remaining metastases almost inevitably give rise to chemoresistant recurrences for which no curative treatments exist. There is an urgent need for complementary strategies to address resistance in these residual tumors. Altering cell membrane lipid composition has emerged as one such strategy. This proposal aims to utilize photodynamic alterations of cell membrane lipids to promote chemotherapy penetration and efficacy in preclinical models of peritoneal metastases. This will be achieved by combining two clinically viable approaches: 1) Co- delivery of easily oxidizable polyunsaturated fatty acids (PUFAs) with lipophilic photoactivatable molecules (photosensitizers) and 2) Induction of lipid peroxidation within cancer cell membranes that occurs downstream of photochemically-generated reactive oxygen species (ROS)—photodynamic priming (PDP). This approach is based on a hypothesis that lipid pathology initiated by incorporating PUFAs into membrane-forming phospholipids, followed by exposure to photochemically-generated ROS, will synergistically “prime” cells for subsequent chemotherapeutic eradication. Intraperitoneal light delivery, proven feasible in University of Pennsylvania trials, allows integration of the proposed strategy within the current standard of care. In this approach, PUFA and photosensitizer would be administered prior to cytoreductive surgery, during which light- irradiation would photodynamically alter cell membranes to enhance response to postoperative chemotherapy. During the mentored K99 phase, Dr. Overchuk will investigate the effects of free PUFA, PDP, and combinations on carboplatin efficacy in orthogonal models of HGSOC. As a clear path to independence, Dr. Overchuk will develop a lipoprotein-mimetic nanoparticle to harness natural lipid trafficking mechanisms for codelivery of PUFAs alongside a photosensitizer. Upon her transition to the R00 phase, Dr. Overchuk will compare PDP using free versus nanoencapsulated PUFAs and photosensitizers with respect to tumor selectivity and carboplatin enhancement. A mentoring committee will guide Dr. Overchuk’s research and facilitate her transition to independence. As primary mentor, Dr. Imran Rizvi will train Dr. Overchuk in physiological models of HGSOC peritoneal metastasis. As co-mentor, Dr. Alexander Kabanov will provide specialized training in nanoformulation development. Drs. Robert Chapkin (PhD), Victoria Bae-Jump (MD/PhD) and Huang Chiao (Joe) Huang (PhD) will bring further expertise in membrane therapies, lipid metabolism, clinical management of HGSOC and translational photomedicine. To summarize, this proposal aims to address key barriers to treating peritoneal metastases with a mechanistically distinct approach and establish a cancer-agnostic platform translatable to a wider variety of malignancies. The mentorship provided by this K99/R00 Award will allow Dr. Overchuk to pursue this clinically relevant research and enable her transition to an independent career.