Friday, May 9, 2025
5/9/2025
Use of microfluidic tumor cultures to enable clinical trials of therapies for ovarian cancer - ABSTRACT With an estimated 20,000 new cases and 13,000 deaths in 2024, ovarian cancers (OCs) remain the deadliest gynecological malignancy. Despite the heterogeneity of this group of cancers in terms of histology, possible cell of origin, and genomic alterations, OCs are almost universally treated with surgery and adjuvant or neoadjuvant chemotherapy that includes the platinum coordination compounds carboplatin or cisplatin. The vast majority of OCs relapse after this treatment and, whether treated with further platinum agents or other therapies, become more resistant with each subsequent therapy. Platinum-resistant ovarian cancer, i.e., ovarian cancer that recurs within 6 months of the most recent platinum-containing therapy, has a median survival of 6-20 months despite the development of newer targeted agents, highlighting the need for improved therapies. In this context, two projects of the Mayo Clinic Ovarian Cancer SPORE (P50 CA136393) are developing and testing two new therapies for platinum-resistant ovarian cancer. Project 2 involves preclinical studies and a phase II clinical trial PLX038, a sustained release formulation of the active TOP1 inhibitor (TOP1i) SN-38. Project 4 involves the development and subsequent phase I clinical testing of natural killer (NK) cells that have been transduced with a chimeric antigen receptor (CAR) targeting mesothelin and modified to sustain their survival and function in vivo. A goal in both projects is identification of OC patients most likely to benefit from these treatments. With previous funding from the NCI Innovative Molecular Analysis Technologies (IMAT) Program, the PIs of this revision project have developed microfluidic devices that permit prolonged survival and proliferation of patient- derived organoids (PDOs) and tumor explants in 3-dimensional culture. A major advantage of these devices is the ability to assess the impact of various treatments, including small molecules and cellular therapies, on both tumor cells and cells in the tumor microenvironment. The revision project will test the hypothesis that responses to therapy in these microfluidic devices correspond to responses of patients treated with the same therapies on the two SPORE-associated clinical trials. In particular, the proposed project will i) compare the TOP1i response of OC patient-derived xenografts (PDXs) treated with PLX038 in vivo with their response, including stabilization of TOP1-DNA covalent complexes and shrinkage, when treated with TOP1i in the microfluidic devices ex vivo (Aim 1); ii) assess the survival, functionality (as measured by cytokine secretion) and killing potency of NK cells expressing CISH miRNA and a MSLN CAR when added to fresh OC explants in the microfluidic devices (Aim 2); and compare the responses of tumor explants cultured with TOP1i or modified MSLN CAR NK cells in microfluidic devices ex vivo with the responses of the source patients to the same treatments in vivo in the course of two SPORE-associated clinical trials (Aim 3). These proposed studies will simultaneously identify whether these devices are able to predict responses to two different types of OC therapy and position the devices as potential companion diagnostics for further development.
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