Abstract 5484: Preclinical evaluation of CAP-0121 for multidrug resistant cancers

Abstract

Abstract CAP-0121 is a second generation illudofulvene agent that produces an unusual type of DNA damage and is being developed to treat ovarian cancer by Califia Pharma. CAP-0121 DNA damage, like other illudofulvenes, can only be recognized and repaired by the Transcription-Coupled Repair pathway, and is ignored by the Global Genome Repair Pathway. The first generation illudofulvene, irofulven, displayed significant activity in clinical trials against ovarian, prostate and hepatocellular tumors. While irofulven has proven to be a potent antitumor agent against drug-resistant tumors, its efficacy is limited by hematologic toxicity that reduced the maximum dosage that can be administered to patients. CAP-0121 is as cytotoxic, or even more cytotoxic, than irofulven when tested in the NCI 60 cell line panel. Despite this increased cytotoxicity noted in vitro, CAP-0121 is less toxic to animals and the maximum tolerated dose is approximately 3 times higher than irofulven (mg/kg basis). CAP-0121 also retains activity against multidrug resistant cell lines including MRP1 and MDR1 expressing variants. As a result CAP-0121 is capable of inducing tumor remission in MDR xenograft models that are unresponsive to 35 conventional and experimental agents, and in which irofulven is only capable of slowing the rate of tumor growth. This response of CAP-0121 in drug resistant xenografts is observed at nontoxic doses. Synergistic action is observed when CAP-0121 is administered in combination with traditional drugs used for treating ovarian cancer, including taxanes, platinum agents, and PARP inhibitors. Citation Format: Michael J. Kelner, Venkata R. Kotamraju. Preclinical evaluation of CAP-0121 for multidrug resistant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5484.