Abstract 6547: Ivospemin and doxorubicin cooperatively modulate polyamine metabolism and the tumor immune microenvironment to improve survival in a murine ovarian cancer model

Abstract Polyamines are polycationic alkylamines that are essential for the continual growth and proliferation of cancer cells. The pharmacological modulation of polyamine metabolism is a promising avenue in cancer therapeutics due to the dependency of numerous cancers on continually elevated polyamine levels. Ivospemin, a spermine analogue, has shown efficacy in slowing pancreatic and ovarian tumor progression in vitro and in vivo and has demonstrated encouraging results in pancreatic cancer clinical trials. We have previously shown that ivospemin exposure decreases polyamine content both in vitro and in vivo through downregulation of the polyamine biosynthetic enzyme ornithine decarboxylase (ODC) and induction of the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase (SSAT). We have also shown that ivospemin increases the efficacy of gemcitabine and topotecan in vivo by delaying tumor onset and reducing overall tumor burden. Here we examine the potential of combining ivospemin with doxorubicin, a common chemotherapeutic used in platinum-resistant ovarian cancer. Ovarian adenocarcinoma lines cotreated with ivospemin and doxorubicin exhibit an additive decrease in survival that is associated with upregulation of SSAT and decreased polyamine levels. Using the syngeneic VDID8+ ovarian model, we evaluated the ability of ivospemin to improve response to doxorubicin. Compared to untreated animals, ivospemin and doxorubicin cotreatment increased median survival by more than 200%, delayed tumor onset, and decreased overall tumor burden. Notably, this benefit was lost in an immunocompromised NSG mouse model. Ascites fluid from immune-competent animals was processed for evaluation of polyamine content by HPLC and immunophenotyping by multiparameter flow cytometry. Combination treatment decreased overall polyamine content by 75% and N1-acetylated spermidine accumulation was observed, consistent with an upregulation of SSAT activity. Compared to single agents, ascites from co-treated animals exhibited an increased presence of CD45+ cells associated with an increase in lymphocyte recruitment. Treatment did not influence peritoneal macrophage numbers, however M1-like macrophages were increased while M2-like macrophages were decreased, resulting in an overall reversal of the M2/M1 ratio in ascites fluid. Cytokine analysis was performed on supernatant from cultured ascites cells to evaluate immune cell activity. Recognizing the non-representative mutational status of the VDID8+ model as a limitation, we are currently evaluating the combination of ivospemin and doxorubicin in genetically defined murine models that better recapitulate human high-grade serous ovarian carcinomas. Citation Format: Cassandra E. Holbert, Ashley C. Nwafor, Jennifer K. Simpson, Tracy Murray Stewart, Robert A. Casero Jr.. Ivospemin and doxorubicin cooperatively modulate polyamine metabolism and the tumor immune microenvironment to improve survival in a murine ovarian cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6547.