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Biology subjects

Cohn, D. E.

Publications and source records attributed to Cohn, D. E..

2 recordsLinked to original sources
bioRxiv2025

HO-3867 mediated modulation of Extracellular vesicles and Tumor microenvironment: A novel immunotherapeutic strategy for ovarian cancer

IntroductionOvarian cancer (OC) remains the most lethal gynecologic malignancy, with poor long-term survival, largely due to its diagnosis at advanced stages and its high rate of recurrence with resistance to platinum therapies. This study evaluates the therapeutic efficacy of HO-3867, a STAT3 inhibitor, and bevacizumab, an anti-VEGF antibody, alone and in combination in an immunocompetent (IC) syngeneic ovarian cancer progression model. MethodsThe ability of HO-3867 to induce macrophage polarization was assessed in RAW264.7 cells, while its impact on anti-tumor immunity was evaluated in splenocytes co-cultured with ID8 and OC ascites cells. Immune modulation, including cytokine induction, extracellular vesicle (EV) release, and endosomal sorting complex required for transport (ESCRT) protein expression, was analyzed in-vitro and using in-vivo OC model. The therapeutic effects of HO-3867 and bevacizumab were examined in vivo by measuring ascites volume, EV secretion levels, and immune cell populations via flow cytometry. ResultsOur results demonstrate that combination therapy significantly reduced ascites accumulation, and limited peritoneal disease spread in ovarian cancer mouse models. EV analysis revealed a decrease in total EVs and CD9+ subpopulations, which correlated with the associated ESCRT proteins involved in EV formation and secretion implicating EVs in tumor progression and immune modulation. Flow cytometry analysis of ascites immune cell populations showed that combination therapy reduced myeloid-derived suppressor cells (MDSCs) and their PD-L1 expression, while enhancing CD8+ T cell cytotoxicity via granzyme B secretion. Cytokine profiling revealed upregulation of IFN-{gamma} and downregulation of IL-6, IL-10 and CXCL-2 suggesting enhanced anti-tumor immune response. Furthermore, HO-3867 promoted macrophage polarization toward tumoricidal M1 phenotype and reduced MDSC expansion in-vitro, enhancing anti-tumor immunity. ConclusionHO-3867 and bevacizumab synergistically reprogram the tumor microenvironment, inhibit EV-mediated progression, and enhance antitumor immunity. These findings support its immunomodulatory potential in ovarian cancer ascites, offering a promising therapeutic strategy.

cancer biology↗
bioRxiv2019

Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma

Androgen Receptor (AR) signaling is a critical driver of hormone-dependent prostate cancer and has also been proposed to have biological activity in female hormone-dependent cancers, including type I endometrial carcinoma (EMC). In this study, we evaluated the preclinical efficacy of a third-generation AR antagonist, enzalutamide, in a genetic mouse model of EMC, Sprr2f-Cre;Ptenfl/fl. In this model, ablation of Pten in the uterine epithelium leads to localized and distant malignant disease as observed in human EMC. We hypothesized that administering enzalutamide through the diet would temporarily decrease the incidence of invasive and metastatic carcinoma, while prolonged administration would result in development of resistance and loss of efficacy. Short-term treatment with enzalutamide reduced overall tumor burden through increased apoptosis but failed to prevent progression of invasive and metastatic disease. These results suggest that AR signaling may have biphasic, oncogenic and tumor suppressive roles in EMC that are dependent on disease stage. Enzalutamide treatment increased Progesterone Receptor (PR) expression within both stromal and tumor cell compartments. Prolonged administration of enzalutamide decreased apoptosis, increased tumor burden and resulted in the clonal expansion of tumor cells expressing high levels of p53 protein, suggestive of acquired Trp53 mutations. In conclusion, we show that enzalutamide induces apoptosis in EMC but has limited efficacy overall as a single agent. Induction of PR, a negative regulator of endometrial proliferation, suggests that adding progestin therapy to enzalutamide administration may further decrease tumor burden and result in a prolonged response.

cancer biology↗