| Summary: | Metastatic prostate cancer (mPCa) is currently incurable. Docetaxel-based chemotherapy, used as first-line treatment for advanced PCa, is marginally effective. As PCa is a heterogeneous disease, use of therapeutics targeting multiple pathways may improve its treatment outcome. Aneustat is first-of-a-class of multivalent immuno-oncology drug candidates; a Phase-I trial has shown it is well-tolerated by patients and has immunomodulatory activity. The main goal of this PhD project is to determine whether Aneustat can be used to improve docetaxel-based therapy of advanced PCa.
In vitro, Aneustat markedly inhibited human metastatic C4-2 PCa cell proliferation/migration in a dose-dependent manner and, combined with docetaxel, showed synergistic growth inhibition. In vivo, a combination of Aneustat and docetaxel synergistically enhanced anticancer activity in a clinically relevant, patient-derived xenograft (PDX) metastatic PCa model without inducing major host toxicity (inhibition of tumor growth, lung micro-metastasis, kidney invasion). Gene expression analysis of microarray data obtained from xenografts, using Ingenuity Pathway Analysis (IPA) and Oncomine software, indicated that Aneustat+docetaxel, as distinct from the single drugs, targeted multiple pathways and cancer-driving genes. Aneustat alone significantly inhibited growth of human LNCaP cells/xenografts; glucose consumption, lactic acid secretion and glycolysis-related gene expressions of LNCaP cells were markedly reduced, indicating it inhibited aerobic glycolysis. Treatment of LNCaP xenografts and first-generation PCa PDX with Aneustat led to marked changes in host immune cell levels (mouse/human), i.e. a higher ratio of CD8⁺T/Treg cells, higher Natural Killer (NK) cell numbers, lower Treg cell and MDSC numbers – changes favoring the host anticancer immune response.
This study shows that combined use of Aneustat and docetaxel can lead to marked, synergistically increased anticancer activity, both in vitro and in vivo. As indicated by IPA and Oncomine analyses, this is due to the combination-induced expansion of the targeting of pathways and cancer-driving genes. Furthermore, as found with first-generation PDX PCa model, Aneustat has immunomodulatory properties, likely stemming from its inhibition of aerobic glycolysis, that may lead to stimulation of the anticancer immune response in immunocompetent hosts. Since a clinically relevant PDX metastatic PCa model was used in this study, treatment with Aneustat+docetaxel is likely valuable for clinical management of advanced PCa. === Medicine, Faculty of === Graduate
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