Abstract 5017: The discovery of novel therapeutics that restore antigen processing pathways in immune-edited metastatic cancers

Abstract

Abstract Cancer immune-editing resulting in immune escape where Major Histocompatibility Complex I (MHC I) molecules and the endogenous Antigen Processing Pathway (APP) leading to MHC I expression are down regulated, are prevalent in metastatic forms of cancer. In the absence of MHC I, these tumors subvert host immune surveillance mechanisms and are thus resistant to many of the immunotherapies approaches that evoke adaptive immunity to eradicate tumors in humans. Previously, we showed that by restoring TAP-1 expression in metastatic disease it is possible to restore the APP and the CTL recognition of tumor specific antigen loaded MHC-I molecules in carcinomas. We continued to investigate this mechanism of TAP deficiencies leading to APP defects and were the first to discover that this phenotype is not regulated by defects or mutations in the TAP-1 gene, but it is epigenetically regulated and can be restored by treatment with Histone Deacetylase Inhibitors (HDACi). Here, we describe a novel mechanism of action of compounds in promoting immune responses against tumors. We have developed a high-throughput screening assay to identify compounds that induce antigen presentation in metastatic prostate and lung carcinomas. We have used this system to screen a pharmacological library made from deep-sea sponge extracts, as it has been found that marine invertebrates are a diverse source of pharmaceutical leads and also of chemical diversity. Our results exploiting this system indicate several extracts isolated from amongst 500 sea sponges result in an increase a significant increase in surface MHC I expression, while at the same time exhibiting low cytotoxicity. The chemical structures of several of the active components of these extracts have been determined and one particularly promising candidate has been synthesized and produced in sufficient quantities to commence animal testing. Initial studies indicate the compound is well tolerated and there is no toxicity in animals at the doses that were studied. Results will be presented regarding the activity of the compound against subcutaneously implanted metastatic tumors. The work described herein will provide new therapeutic candidates for harnessing the power of the immune system to recognize and destroy metastatic cancers. Citation Format: Lilian Nohara, Reinhard Gabathuler, Paul Ahn, Ping Cheng, David Williams, Raymond Andersen, Wilfred A. Jefferies. The discovery of novel therapeutics that restore antigen processing pathways in immune-edited metastatic cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5017. doi:10.1158/1538-7445.AM2015-5017