Genetic and epigenetic events have been implicated in the downregulation of the cellular antigen processing and presentation machinery (APM), which in turn, has been associated with cancer evasion of the immune system. When these essential components are lacking, cancers develop the ability to subvert host immune surveillance allowing cancer cells to become invisible to the immune system and, in turn, promote cancer metastasis. Here we describe and validate the first high-throughput cell-based screening assay to identify chemical extracts and unique chemical entities that reverse the downregulation of APM components in cell lines derived from metastatic tumours. Through the screening of a library of 480 marine invertebrate extracts followed by bioassay-guided fractionation, curcuphenol, a common sesquiterpene phenol derived from turmeric, was identified as the active compound of one of the extracts. We demonstrate that curcuphenol induces the expression of the APM components, TAP-1 and MHC-I molecules, in cell lines derived from both metastatic prostate and lung carcinomas. Turmeric and curcumins that contain curcuphenol have long been utilized not only as a spice in the preparation of food, but also in traditional medicines for treating cancers. The remarkable discovery that a common component of spices can increase the expression of APM components in metastatic tumour cells and, therefore reverse immune-escape mechanisms, provides a rationale for the development of foods and advanced nutraceuticals as therapeutic candidates for harnessing the power of the immune system to recognize and destroy metastatic cancers.

AbstractMechanisms controlling the emergence of lethal neuroendocrine prostate cancer (NEPC), especially those that are consequences of treatment-induced suppression of the androgen receptor (AR), remain elusive. Using a unique model of AR pathway inhibitor–resistant prostate cancer, we identified AR-dependent control of the neural transcription factor BRN2 (encoded by POU3F2) as a major driver of NEPC and aggressive tumor growth, both in vitro and in vivo. Mechanistic studies showed that AR directly suppresses BRN2 transcription, which is required for NEPC, and BRN2-dependent regulation of the NEPC marker SOX2. Underscoring its inverse correlation with classic AR activity in clinical samples, BRN2 expression was highest in NEPC tumors and was significantly increased in castration-resistant prostate cancer compared with adenocarcinoma, especially in patients with low serum PSA. These data reveal a novel mechanism of AR-dependent control of NEPC and suggest that targeting BRN2 is a strategy to treat or prevent neuroendocrine differentiation in prostate tumors.Significance: Understanding the contribution of the AR to the emergence of highly lethal, drug-resistant NEPC is critical for better implementation of current standard-of-care therapies and novel drug design. Our first-in-field data underscore the consequences of potent AR inhibition in prostate tumors, revealing a novel mechanism of AR-dependent control of neuroendocrine differentiation, and uncover BRN2 as a potential therapeutic target to prevent emergence of NEPC. Cancer Discov; 7(1); 54–71. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1

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