Funding & Research

Despite recent advances in immunotherapy, this treatment modality has yet to confer significant benefits for patients with prostate cancer. One promising approach to enhancing immune responses in prostate cancer patients relies on a combination of immunotherapy with other treatment modalities. Epigenetic therapies are particularly appealing in this regard, since epigenetic drugs can change the transcriptome of tumor cells, possibly making them more immunogenic. Indeed, this concept has previously been demonstrated with a class of epigenetic drugs that target a family of epigenetic proteins called bromodomains. While valuable as a proof of concept that an epigenetic drug can reprogram transcriptome to increase immunogenicity of prostate tumors, bromodomain inhibitors suffer from high toxicity and have under-performed in clinical trials. Building on preliminary findings that modulation of KDM5 family of histone demethylases stimulates interferon response in cancer, our objective is to investigate effects of a knockout of KDM5 demethylases on immunogenicity of prostate cancer, and to develop small molecule probes that mimic cellular effects of knockout to chemically enhance prostate cancer immunogenicity. Here we present our progress on development of cellular models and chemical modulators necessary to achieve this objective. This work is a collaboration of the labs of Larry Fong, an expert in cancer immunology, and Danica Fujimori, an expert in chemical biology of epigenetic regulation.

Prostate Cancer (PCa) is the most common malignancy in American men, and a leading cause of cancer associated deaths in the US. Highly effective therapies for the treatment of prostate cancer have been developed, including Androgen Receptor signaling inhibitors (ARSIs) such as enzalutamide and abiraterone, but problematically many patients develop acquired drug resistance demonstrating there is an urgent need for new therapies to overcome drug resistance. We have shown the WNT signaling pathway is a major drive of drug resistance in metastatic PCa patients. Based on these findings, we performed genome-wide unbiased CRISPR genetic screens that have systematically revealed genes that activate WNT signaling in PCa. Our results identified PPP2R5C and CASP8AP2 as top uncharacterized negative regulators of WNT pathway activity while others such as SSBP3 and TCF7L2 are positive regulators of WNT pathway activity in PCa models thus revealing novel biological processes that drive WNT signaling and acquired ARSI resistance in PCa. We are now pursuing the biology of these findings in further experiments and in additional models of PCa to establish generality and translatability. We envision this research enabling the design of anti-cancer strategies that circumvent acquired resistance to ARSIs.

A master regulator of an important cellular process called mRNA translation; the eukaryotic translation initiation factor (eIF4E) regulates many oncogenic pathways. At the same time, eIF4E was thought to be crucial for the body to develop and function correctly; thus, it had been widely considered “undruggable.” In a surprising finding, we showed that it can be reduced in half in mice with no apparent ill effects. This proposal is centered around the concept that prostate cancer cells required an overdrive of eIF4E activities to control the translation of distinct oncogenic mRNAs and ensure their survival while normal cells are not addicted to high level of eIF4E activities hence, experience minimal impact upon eIF4E inhibition. This concept is ideal to exploit in designing novel combinational therapies to specifically kill prostate cancer cells while sparing normal cells.

Using patient derived xenografts (PDXs), where human prostate cancer tissue is implanted into mice, our compelling preliminary data reveal that the ability of key oncogenic pathways underlying prostate cancer hijack eIF4E to fuel cancer cell growth and tumorigenesis, thereby exposing an “Achilles’ Heel” of this oncogenic pathway. We demonstrated that limiting eIF4E activity with a novel small molecule eFT508 (Tomivosertib) dramatically results in profound tumor regression, metastatic burden and prolonged survival. We found that eIF4E directly regulate the translation of the androgen receptor and the spliced variant AR-V7 (a variant of the androgen receptor that does not need testosterone to work) as one of many other mitogenic genes that regulate immune resistance, tumor metabolism and cellular proliferation and resisting cell death. eFT508 (Tomivosertib) is currently in phase 2 trial for some solid cancer and based on our preliminary data and the experiments proposed in this grant, we seek to ultimately launch eFT508 for the most lethal form of prostate cancer.