Therapy for prostate cancer is not yet individualized based on the molecular drivers found within each individual’s cancers. This makes prostate cancer unlike other common cancers, such as breast, colon, and lung cancer.
The difference highlights the critical need to understand the fundamental biology underlying aggressive prostate cancer, in order to radically improve outcomes. The UCSF Benioff Initiative looks to fund projects and core resources that aim to accelerate research in aggressive prostate cancer.
To accomplish this the BIPCR:
- Seeks to partner with departments on the recruitment of basic scientists to UCSF, working in part or fully on prostate cancer.
- Provided funding for the generation of resources for UCSF prostate cancer researchers, contributing to recruitments and team-based science within specified research directions. Pilot funding is available to groups interested in developing a core resource or applying their current practices to the field of prostate cancer. These projects will be assessed on an individual basis and interested groups should first contact the BIPCR at [email protected] to discuss their proposals.
Aggarwal R, Rydzewski NR, Zhang L, Foye A, Kim W, Helzer KT, Bakhtiar H, Chang SL, Perry MD, Gleave M, Reiter RE, Huang J, Evans CP, Alumkal JJ, Lang JM, Yu M, Quigley DA, Sjöström M, Small EJ, Feng FY, Zhao SG. Prognosis Associated With Luminal and Basal Subtypes of Metastatic Prostate Cancer. JAMA Oncol. 2021 Nov 1;7(11):1644-1652. doi: 10.1001/jamaoncol.2021.3987. PMID: 34554200; PMCID: PMC8461554.
Melnyk JE, Steri V, Nguyen HG, Hwang YC, Gordan JD, Hann B, Feng FY, Shokat KM. Targeting a splicing-mediated drug resistance mechanism in prostate cancer by inhibiting transcriptional regulation by PKCβ1. Oncogene. 2022 Jan 27. doi: 10.1038/s41388-022-02179-z. Epub ahead of print. PMID: 35087237.
Song H, Weinstein HNW, Allegakoen P, Wadsworth MH 2nd, Xie J, Yang H, Castro EA, Lu KL, Stohr BA, Feng FY, Carroll PR, Wang B, Cooperberg MR, Shalek AK, Huang FW. Single-cell analysis of human primary prostate cancer reveals the heterogeneity of tumor-associated epithelial cell states. Nat Commun. 2022 Jan 10;13(1):141. doi: 10.1038/s41467-021-27322-4. PMID: 35013146; PMCID: PMC8748675.
Rydzewski NR, Peterson E, Lang JM, Yu M, Laura Chang S, Sjöström M, Bakhtiar H, Song G, Helzer KT, Bootsma ML, Chen WS, Shrestha RM, Zhang M, Quigley DA, Aggarwal R, Small EJ, Wahl DR, Feng FY, Zhao SG. Predicting cancer drug TARGETS - TreAtment Response Generalized Elastic-neT Signatures. NPJ genomic medicine. 2021 Sep 21;6(1):76. doi: 10.1038/s41525-021-00239-z.
Das R, Sjöström M, Shrestha R, Yogodzinski C, Egusa EA, Chesner LN, Chen WS, Chou J, Dang DK, Swinderman JT, Ge A, Hua JT, Kabir S, Quigley DA, Small EJ, Ashworth A, Feng FY, Gilbert LA. An integrated functional and clinical genomics approach reveals genes driving aggressive metastatic prostate cancer. Nat Commun. 2021 Jul 29;12(1):4601. doi: 10.1038/s41467-021-24919-7. PMID: 34326322; PMCID: PMC8322386.
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Zhou, X., Han, S., Wilder-Romans, K., Sun, G. Y., Zhu, H., Liu, X., Tan, M., Wang, G., Feng, F. Y., & Sun, Y. (2020). Neddylation inactivation represses androgen receptor transcription and inhibits growth, survival and invasion of prostate cancer cells. Neoplasia (New York, N.Y.), 22(4), 192–202. https://doi.org/10.1016/j.neo.2020.02.002
MOP Collaborative Projects
Principal Investigators: Charles Craik, PhD* & Michael Evans, PhD^ Project Title: Beyond ligand/receptor complexes: maximizing tumor responses to targeted radiotherapy with a conditionally activated membrane binding probe.
Principal Investigators: Adam Renslo, PhD* & Michael Evans, PhD^ Project Title: Evaluating the in vivo efficacy and molecular pharmacology of artefenomel in castration-resistant prostate cancer models
Principal Investigators: Michael McManus, PhD* Project Title: Unlocking the key drivers and dependencies of Prostate Cancer using CRISPR GEMMS.
*HDFCCC Molecular Oncology Program Member ^HDFCCC Prostate Cancer Program Member
Principal Investigators: Kole Roybal, PhD & Bin Liu, PhD
Project Title: Synthetic receptor--‐engineered T cells for prostate cancer therapy.
Principal Investigator: Nadav Ahituv, PhD
Project Title: Highly specific and sensitive prostate cancer diagnosis using nullomers.
Principal Investigators: Davide Ruggero, PhD, Al Burlingame, PhD & Hao Nguyen, MD, PhD
Project Title: Characterization of the prostate cancer proteome and its functional implications in cancer evolution.
Principal Investigators: Michael Evans, PhD & Adam Renslo, PhD
Project Title: Exploiting ferroaddiction in castration resistant prostate cancer for precision therapy.
Principal Investigator: Renuka Sriram, PhD
Project Title: Metabolic Characterization and Detection of Targeted Therapeutic Response of PSMA-negative Transdifferentiated Advanced Prostate Cancer with Hyperpolarized 13C MRI.
Principal Investigator: Ross Okimoto, MD & Franklin Huang, MD, PhD
Project Title: Molecular and functional dissection of the CIC-ERF co-deletion in aggressive human prostate cancer.
Principal Investigators: Robert Flavell, MD, PhD & Bin Liu, PhD
Project Title: Combination of antibody drug conjugate and radioligand or external beam radiotherapy for treatment of metastatic castration resistant prostate cancer.
Principal Investigator: Lei Wang, PhD
Project Title: Developing covalent protein drugs via PERx to target aggressive prostate cancer.
Principal Investigators: Danica Fujimori, PhD & Lawrence Fong, MD
Project Title: Potentiating Prostate Cancer Immunogenicity through Epigenetic Modulation
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.
Principal Investigators: Matthew Krummel, PhD & Vincent Chan, PhD
Co-Investigators: Felix Feng, MD & Eric Small, MD
Project Title: Investigating the Tumor Immune Microenvironment in Metastatic Prostate Cancer
Addition support for this project will be provided by the Bakar ImmunoX Initiative at UCSF.
Principal Investigator: David Quigley, PhD
Project Title: Investigating the evolution of targeted therapy resistance in advanced prostate tumors
This project will be cosponsored with the Center for BRCA Research.
Principal Investigators: Robert Blelloch, MD, PhD & James Fraser, PhD
Project Title: Enhancing the anti-tumor immune response in prostate cancer through the inhibition of exosomal PD-L1
Principal Investigators: Luke Gilbert, PhD & Eric Small, MD
Project Title: Systematic elucidation of WNT signaling in Prostate Cancer
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.
Principal Investigators: Davide Ruggero, PhD & Hao Nguyen, MD, PhD
Project Title: Deciphering the role of the translational oncogenic program in prostate cancer
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.
The BIPCR believes that the consortium model will allow participants to take advantage of cross-disciplinary expertise available at UCSF and our partner groups, regardless of prior experience working in prostate cancer research. Bringing together teams of researchers with a wide knowledge base will enable us to tackle complex and important problems. The cooperative nature of the consortiums will allow us to address ambitious projects, bring complementary knowledge and diverse research methods.
- Living Cellular Therapies Consortium Led by: Alan Ashworth, PhD, FRS Designed as an interdisciplinary research collaboration, provide opportunities for investigators to apply their best ideas, and lead to the development of innovative cellular therapy approaches.
- Genomics Consortium Led by: Felix Feng, MD. The consortium seeks to address the gaps in our current genomics data sets and apply our resources to answer pressing, unanswered questions in the field.
If you are a UCSF researcher interested in joining either the Living Cellular Therapies or Genomics Consortium, please email [email protected].