The PCF Challenge Award Winners – Class of 2019 recipients are:
Principal Investigators: John Lee, MD, PhD (Fred Hutchinson Cancer Research Center), Peter Nelson, MD (Fred Hutchinson Cancer Research Center)
Co-Investigators: Vicky Qian Wu, PhD (Fred Hutchinson Cancer Research Center), Navin Pinto, MD (Seattle Children’s Research Institute), Julie Park, MD (Seattle Children’s Research Institute), Diana DeLucia, PhD (Fred Hutchinson Cancer Research Center), Michael Jensen, MD (Seattle Children’s Research Institute)
Project Title: L1CAM Chimeric Antigen Receptor T Cell Therapy for Small Cell Neuroendocrine Prostate Cancer
- Small cell neuroendocrine prostate cancer (SCNPC) is a highly aggressive and incurable form of advanced, therapy-resistant prostate cancer. The development of new treatments that are effective against SCNPC is an urgent unmet medical need.
- Dr. John Lee and team are developing a novel CAR-T cell immunotherapy able to target and kill SCNPC cells.
- CAR T cells are genetically engineered immune cells, that are made by uploading a patient’s own T cells with a gene that enables them to target and kill cells expressing a specific target protein.
- Dr. Lee and team previously found that L1CAM may represent an ideal CAR T cell target in SCNPC, neuroblastoma, and other cancers. The team has already developed a L1CAM-targeting CAR T cell and have initiated a clinical trial testing this CAR T cell in patients with neuroblastoma.
- In this project, the team will evaluate the potential efficacy of L1CAM-CAR T cells in preclinical prostate cancer models.
- The team will also perform studies to improve the safety, efficacy and persistence of L1CAM-targeting CAR T cells, in order to develop a treatment that will be most effective in prostate cancer. Strategies to improve CAR T cells, such as adding in additional genetically engineered proteins to enable the T cells to resist immune suppression or have improved tumor-specific targeting and better safety, will be tested.
- Finally, the team will initiate a phase 1 clinical trial testing the most promising L1CAM CAR T cell version in men with advanced SCNPC.
- If successful, this project will develop a promising new immunotherapy that is effective in men with one of the worst forms of prostate cancer.
What this means to patients: Small cell neuroendocrine prostate cancer (SCNPC) is an aggressive and incurable form of prostate cancer for which effective treatments are urgently needed. Dr. Lee and team will develop a novel CAR T cell immunotherapy against SCNPC that will engineer a patients’ own immune cells to target and kill their cancer, and will test the safety and efficacy of this treatment in clinical trials.
Principal Investigator: Eliezer Van Allen, MD (Harvard: Dana Farber Cancer Institute), Nikolaus Schultz, PhD (Memorial Sloan Kettering Cancer Center), Wassim Abida, MD, PhD (Memorial Sloan Kettering Cancer Center), Deborah Schrag, MD, MPH (Harvard: Dana Farber Cancer Institute)
Co-Investigators: Haitham Elmarakeby, PhD (Harvard: Dana Farber Cancer Institute)
Project Title: A Genomics-Guided Clinical Interpretation and Translational Discovery Engine for Prostate Cancer
- Prostate cancer is a highly variable disease, which differs across and even within patients. Understanding the biological and clinical variations and how best to treat individual patients is of great need. The ability to harness and learn from the vast amounts of existing multi-dimensional patient data will enable researchers and clinicians to identify and apply optimal precision medicine treatment strategies for all patients.
- Eliezer Van Allen and team will develop a prostate cancer patient registry that will capture clinical data (which includes treatments and outcomes), pathology and imaging data, and data on tumor mutations, from over 10,000 patients spanning all stages of disease.
- The team will develop artificial intelligence algorithms to identify clinical and/or molecular features that predict patient outcomes and responses to treatments. Relationships that are identified between genomic alterations and prostate cancer outcomes will be studied and validated in experimental models.
- A significant amount of clinical information is included in medical reports in a non-standardized fashion. The team will develop biomedical natural language models that can extract information from medical reports including disease classification, regression, and survival prediction. The team will also build algorithms to read radiographic images and convert this information into standardized data.
- All of these data will be combined with other patient clinical and molecular data in the registry and used to create a single model that can predict patient outcomes and treatment responses.
- The team will also develop a digital clinical trials framework and an algorithm that will enable clinicians to match patients to precision medicine clinical trials based on their clinical, genomic, and other features.
- If successful, this project will develop a rich data resource for the research and clinical community, as well as algorithms to learn from this data and to apply it directly toward making immediate optimal precision medicine treatment decisions for patients with prostate cancer.
What this means to patients: Precision medicine is an emergent clinical approach in which patients’ treatment plans are made based on their unique personal and tumor features. Dr. Van Allen and team will develop a prostate cancer registry that contains multi-dimensional patient data, and create algorithms that can predict patient outcomes. The team will also build a digital resource to match patients with optimal precision medicine clinical trials. This project will significantly accelerate precision medicine for all men with prostate cancer.
Principal Investigator: Charles Drake, MD, PhD (Columbia University; NewYork-Presbyterian)
Co-Investigators: Raul Rabadan, PhD (Columbia University), Matthew Dallos, MD (Columbia University; NewYork-Presbyterian)
Project Title: Maximizing Androgen Deprivation ImmunoGenICity through PD-1 and IL-8 Blockade in Lethal Prostate Cancer (MAGIC-8)
- Immunotherapy is a promising type of cancer therapy that activates a patient’s own immune system to fight their cancer. Immunotherapy has been highly effective in some cancers such as melanoma and lung cancer, but has yet to be optimized for prostate cancer.
- Charles Drake and team are developing a new immunotherapy treatment regimen that can effectively activate anti-tumor immune responses in prostate cancer.
- The team previously discovered that prostate tumors secrete an immune suppressive protein, IL-8, especially during treatment with androgen deprivation therapy (ADT).
- Based on these findings, the team is conducting a clinical trial (MAGIC-8) which combines a novel IL-8-targeting treatment, with the immune activating therapy nivolumab, and ADT, in men with hormone-sensitive recurrent prostate cancer.
- In this project, the team will use samples from the patients on this trial to investigate key biological changes needed to re-establish anti-tumor immunity in prostate cancer and identify biomarkers that can predict treatment responses.
- The team will determine the impact of this immunotherapy combination treatment regimen on the types and numbers of immune cells infiltrating the tumor, including whether the treatment alters the balance between tumor-killing and tumor-promoting immune cell types.
- How this immunotherapy regimen affect the total body (systemic) immune system state will be investigated.
- Whether specific tumor mutations or expression of master cancer-driving proteins are associated with clinical responses to treatment with IL-8-blockade and nivolumab will be investigated.
- If successful. This project will result in the development of a new immunotherapy regimen that will extend the lives of patients, as well as uncover biology and biomarkers of treatment responses.
What this means to patients: New strategies are needed in order to harness the power of the immune system as an effective therapeutic in men with prostate cancer. Dr. Drake and team are conducting a clinical trial testing a novel immunotherapy regimen that combines a drug that blocks immune suppression with a drug that enhances anti-cancer immune activity. This project will determine the clinical and biological effects of this treatment in patients, and develop biomarkers that can predict which patients are most likely to respond.
Principal Investigators: Veda Giri, MD (Thomas Jefferson University), Stacy Loeb, MD (New York University)
Co-Investigators: Amy Leader, PhD (Thomas Jefferson University), Scott Keith, PhD, (Thomas Jefferson University), Philip Massey, PhD (Drexel University), Colette Hyatt, MS (Thomas Jefferson University), Heather Cheng, MD, PhD (University of Washington)
Project Title: Technology-enhanced AcceleRation of Germline Evaluation for Therapy – The TARGET study
- Approximately 12% of men with metastatic prostate cancer harbor inherited mutations in DNA damage repair (DDR) genes, such as BRCA1 and BRCA2, which likely drove the development of their disease.
- Based on these findings, NCCN guidelines now recommend genetic counseling and genetic testing for cancer risk genes in all men with metastatic prostate cancer, all men with unfavorable intermediate risk to high risk prostate cancer, men with Gleason score >=7 of Ashkenazi Jewish ancestry, and men with lower risk disease based upon family history. These recently expanded criteria have resulted in significant knowledge, practice, and awareness gaps regarding genetic testing for prostate cancer at the provider, patient, and population levels.
- Veda Giri and team propose to comprehensively assess technology-based solutions to address these knowledge, practice, and awareness gaps regarding genetic testing for men with prostate cancer.
- The team will identify provider-based barriers and facilitators to implementation of genetic counseling and testing for men with prostate cancer by performing interviews with medical oncologists, radiation oncologists and urologists across practice settings.
- The team is developing a genetics mobile app for providers which has educational modules on prostate cancer genetic counseling and testing and includes a decision-support tool to identify men with prostate cancer who meet NCCN guidelines for genetic testing. The team will test the quality and performance of the app with urologists, medical and radiation oncologists, and will use feedback to refine the app.
- The team will develop an interactive, multimedia web-based pretest genetic education (WBGE) tool for patients and conduct a randomized trial comparing this tool with traditional genetic counseling for facilitating informed and timely genetic testing for men with lethal/predicted lethal prostate cancer. The provider-based genetics mobile app will be used to aid physicians in identifying patients who should be accrued to this trial.
- The team will develop and test social media strategies and ad campaigns to educate and increase public awareness about prostate cancer genetics.
- If successful, this project will develop mobile and web-based tools to educate physicians, patients and the public on prostate cancer genetics and facilitate timely identification of men with prostate cancer who meet NCCN guidelines for genetic testing.
What this means to patients: A significant number of men with prostate cancer carry inherited cancer risk genes which drove the development of their disease. Dr. Giri and team will develop tools to educate physicians, patients and the public on prostate cancer genetics and identify patients who should undergo genetic counseling and testing. These studies will improve outcomes for patients and their families as identification of inherited cancer risk genes can inform precision treatment selection for prostate cancer patients and identify families at increased risk for prostate and other cancers.
Principal Investigators: Salma Kaochar, PhD (Baylor College of Medicine), Nicholas Mitsiades, MD, PhD (Baylor College of Medicine)
Co-Investigators: Michael Ittmann, MD, PhD (Baylor College of Medicine/Michael E. DeBakey Veterans Affairs Medical Center), Anita Sabichi, MD (Baylor College of Medicine/Michael E. DeBakey Veterans Affairs Medical Center), Cristian Coarfa, PhD (Baylor College of Medicine), Lori Banks, PhD (Baylor College of Medicine), Lutfi Abu Elheiga, PhD (Baylor College of Medicine)
Project Title: Targeting Castration Resistant Prostate Cancer with Novel Onco-Metabolic Inhibitors
- Altered metabolism is a critical factor in prostate cancer progression, as cancer cells depend on increased energy and production of metabolites including lipids and cholesterol to maintain rapid cell growth. There are currently no approved drugs for prostate cancer that target altered metabolism.
- The sterol regulatory element binding proteins (SREBPs) are master regulators of the enzymes that synthesize cholesterol and unsaturated fatty acids. SREBPs are frequently overexpressed in prostate cancer and are associated with disease aggressiveness and unfavorable outcomes. Inhibiting SREBPs may represent a promising new treatment strategy for metabolically driven tumors such as prostate cancer.
- Salma Kaochar and team will investigate the therapeutic potential of targeting SREBPs in prostate cancer.
- The team will investigate the expression of SREBPs in large prostate cancer patient cohorts, and determine their associations with clinical factors including cancer aggressiveness and patient outcomes.
- Whether SREBP expression correlates with other prostate cancer oncogenic pathways such as the androgen receptor (AR), MYC, and EZH2, will be determined.
- FGH-1927 is a novel SREBP-inhibitor with promising drug-like properties that was originally developed for the treatment of obesity and metabolic disorders and has not yet been tested in cancer. The team will determine the anti-cancer activity and mechanism of action of FGH-1927 in preclinical prostate cancer models.
- If successful, this project will establish key proof-of-concept mechanistic, efficacy and safety data for the use of a novel small molecule inhibitor of SREBPs for the treatment of lethal castration resistant prostate cancer (CRPC).
What this means to patients: Increased production of lipids and cholesterol are a hallmark of lethal prostate cancer. Dr. Kaochar and team will investigate the potential for targeting SREBPs, master regulators of lipid and cholesterol synthesis, as a novel treatment strategy in prostate cancer. This may lead to a new class of treatments for prostate cancer that may have particular relevance in prostate cancer patients who are obese, are African American, or have castration resistant prostate cancer (CRPC), as these are even more highly associated with altered metabolism.
Principal Investigators: Sarki Abdulkadir, MD, PhD (Northwestern University), Gary Schiltz, PhD (Northwestern University)
Co-Investigators: Debabrata Chakravarti, PhD (Northwestern University), Bin Zhang, MD (Northwestern University), Michael Burns, MD, PhD (Northwestern University)
Project Title: Targeting MYC in Prostate Cancer
- The MYC proteins (c-MYC, L-MYC and N-MYC) are critical cancer-promoting genes that drive up to 70% of all cancers, including a significant proportion of prostate cancers.
- Preclinical studies have suggested that MYC may be an effective treatment target in advanced prostate cancer. However, MYC has proved difficult to target, and there are currently no clinically viable small molecule MYC-inhibitors available.
- Sarki Abdulkadir and team will develop new small molecule inhibitors for targeting MYC in prostate cancer.
- The team has already developed a series of MYC inhibitors that have shown excellent pharmacokinetic, toxicological and anti-tumor activity profiles in MYC-driven models of prostate cancer and leukemia. In this project, the team will perform additional chemistry to create MYC-inhibitors with further improved potency, selectivity, pharmacokinetics, and safety, which can be tested in clinical trials.
- The effect of MYC-inhibitors on MYC activity and prostate cancer cell growth will be determined using preclinical prostate cancer models.
- The potential for combining MYC-inhibitors with other treatments such as AR-targeted therapy, platinum chemotherapy, and the AURKA inhibitor CD532, will be investigated in preclinical models.
- Finally, the team will determine whether MYC-inhibitors can sensitize prostate cancer to treatment with checkpoint immunotherapy, and identify the mechanisms that contribute to synergy between these treatments.
- If successful, this project will result in the development of a new class of MYC-targeting therapies that will be active in prostate cancer as well as many other types of cancers, and identify promising combination treatment strategies.
What this means to patients: The MYC genes are some of the most important drivers of prostate cancer and many other types of cancer, but effective drugs that can target these proteins have yet to be developed. Dr. Abdulkadir and team will develop a new class of MYC-inhibitors that will be ready for testing in clinical trials and will identify combination treatment strategies for further increasing the efficacy of these new drugs.
Principal Investigator: Andrea Alimonti, MD (Institute of Oncology Research), Johann de Bono, MD, PhD (The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust)
Co-Investigators: Arianna Calcinotto, PhD (Institute of Oncology Research), Adam Sharp, MD, PhD (The Institute of Cancer Research and The Royal Marsden Hospital), Antje Neeb, PhD (The Institute of Cancer Research), Bora Gurel, MD (The Institute of Cancer Research), Jon Welti, PhD (The Institute of Cancer Research), Daniela Brina, PhD (Institute of Oncology Research)
Project Title: Targeting Tumor-Infiltrating Myeloid Cells for Prostate Cancer Therapy
- Myeloid-derived suppressor cells (MDSCs) are a class of immune cells that infiltrate tumors in large numbers and promote cancer growth. Targeting these cells represents a promising therapeutic approach, however effective treatments remain to be developed.
- Andrea Alimonti and team have found that MDSCs fuel prostate cancer growth by secreting the protein IL-23. The team will investigate other mechanisms by which MDSCs drive prostate cancer growth and the therapeutic potential for targeting IL-23.
- To better understand the role of MDSCs in prostate cancer and identify druggable targets, the team will identify proteins that are secreted or present on the surface of MDSCs in prostate tumors.
- The team will test the impact of targeting these factors in preclinical prostate cancer models and will determine how they impact tumor growth, or if they are associated with specific tumor mutations or patient outcomes.
- The team will determine if any of the factors secreted by MDSCs can be co-targeted with IL-23 to maximize anti-tumor activity, using preclinical models.
- The team will initiate a phase 1/2 clinical trial testing the safety and efficacy of the therapeutic anti-IL-23 antibody tildrakizumab in combination with abiraterone in advanced prostate cancer.
- Correlative studies will be performed using samples from patients on this trial to identify mechanisms of action, potential biomarkers for selecting patients most likely to benefit, and any drug-resistance mechanisms.
- If successful, this project will lead to an effective new treatment for men with prostate cancer.
What this means to patients: Myeloid-derived suppressor cells (MDSCs) are a class of immune cells which drive prostate cancer growth and represent promising therapeutic targets. Dr. Alimonti and team will determine the mechanisms by which MDSCs drive tumor growth and identify druggable targets. The team will initiate a proof-of-concept clinical trial to test an inhibitor of a major tumor-driving protein secreted by MDSCs, IL-23, which may lead to a new, life-prolonging treatment for patients.
Principal Investigators: Johannes Czernin, MD (University of California, Los Angeles), Caius Radu, MD (University of California, Los Angeles), Matthew Rettig, MD (University of California, Los Angeles)
Co-Investigators: Jeremie Calais, MD, MSc (University of California, Los Angeles), Robert Reiter, MD, MBA (University of California, Los Angeles), Magnus Dahlbom, PhD (University of California, Los Angeles), Roger Slavik, PhD (University of California, Los Angeles), David Dawson, MD, PhD (University of California, Los Angeles), David Ulmert, MD, PhD (University of California, Los Angeles), Katharina Lueckerath, PhD (University of California, Los Angeles), Christine Mona, PhD (University of California, Los Angeles)
Project Title: Towards Curative RLT in Prostate Cancer Through Dosimetry Optimization, Combination Therapies, and Stroma Targeting
- PSMA-targeted radionuclide therapy is a novel and highly promising new treatment under development for prostate cancer. This new therapy is composed of radioactive isotopes attached to molecules that target the prostate cancer protein PSMA, thereby bringing radiation directly to tumor cells and killing them.
- PSMA-targeted radionuclide therapy has been promising in clinical trials for metastatic castration resistant prostate cancer (mCRPC), however ~50% of patients with PSMA-positive tumors do not respond to this treatment.
- Dr. Johannes Czernin and team will investigate the mechanisms of treatment responses and resistance and develop clinical strategies to improve the efficacy of PSMA-targeted radionuclide therapy.
- In this project, Dr. Czernin and team will use prostate cancer preclinical models to determine the optimal radiation doses for PSMA-targeted radionuclide therapies that use alpha- or beta-particle emitting isotopes, as single agents or in combination.
- The team will identify mechanisms of tumor resistance to PSMA-targeted radionuclide therapy, and identify new combination treatment strategies to overcome resistance.
- Whether cancer associated fibroblasts or other cells in the tumor microenvironment play a role in resistance to PSMA-targeted radionuclide therapy will be investigated. The team will also test a novel radionuclide therapy targeting the fibroblast activation protein (FAP) on cancer associated fibroblasts, in combination with PSMA-targeted radionuclide therapy.
- If successful, this project will optimize clinical use of PSMA-targeted radionuclide therapy for the treatment of advanced prostate cancer, and identify promising new combination treatment strategies that may further improve patient outcomes.
What this means to patients: PSMA-targeted radionuclide therapy is a promising new treatment approach, but more research is needed to maximize its clinical efficacy. Dr. Czernin and team will establish the optimal dose and treatment approach for PSMA-targeted radionuclide therapy, and will identify new combination treatment approaches to avoid the development of therapeutic resistance and further improve patient outcomes.
Principal Investigators: Gerhardt Attard, MD, PhD (University College London), Mahesh Parmar, MSc (University College London), Noel Clarke, MBBS (The Christie NHS Foundation Trust)
Co-Investigators: Marina Parry, PhD (University College London), Daniel Berney, MBBS (Queen Mary University of London), Louise Brown, PhD (University College London), Nicholas James, MBBS, PhD (Queen Elizabeth Hospital)
Project Title: Expression-Based Treatment Stratification of Hormone-Sensitive Prostate Cancer Starting Long-Term Androgen Deprivation Therapy in the Multi-Centre STAMPEDE Platform Trial
- Recent phase III clinical trials have established that in men with metastatic hormone sensitive prostate cancer (mHSPC) who are starting treatment with long-term androgen deprivation therapy (ADT), the addition of docetaxel chemotherapy or androgen receptor (AR)-targeted therapies (abiraterone, enzalutamide, apalutamide, darolutamide) can improve progression free and/or overall survival. However, it is still unclear whether certain men would benefit most from ADT alone, or a specific combination therapy.
- Dr. Gerhardt Attard and team are studying whether certain men would benefit most from ADT alone vs. ADT + an AR-targeted therapy, using patient samples from the STAMPEDE clinical trial.
- STAMPEDE is a multi-arm, multi-stage randomized clinical trial being conducted in Europe (UK and Switzerland) that is comparing the efficacy of several different treatment regimens in men with prostate cancer who are starting long-term ADT. One practice-changing finding made by STAMPEDE was that the addition of abiraterone in men starting ADT improves overall survival.
- In this project, Dr. Attard and team will investigate gene expression in tumors from patients on STAMPEDE who were randomized to receive ADT vs. ADT + abiraterone. This data will be used to develop and validate a gene expression-based biomarker to identify patients that derive the greatest benefit from addition of AR-targeted therapy to ADT.
- The team will investigate whether radiological disease volume, pattern of metastases at presentation, and sites of metastatic progression, can be integrated with the gene expression-biomarker to better define which treatments are most beneficial for which patients.
- These studies will be integrated into the STAMPEDE trial protocol such that if successful, the results generated will be considered “level 1” evidence and support clinical implementation of this biomarker for selection of patients for addition of AR-targeting therapies at start of long-term ADT.
What this means to patients: The addition of docetaxel chemotherapy or AR-targeted therapies in men with advanced prostate cancer who are starting long-term ADT can significantly improve outcomes, however is it still unclear which treatment strategy will be most beneficial for an individual patient. Dr. Attard and team will develop a clinical-grade biomarker that will enable the identification of patients who should receive ADT alone vs. ADT + AR-targeted therapy. This project will lead to improved management and outcomes of men with hormone-sensitive prostate cancer.
Principal Investigators: Li Xin, PhD (University of Washington), Pete Nelson, MD, PhD (Fred Hutchinson Cancer Research Center), Calvin Kuo, MD, PhD (Stanford University)
Co-Investigators: Xing Wei, PhD (University of Washington), Eva Corey, PhD, (University of Washington), Colm Morrissey, PhD (University of Washington)
Project Title: A Systematic Approach for Targeting WNT Signaling in Metastatic Prostate Cancer
- The WNT pathway is a fundamental growth control pathway that is important during development and for maintenance of stem cells, but can also drive cancer. WNT pathway mutations have been identified in ~18% of metastatic castration-resistant prostate cancer (mCRPC) cases. However, the role of the WNT pathway in prostate cancer and its potential as a therapeutic target is largely unknown.
- Li Xin and team will investigate the biology of the WNT pathway in prostate cancer and identify therapeutic strategies for targeting the WNT pathway.
- The team will investigate which WNT pathway signaling proteins are expressed in advanced prostate cancer patient samples and whether tumor cells or other cell types in the tumor microenvironment express these proteins.
- The role of WNT signaling in tumor vs. non-tumor (stromal) cells within prostate tumors will be investigated in preclinical models. Whether stromal WNT signaling affects prostate cancer progression, and whether the TGFβ signaling pathway is involved in these effects will be determined. This knowledge will instruct whether simultaneous inhibition of the WNT pathway in both tumor and stroma is beneficial or should be avoided.
- The WNT signaling pathway includes 19 WNT ligands and 10 different FZD receptors. The team will investigate whether targeting multiple FZD receptors has therapeutic potential for the treatment of prostate cancer in preclinical models.
- If successful, this project will detail the role of the WNT pathway in prostate cancer and identify optimal therapeutic strategies for targeting WNT.
What this means to patients: The WNT signaling pathway is a common cancer driver and may be a promising therapeutic target in prostate cancer. Dr. Xin and team will identify which WNT proteins are expressed by which cells in prostate tumors, and determine their role in prostate cancer biology and as potential therapeutic targets. The knowledge gained from this project will advance the development of successful WNT-targeting therapeutics in prostate cancer.
Principal Investigator: Hao Nguyen, MD, PhD (University of California, San Francisco)
Co-Investigators: Davide Ruggero, PhD (University of California, San Francisco), Peter Carroll, MD, MPH (University of California, San Francisco)
Project Title: Targeting the Translational Oncogenic Program Through eIF4E and eIF4A in Metastatic Castration Resistant Prostate Cancer Using Three Novel Small Molecule Inhibitors (eFT 508/Tomivosertib, eFT 2560, and eFT 226)
- eIF4E is a protein that is required for gene expression and is necessary for life. Cancer cells also need this protein to maintain their survival, and typically boost its activity. Whether targeting eIF4E may be have therapeutic benefit in cancer needs to be studied.
- Hao Nguyen and team have discovered that eIF4E is highly active in all stages of prostate cancer. The team will investigate its potential as a therapeutic target and the mechanisms by which it drives prostate cancer growth.
- The team will test the efficacy of several small molecule inhibitors of eIF4E and its partner eIF4A in combinations with one another or with enzalutamide in a preclinical patient-derived prostate cancer models. The inhibitors to be tested include two developed by the team, and a third that was previously developed and is currently in a stage 2 clinical trial in advanced prostate cancer.
- The mechanisms by which eIF4E/A drive prostate cancer growth and the effects of eIF4E/A-inhibition on prostate cancer gene expression will be determined.
- Whether eIF4E levels or activity in prostate cancer samples can be used as biomarkers to select patients who are most likely to respond to eIF4E and eIF4A-targeted therapies will be determined.
- The mechanisms by which prostate cancer cells develop resistance to eIF4E and eIF4A-targeted therapies will be determined.
- If successful, this project will determine the biology by which eIF4E/A drive prostate cancer and lead to clinical trials for this new class of drugs.
What this means to patients: eIF4E is a protein that drives prostate cancer growth and progression. Dr. Nguyen and team will determine the biology by which eIF4E and its partner eIF4A drive cancer growth and will determine the therapeutic potential for targeting these proteins, which may lead to clinical trials for a new class of drugs that may impact all stages of prostate cancer.
Principal Investigator: Donald McDonnell, PhD (Duke University)
Co-Investigators: Damian Young, PhD (Baylor College of Medicine), Ryan Soderquist, PhD (Duke University), Andrew Armstrong, MD (Duke University), Kris Wood, PhD (Duke University)
Project Title: HOXB13 as a Therapeutic Target in Prostate Cancer
- The androgen receptor (AR) is a critical driver of prostate cancer and a major therapeutic target. However, cancers often develop resistance to AR-targeted therapy and progress to lethal disease.
- HOXB13 has been identified as a major co-factor of AR in prostate cancer but also drives the growth of AR-negative castration-resistant prostate cancer.
- Donald McDonnell and team will investigate the therapeutic potential for targeting HOXB13 in prostate cancer.
- The team will employ drug discovery and chemistry approaches to develop small molecules that cause the degradation of HOXB13 proteins in prostate cancer cells.
- The anti-cancer activity of the most promising HOXB13-targeting drugs developed will be evaluated in preclinical models.
- The team will study whether HOXB13 expression in circulating tumor cells (CTCs) may serve as a pharmacodynamic marker for evaluating the activity of HOXB13-targeting drugs in patients and to identify patients appropriate for therapy.
- Other genes that promote the expression or activity of HOXB13 in prostate cancer will be identified and their potential as therapeutic targets alone and in combination with HOXB13-inhibitors will be investigated. If promising targets are identified, the team may develop drugs against these targets.
- If successful, this project will develop a promising new class of HOXB13-targeting drugs that can enter testing in clinical trials and define the patient populations in whom these drugs are most likely to be successful.
What this means to patients: HOXB13 has been identified as a critical driver of AR-dependent and AR-independent prostate cancers but has not yet been explored as a therapeutic target. Dr. McDonnell and team will develop a novel class of HOXB13-targeting drugs as well as identify other HOXB13-regulators that are promising therapeutic targets. This may lead to a new treatment that may have utility at all stages of prostate cancer.
Principal Investigators: Joshua Lang, MD, MSc (University of Wisconsin), Steve Cho, MD (University of Wisconsin), Kenneth Pienta, MD (Johns Hopkins University), David Jarrard, MD (University of Wisconsin), David Quigley, PhD (University of California, San Francisco)
Co-Investigators: David Beebe, PhD (University of Wisconsin), John Denu, PhD (University of Wisconsin), Shane Wells, MD (University of Wisconsin), Wei Huang, MD (University of Wisconsin), Alejandro Roldán-Alzate, PhD (University of Wisconsin), Tyler Bradshaw, PhD (University of Wisconsin), Irene Ong, PhD (University of Wisconsin), David Kosoff, MD (University of Wisconsin), Sarah Amend, PhD (Johns Hopkins University)
Discovering drivers of treatment response and resistance in the multi-focal prostate tumor microenvironment
- The men at greatest risk of progressing to castration resistance prostate cancer (CRPC) and death are those that initially present with multiple high-grade primary prostate tumors (“multi-focal”), and/or with distant metastases.
- Joshua Lang and team hypothesize that tumor heterogeneity (molecular and genomic diversity of the tumor cell population) and support from non-tumor cells in the tumor microenvironment, are two major factors that enable multi-focal primary prostate cancer to develop resistance to therapy.
- In this project, Dr. Lang and team will investigate the mechanisms that give rise to multi-focal, treatment-resistant prostate cancer.
- The team will conduct a clinical trial testing a combination of docetaxel + hormonal therapy prior to prostatectomy in men diagnosed with high-risk non-metastatic prostate cancer or with limited numbers of distant metastases. Patients on this trial will first undergo PSMA-PET + MRI imaging to identify sites of disease at diagnosis and after receiving treatment with docetaxel + hormonal therapy. Thereafter, patients will undergo radical prostatectomy. Patients will undergo a third PSMA-PET/MRI scan at the time of PSA progression or 12 months post-prostatectomy, whichever occurs first.
- The team will investigate whether any PSMA-PET/MRI imaging features are able to predict treatment response vs. resistance. Other new imaging technologies will also be tested in a subset of patients.
- Prostatectomy specimens will be dissected using a special “3D-mold” methodology, which enables the tumor sites evaluated to be mapped to the PSMA-PET/MRI scans. Different sites of primary prostate cancer corresponding to those that responded vs. were resistant to therapy (as determined by pre- vs. post-treatment PSMA-PET/MRI scans), will be dissected and evaluated for distinguishing genomic alterations, gene expression patterns, and the types and activities of non-tumor cells present.
- The team will also evaluate the types and activities of different populations of immune cells from tumor sites that responded vs. progressed on therapy.
- If successful, this team will identify mechanisms and biomarkers of high-risk primary prostate cancers that respond vs. develop resistance to treatment with docetaxel + hormonal therapy. This will enable better identification of patients who have higher-risk disease, as well as lead to new therapeutic concepts.
What this means for patients: Men diagnosed with high risk prostate cancer present a treatment dilemma that needs clarity. Dr. Joshua Lang and team will combine advanced imaging, 3-dimensional reconstruction of the prostate and associated cancer, biology and medical intervention to improve outcomes for patients with this subtype of prostate cancer. Funding this research project could prevent or slow metastatic prostate cancer in as many as 10,000 patients per year.