Prostate cancer research: The next generation; report from the 2019 Coffey-Holden Prostate Cancer Academy Meeting.

INTRODUCTION: The 2019 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Prostate Cancer Research: The Next Generation," was held 20 to 23 June, 2019, in Los Angeles, California. METHODS: The CHPCA Meeting is an annual conference held by the Prostate Cancer Foundation, that is uniquely structured to stimulate intense discussion surrounding topics most critical to accelerating prostate cancer research and the discovery of new life-extending treatments for patients. The 7th Annual CHPCA Meeting was attended by 86 investigators and concentrated on many of the most promising new treatment opportunities and next-generation research technologies. RESULTS: The topics of focus at the meeting included: new treatment strategies and novel agents for targeted therapies and precision medicine, new treatment strategies that may synergize with checkpoint immunotherapy, next-generation technologies that visualize tumor microenvironment (TME) and molecular pathology in situ, multi-omics and tumor heterogeneity using single cells, 3D and TME models, and the role of extracellular vesicles in cancer and their potential as biomarkers. DISCUSSION: This meeting report provides a comprehensive summary of the talks and discussions held at the 2019 CHPCA Meeting, for the purpose of globally disseminating this knowledge and ultimately accelerating new treatments and diagnostics for patients with prostate cancer.

Tumor cell heterogeneity and resistance; report from the 2018 Coffey-Holden Prostate Cancer Academy Meeting.

INTRODUCTION: The 2018 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Tumor Cell Heterogeneity and Resistance," was held in Los Angeles, California from June 21 to 24, 2018. METHODS: The CHPCA Meeting is a unique, discussion-oriented scientific conference convened annually by the Prostate Cancer Foundation (PCF), which focuses on the most critical topics in need of further study to advance the treatment of lethal prostate cancer. The 6th Annual CHPCA Meeting was attended by 70 investigators and concentrated on prostate cancer heterogeneity and treatment resistance. RESULTS: The meeting focused on topics including: recognition of tumor heterogeneity, molecular drivers of heterogeneity, the role of the tumor microenvironment, the role of heterogeneity in disease progression, metastasis and treatment resistance, clinical trials designed to target resistance and tumor heterogeneity, and immunotherapeutic approaches to target and overcome tumor heterogeneity. DISCUSSION: This review article summarizes the presentations and discussions from the 2018 CHPCA Meeting in order to share this knowledge with the scientific community and encourage new studies that will lead to improved treatments and outcomes for men with prostate cancer.

Beyond the androgen receptor II: New approaches to understanding and treating metastatic prostate cancer; Report from the 2017 Coffey-Holden Prostate Cancer Academy Meeting.

INTRODUCTION: The 2017 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Beyond the Androgen Receptor II: New Approaches to Understanding and Treating Metastatic Prostate Cancer," was held in Carlsbad, California from June 14-17, 2017. METHODS: The CHPCA is an annual scientific conference hosted by the Prostate Cancer Foundation (PCF) that is uniquely designed to produce extensive and constructive discussions on the most urgent and impactful topics concerning research into the biology and treatment of metastatic prostate cancer. The 2017 CHPCA Meeting was the 5th meeting in this annual series and was attended by 71 investigators focused on prostate cancer and a variety of other fields including breast and ovarian cancer. RESULTS: The discussions at the meeting were concentrated on topics areas including: mechanisms and therapeutic approaches for molecular subclasses of castrate resistant prostate cancer (CRPC), the epigenetic landscape of prostate cancer, the role of DNA repair gene mutations, advancing the use of germline genetics in clinical practice, radionuclides for imaging and therapy, advances in molecular imaging, and therapeutic strategies for successful use of immunotherapy in advanced prostate cancer. DISCUSSION: This article reviews the presentations and discussions from the 2017 CHPCA Meeting in order to disseminate this knowledge and accelerate new biological understandings and advances in the treatment of patients with metastatic prostate cancer.

Beyond Seed and Soil: Understanding and Targeting Metastatic Prostate Cancer; Report From the 2016 Coffey-Holden Prostate Cancer Academy Meeting.

INTRODUCTION: The 2016 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Beyond Seed and Soil: Understanding and Targeting Metastatic Prostate Cancer," was held from June 23 to June 26, 2016, in Coronado, California. METHODS: For the 4th year in a row, the Prostate Cancer Foundation (PCF) hosted the CHPCA Meeting, a think tank-structured scientific conference, which focuses on a specific topic of critical unmet need on the biology and treatment of advanced prostate cancer. The 2016 CHPCA Meeting was attended by 71 investigators from prostate cancer and other fields, who discussed the biology, study methodologies, treatment strategies, and critical unmet needs concerning metastatic prostate cancer, with the ultimate goal of advancing strategies to treat and eliminate this disease. RESULTS: The major topics of discussion included: the molecular landscape and molecular heterogeneity of metastatic prostate cancer, the role of the metastatic microenvironment, optimizing immunotherapy in metastatic prostate cancer, learning from exceptional responders and non-responders, targeting DNA repair deficiency in advanced prostate cancer, developing and applying novel biomarkers and imaging techniques, and potential roles for the microbiome in prostate cancer. DISCUSSION: This article reviews the topics presented and discussions held at the CHPCA Meeting, with a focus on the unknowns and next steps needed to advance our understanding of the biology and most effective treatment strategies for metastatic prostate cancer. Prostate 77:123-144, 2017. © 2016 Wiley Periodicals, Inc.

The genomic complexity of primary human prostate cancer.

Prostate cancer is the second most common cause of male cancer deaths in the United States. However, the full range of prostate cancer genomic alterations is incompletely characterized. Here we present the complete sequence of seven primary human prostate cancers and their paired normal counterparts. Several tumours contained complex chains of balanced (that is, 'copy-neutral') rearrangements that occurred within or adjacent to known cancer genes. Rearrangement breakpoints were enriched near open chromatin, androgen receptor and ERG DNA binding sites in the setting of the ETS gene fusion TMPRSS2-ERG, but inversely correlated with these regions in tumours lacking ETS fusions. This observation suggests a link between chromatin or transcriptional regulation and the genesis of genomic aberrations. Three tumours contained rearrangements that disrupted CADM2, and four harboured events disrupting either PTEN (unbalanced events), a prostate tumour suppressor, or MAGI2 (balanced events), a PTEN interacting protein not previously implicated in prostate tumorigenesis. Thus, genomic rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms.

The 22nd annual prostate cancer foundation scientific retreat report.

The 22nd Annual Prostate Cancer Foundation (PCF) Scientific Retreat was convened in Washington, D.C. from October 8 to 10, 2015. This event is the foremost scientific conference in the world focusing on basic, translational, and clinical prostate cancer research with the highest potential for accelerating the understanding of prostate cancer biology and improving the lives and outcomes of prostate cancer patients. Topics highlighted during the 2015 Retreat included: (i) new strategies and treatments for localized high-risk, hormone-naïve, oligometastatic, castrate-resistant, and treatment-refractory prostate cancer settings; (ii) the biology and genomics of tumor heterogeneity and tumor evolution; (iii) new understandings on the mechanisms and targeting of oncogenic drivers of prostate cancer; (iv) bioengineering of novel therapies and drug delivery methods; (v) innovative approaches to tumor immunotherapy; (vi) emerging molecular imaging technologies with improved sensitivity and specificity; and (vii) advancements in prognostic and predictive biomarkers and precision medicine strategies. Prostate 76:1037-1052, 2016. © 2016 Wiley Periodicals, Inc.

Multidisciplinary intervention of early, lethal metastatic prostate cancer: Report from the 2015 Coffey-Holden Prostate Cancer Academy Meeting.

BACKGROUND: The 2015 Coffey-Holden Prostate Cancer Academy Meeting, themed: "Multidisciplinary Intervention of Early, Lethal Metastatic Prostate Cancer," was held in La Jolla, California from June 25 to 28, 2015. METHODS: The Prostate Cancer Foundation (PCF) sponsors an annual, invitation-only, action-tank-structured meeting on a critical topic concerning lethal prostate cancer. The 2015 meeting was attended by 71 basic, translational, and clinical investigators who discussed the current state of the field, major unmet needs, and ideas for addressing earlier diagnosis and treatment of men with lethal prostate cancer for the purpose of extending lives and making progress toward a cure. RESULTS: The questions addressed at the meeting included: cellular and molecular mechanisms of tumorigenesis, evaluating, and targeting the microenvironment in the primary tumor, advancing biomarkers for clinical integration, new molecular imaging technologies, clinical trials, and clinical trial design in localized high-risk and oligometastatic settings, targeting the primary tumor in advanced disease, and instituting multi-modal care of high risk and oligometastatic patients. DISCUSSION: This article highlights the current status, greatest unmet needs, and anticipated field changes that were discussed at the meeting toward the goal of optimizing earlier interventions to potentiate cures in high-risk and oligometastatic prostate cancer patients.

The 21st Annual Prostate Cancer Foundation Scientific Retreat report.

The 21st Annual Prostate Cancer Foundation (PCF) Scientific Retreat was held from October 23-25, 2014, in Carlsbad, CA. This event is the world's foremost scientific meeting focusing on prostate cancer and brings together leading basic, translational and clinical researchers in prostate cancer and other diverse disciplines to discuss the newest findings most likely to advance the understanding of prostate cancer and the clinical care of prostate cancer patients. This year's meeting highlighted themes including: (i) research integrity and standards for scientific reproducibility; (ii) prostate cancer disparities; (iii) mechanisms and models of prostate cancer progression and dormancy; (iv) mechanisms of therapeutic resistance; and (v) advancements in precision medicine treatments, treatment models, and predictive and prognostic biomarkers.

Beyond immune checkpoint blockade: new approaches to targeting host-tumor interactions in prostate cancer: report from the 2014 Coffey-Holden prostate cancer academy meeting.

INTRODUCTION: The 2014 Coffey-Holden Prostate Cancer Academy Meeting, held in La Jolla, CA from June 26 to 29, 2014, was themed: "Beyond Immune Checkpoint Blockade: New Approaches to Targeting Host-Tumor Interactions in Prostate Cancer." METHODS: Sponsored by the Prostate Cancer Foundation (PCF), this annual, invitation-only meeting is structured as an action-tank, and brought together 72 investigators with diverse academic backgrounds to discuss the most relevant topics in the fields of prostate cancer immunotherapy and the tumor microenvironment. RESULTS: The questions addressed at the meeting included: mechanisms underlying the successes and failures of prostate cancer immunotherapies, how to trigger an effective immune response against prostate cancer, the tumor microenvironment and its role in therapy resistance and tumor metastasis, clinically relevant prostate cancer mouse models, how host-tumor interactions affect current therapies and tumor phenotypes, application of principles of precision medicine to prostate cancer immunotherapy, optimizing immunotherapy clinical trial design, and complex multi-system interactions that affect prostate cancer and immune responses including the effects of obesity and the potential role of the host microbiome. DISCUSSION: This article highlights the most significant recent progress and unmet needs that were discussed at the meeting toward the goal of speeding the development of optimal immunotherapies for the treatment of prostate cancer.

The 20th Annual Prostate Cancer Foundation Scientific Retreat report.

The 20th Annual Prostate Cancer Foundation (PCF) Scientific Retreat was held from October 24 to 26, 2013, in National Harbor, Maryland. This event is held annually for the purpose of convening a diverse group of leading experimental and clinical researchers from academia, industry, and government to present and discuss critical and emerging topics relevant to prostate cancer (PCa) biology, and the diagnosis, prognosis, and treatment of PCa patients, with a focus on results that will lend to treatments for the most life-threatening stages of this disease. The themes that were highlighted at this year's event included: (i) mechanisms of PCa initiation and progression: cellular origins, neurons and neuroendocrine PCa, long non-coding RNAs, epigenetics, tumor cell metabolism, tumor-immune interactions, and novel molecular mechanisms; (ii) advancements in precision medicine strategies and predictive biomarkers of progression, survival, and drug sensitivities, including the analysis of circulating tumor cells and cell-free tumor DNA-new methods for liquid biopsies; (iii) new treatments including epigenomic therapy and immunotherapy, discovery of new treatment targets, and defining and targeting mechanisms of resistance to androgen-axis therapeutics; and (iv) new experimental and clinical epidemiology methods and techniques, including PCa population studies using patho-epidemiology.

Beyond the androgen receptor: new approaches to treating metastatic prostate cancer. Report of the 2013 Prouts Neck Prostate Cancer Meeting.

INTRODUCTION: The Prouts Neck Meetings on Prostate Cancer began in 1985 through the efforts of the Organ Systems Branch of the National Cancer Institute to stimulate new research and focused around specific questions in prostate tumorigenesis and therapy. METHODS: These meetings were think tanks, composed of around 75 individuals, and divided equally between young investigators and senior investigators. Over the years, many new concepts related to prostate cancer resulted from these meetings and the prostate cancer community has sorely missed them since the last one in 2007. RESULTS: We report here the first of a new series of meetings. The 2013 meeting focused on defining how the field of treatment for metastatic prostate cancer needs to evolve to impact survival and was entitled: "Beyond AR: New Approaches to Treating Metastatic Prostate Cancer." As castrate resistant prostate cancers escape second generation anti-androgen agents, three phenotypes/genotypes of CRPC appear to be increasing in prevalence and remain resistant to treatment: NeuroEndocrine Prostate Cancer, Persistent AR-Dependent Prostate Cancer, and Androgen Receptor Pathway Independent Prostate Cancer. DISCUSSION: It is clear that new treatment paradigms need to be developed for this diverse group of diseases. The Prouts Neck 2013 Meeting on Prostate Cancer helped to frame the current state of the field and jumpstart ideas for new avenues of treatment.

Frequent somatic mutations of the transcription factor ATBF1 in human prostate cancer.

Cancer often results from the accumulation of multiple genetic alterations. Although most malignancies are sporadic, only a small number of genes have been shown to undergo frequent mutations in sporadic cancers. The long arm of chromosome 16 is frequently deleted in human cancers, but the target gene for this deletion has not been identified. Here we report that ATBF1, which encodes a transcription factor that negatively regulates AFP and MYB but transactivates CDKN1A, is a good candidate for the 16q22 tumor-suppressor gene. We narrowed the region of deletion at 16q22 to 861 kb containing ATBF1. ATBF1 mRNA was abundant in normal prostates but more scarce in approximately half of prostate cancers tested. In 24 of 66 (36%) cancers examined, we identified 22 unique somatic mutations, many of which impair ATBF1 function. Furthermore, ATBF1 inhibited cell proliferation. Hence, loss of ATBF1 is one mechanism that defines the absence of growth control in prostate cancer.

2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF.

Inhibition of angiogenesis is an important new modality for cancer treatment. 2-methoxyestradiol (2ME2) is a novel antitumor and antiangiogenic agent, currently in clinical trials, whose molecular mechanism of action remains unclear. Herein, we report that 2ME2 inhibits tumor growth and angiogenesis at concentrations that efficiently disrupt tumor microtubules (MTs) in vivo. Mechanistically, we found that 2ME2 downregulates hypoxia-inducible factor-1 (HIF) at the posttranscriptional level and inhibits HIF-1-induced transcriptional activation of VEGF expression. Inhibition of HIF-1 occurs downstream of the 2ME2/tubulin interaction, as disruption of interphase MTs is required for HIF-alpha downregulation. These data establish 2ME2 as a small molecule inhibitor of HIF-1 and provide a mechanistic link between the disruption of the MT cytoskeleton and inhibition of angiogenesis.

Prostate Cancer Racial Disparities: A Systematic Review by the Prostate Cancer Foundation Panel.

CONTEXT: Prostate cancer (PCa) is a complex disease that disproportionately impacts Black men in the USA. The structural factors that drive heterogeneous outcomes for patients of differing backgrounds are probably the same ones that result in population-level disparities. The relative contribution of drivers along the PCa disease continuum is an active area of investigation and debate. OBJECTIVE: To critically synthesize the available evidence on PCa disparities from a population-level perspective in comparison to data from "equal access and equal care settings" and to provide a consensus summary of the state of PCa disparities. EVIDENCE ACQUISITION: A plenary panel on PCa disparities presented at the Prostate Cancer Foundation meeting on October 24, 2019 and ensuing discussions are reported here. We used a systematic literature review approach and the Preferred Reporting Items for Systematic Reviews and Meta-analyses to select the most relevant publications. A total of 3333 publications between 2011 and 2021 were retrieved, of which 52 were included in the review; an additional 13 articles on screening guidelines, seminal clinical trials, and statistical methodology were used in the evidence synthesis. EVIDENCE SYNTHESIS: Race disparities in PCa are a result of a complex interaction between socioeconomic factors impacting access to care and ancestral/genetic factors that may influence tumor biology. Black men in the USA continue to have a nearly 1.8 times higher population-level incidence rate than White men. Failure to account for the race-specific incidence burden would continue to lead to residual disparity even after achieving relatively similar outcomes after primary treatment, resulting in a higher long-term mortality burden. Selection bias remains possible in PCa studies, which often rely on highly specific cohorts of Black men with higher use of health care resources that may not represent the average Black patient in the USA. Novel methods including mediation analysis and genetic ancestry rather than self-identified race can optimize analytical models investigating racial disparities and may lead to a better understanding of PCa genomic diversity and behavior. CONCLUSIONS: Our findings emphasize the importance of racially diverse studies, including precision -omics, prevention, and targeted therapy initiatives, to elucidate mechanisms underlying racial differences in outcomes and response to therapy. We propose novel approaches for studying and addressing PCa disparities. Contemporary methods, particularly in the domain of mediation analysis, can promote scientific rigor in understanding these disparities. PATIENT SUMMARY: Inaccurate data interpretation or lack of data altogether for Black men can impact policy and ultimately affect millions of individuals of African origin worldwide. Our review identifies a need to develop and prioritize a strategy for including Black and other men with prostate cancer in intervention studies and randomized clinical trials to halt the widening prostate cancer disparities.

The 17th Annual Prostate Cancer Foundation scientific retreat: meeting report.

Annually the Prostate Cancer Foundation (PCF) organizes a scientific retreat to assemble the premier prostate cancer researchers from around the world to share and review the latest progress made in the field and to evaluate future directions. This report highlights some of the most significant advances made in prostate cancer research in 2010 that were presented at the 17th Annual PCF Scientific Retreat.

Epigenetic and transcriptional analysis reveals a core transcriptional program conserved in clonal prostate cancer metastases.

The epigenomic regulation of transcriptional programs in metastatic prostate cancer is poorly understood. We studied the epigenomic landscape of prostate cancer drivers using transcriptional profiling and ChIP-seq in four clonal metastatic tumors derived from a single prostate cancer patient. Our epigenomic analyses focused on androgen receptor (AR), which is a key oncogenic driver in prostate cancer, the AR pioneer factor FOXA1, chromatin insulator CCCTC-Binding Factor, as well as for modified histones H3K27ac and H3K27me3. The vast majority of AR binding sites were shared among healthy prostate, primary prostate cancer, and metastatic tumor samples, signifying core AR-driven transcriptional regulation within the prostate cell lineage. Genes associated with core AR-binding events were significantly enriched for essential genes in prostate cancer cell proliferation. Remarkably, the metastasis-specific active AR binding sites showed no differential transcriptional output, indicating a robust transcriptional program across metastatic samples. Combined, our data reveal a core transcriptional program in clonal metastatic prostate cancer, despite epigenomic differences in the AR cistrome.

The Prostate Cancer Foundation 16th Annual Scientific Retreat: meeting report.

The 16th Annual Prostate Cancer Foundation (PCF) Scientific Retreat was held September 23-25, 2009 at Incline Village, NV. This report highlights some of the game-changing research reports from this conference.

Prostate Cancer Foundation-Department of Veterans Affairs Partnership: A Model of Public-Private Collaboration to Advance Treatment and Care of Invasive Cancers.

BACKGROUND: Prostate cancer is the most frequently diagnosed and treated cancer in the US Department of Veterans Affairs (VA). As the leading philanthropic source for prostate cancer research, the Prostate Cancer Foundation (PCF) entered into a unique public-private biomedical research partnership with the VA with the goal of addressing the urgent health challenges faced by veterans with prostate cancer. OBSERVATIONS: With a commitment of $50 million from PCF and the VA's vast medical center infrastructure, the PCF-VA partnership has established 12 precision oncology Centers of Excellence to date, forming a collaborative network called the Precision Oncology Program for Cancer of the Prostate (POPCaP) Network. A 4-year review reveals the importance of executive leadership, mission-driven advocacy, setting shared ambitious goals, maximizing existing infrastructure and human capital, recruiting talent and resources, and creating space for adaptation and iteration in the context of a learning health care system. CONCLUSIONS: The PCF-VA partnership seeks to continue translating clinical research into national standards of care for veterans and serves as an innovative model of public-private collaborations for future health initiatives.

Accelerating precision medicine in metastatic prostate cancer.

Despite advances in prostate cancer screening and treatment, available therapy options, particularly in later stages of the disease, remain limited and the treatment-resistant setting represents a serious unmet medical need. Moreover, disease heterogeneity and disparities in patient access to medical advances result in significant variability in outcomes across patients. Disease classification based on genomic sequencing is a promising approach to identify patients whose tumors exhibit actionable targets and make more informed treatment decisions. Here we discuss how we can accelerate precision oncology to inform broader genomically-driven clinical decisions for men with advanced prostate cancer, drug development and ultimately contribute to new treatment paradigms.