Christopher J. Logothetis, M.D.,
Timothy C. Thompson, Ph.D.,
The MD Anderson Cancer Center Prostate Cancer SPORE (Prostate Cancer SPORE) has created a stable and dynamic infrastructure for translational research to meet and successfully address specific challenges in reducing suffering and mortality rates for men with prostate cancer. We continue to build on our capacity to conduct novel, innovative clinical trials and believe that new research projects conducted by our translational research team will yield substantial progress and meaningful changes in clinical practice. In the current proposal, we define our translational research challenges and goals as 1) quantitative definition of prostate cancer risk to eliminate overtreatment of low-risk prostate cancer, 2) development of novel therapeutic approaches to overcoming resistance of castration-resistant prostate cancer (CRPC) to available therapies, and 3) development of novel alternative strategies for CRPC and treatment-refractory disease. We will achieve these translational research goals by identifying and testing novel predictive and prognostic biomarkers to determine the need for therapy in patients with early-stage prostate cancer, developing and testing novel immunotherapy for CRPC, developing and testing a novel approach to overcoming osteocrine-mediated resistance of bone metastasis to therapy, and developing and testing lead-in combination therapy to maximize DNA damage response-targeted therapy for CRPC. We will accomplish our goals via 4 research projects (including one population science research project), 3 support cores (Administrative, Biostatistics and Bioinformatics, and Biospecimen and Pathology), a dynamic Developmental Research Program, and an effective Career Enhancement Program. We are optimistic that our research efforts will contribute to reductions in the incidence, morbidity, and mortality of this devastating disease by translating basic research findings into clinical practice.
Project 1: Integrating Ipilimumab Immunotherapy with Approved Treatment Strategies in CRPC
James P. Allison, Ph.D., Scientific Co-Leader
Padmanee Sharma, M.D., Ph.D., Clinical Co-Leader
The mainstay therapy for castration-resistant prostate cancer (CRPC) consists of agents targeting the androgen receptor (AR) signaling pathway and chemotherapies, which induce anti-tumor responses, and in select men a vaccine and a radiopharmaceutical bone-targeting therapy. The responses with all of these therapies tend to be short-lived. Conversely, treatment with cytotoxic T-lymphocyte antigen 4 (CTLA-4)-targeting drug, ipilimumab, which promotes enhanced T-cell responses and generates memory immune responses, has led to durable regression of metastatic disease and an overall survival benefit. A recent phase 3 trial of ipilimumab in patients with CRPC demonstrated dramatic responses in a subset of them and improved survival in those with favorable clinical characteristics, who also tend to have good responses to therapies targeting the AR signaling pathway. Previous studies demonstrated that inhibition of AR signaling has positive effects on the immune system. We hypothesize that patients with cancers that regress with therapies targeting AR signaling will benefit from the addition of anti-CTLA-4 (ipilimumab) immunotherapy. In addition, given the lack of imaging capabilities to differentiate between tumor growth and tumor infiltration by immune cells as a result of immunotherapy, we propose to develop radiolabeled antibody imaging to evaluate tumor responses to immunotherapy. We aim to rationally integrate anti-CTLA-4 (ipilimumab) immunotherapy with agents targeting the AR signaling pathway to provide durable clinical benefit with improved survival in patients with prostate cancer, and utilize novel imaging techniques to accurately identify tumor responses.
In this project, we will identify molecular changes associated with clinical outcomes of anti-CTLA-4 (ipilimumab) immunotherapy for prostate cancer by examining matched tumor and peripheral blood specimens obtained in recently completed clinical trials. We will perform in-depth examination of the specimens using immunohistochemistry, immunofluorescence, flow cytometry, gene expression studies, and serum cytokine analyses. We will prospectively evaluate the most promising molecular determinants in our novel clinical trial with the aim of linking the interactions between the immune system and the AR signaling pathway. Finally, because our group has identified other immunologic molecules that may be targeted with radiolabeled antibodies for imaging, we propose to evaluate this possibility in murine models to provide data for future clinical trials. Our proposed studies will provide data to enable integration of anti-CTLA-4 (ipilimumab) immunotherapy into a treatment strategy for prostate cancer that induces durable responses and improves overall survival, with the goal of curing the disease. We propose to accomplish this in three Specific Aims.
Aim 1. To identify biological changes indicative of mechanistic pathways that contribute to clinical outcomes in matched tumor and blood specimens obtained from prostate cancer patients given drugs targeting the AR signaling pathway plus anti-CTLA-4 (ipilimumab) immunotherapy.
Aim 2. To determine clinical outcomes after treatment with AR-targeting agents (ARN-509 + abiraterone acetate) followed by concurrent anti-CTLA-4 (ipilimumab) immunotherapy and prospectively evaluate the effectiveness of selected biological pathways identified in Aim 1 to be indicative of mechanistic pathways that contribute to clinical outcomes.
Aim 3. To determine the efficacy of targeting B7-H3 and B7-H4 with radiolabeled monoclonal antibodies as a non-invasive means to detect prostate cancer.
Project 2: Targeting Tumor Microenvironment-Induced Therapy Resistance in Prostate Cancer Bone Metastasis
Sue-Hwa Lin, Ph.D., Scientific Co-Leader
Gary E. Gallick, Ph.D., Scientific Co-Leader
John C. Araujo, M.D., Ph.D., Clinical Co-Leader
Prostate cancer mortality arises primarily from bone metastasis. Recently, several new targeted therapeutics for bone metastasis have improved patient survival. However, resistance to these therapies invariably develops. Thus, there is an urgent need to improve therapy efficacy for bone metastasis. The current theory whereby tumor cells acquire resistance is adaptation of tumor cells in response to therapeutic agents. However, we suspect that “pre-existing” resistance due to tumor/bone interactions prior to therapy may contribute to the unsatisfactory therapy outcomes. Applying agents that block or prevent this “pre-existing” resistance should increase therapy efficacy. To overcome therapy resistance, it is necessary to understand how the aberrant (woven) bone in prostate cancer bone metastases helps the tumor cells survive and resist therapy. We have treated a bone-forming prostate cancer xenograft with cabozantinib, a drug currently being tested for treating bone metastasis, and made a novel finding that therapy-resistant islets of viable tumor cells are mainly localized around tumor-induced woven bone. We have also identified factors (we named “osteocrines”) present in the woven bone and found that they activated survival pathways in tumor cells. These findings lead to our overall hypothesis that osteocrines present in the tumor-induced woven bone are able to activate survival pathways and render prostate cancer cells resistant to therapy.
To test this hypothesis, we will determine:
1. How osteocrines activate signaling pathways that increase prostate cancer cell resistance to therapies?
2. Can these pathways be affected by drugs or antibodies that block the identified osteocrine signaling mechanisms.
3. Are osteocrine pathways activated in human prostate cancer bone metastases.
The goal of this project is to test whether blocking osteocrine-mediated therapy resistance is a promising strategy for enhancing treatment efficacy for patients with bone metastasis. If proven effective in the xenograft animal model, we will test these inhibitors in clinical trials. The inhibitors that we will be testing are already in clinical trials. Our proposed study will bring a new concept, i.e. inhibition of osteocrine-mediated therapy resistance, to bone metastasis treatment. We predict that combining inhibition of tumor microenvironment-mediated therapy resistance with current therapeutics used in bone metastatic prostate cancer will lead to synergistic effects in halting prostate cancer progression in bone.
Aim 1. Examine the ability of osteocrines to confer therapy resistance through activation of FAK. Because many of the osteocrines are integrin ligands that lead to FAK phosphorylation at FAK-Y397, we will study the role of pFAK-Y397 in conferring resistance to therapy in vitro and in vivo.
Aim 2. Examine the effects of second-generation FAK inhibitors (VS-6063 or VS-4718) on overcoming osteocrine-induced therapy resistance in xenograft mouse models. We will: (1) examine the effect of VS-6063 or VS-4718 in inhibiting pFAK-Y397 in prostate cancer cells in vitro; (2) examine the pharmacodynamics of VS-6063 or VS-4718 in prostate cancer xenografts; (3) examine whether the combination of VS-6063 or VS-4718 with chemotherapy can decrease therapy resistance in xenograft models.
Aim 3. Conduct a clinical trial to examine the toxicity and efficacy of a FAK inhibitor (VS-6063 or VS-4718) in men with treatment-refractory bone-metastatic castrate-resistant prostate cancer. We will determine: (1) whether VS-6063 (defactinib) is able to inhibit FAK phosphorylation in mCRPC; (2) whether there is clinical benefit of VS-6063, e.g., if progression-free survival is prolonged in bone metastatic prostate cancer patients; and (3) if there is a molecular signature from the serum or bone marrow tissue profile that indicates a particular patient population is more likely to respond to FAK inhibition with VS-6063.
Project 3: Targeting Androgen Receptor and PARP for Synthetic Lethality in CRPC
Timothy C. Thompson, Ph.D., Scientific Co-Leader
Christopher J. Logothetis, M.D., Clinical Co-Leader
Paul Corn, M.D., Ph.D., Clinical Co-Leader
Metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease for which novel molecular mechanism-based combination therapy strategies are needed. We identified an androgen receptor (AR)- and c-Myb–co-regulated DNA damage response (DDR) gene signature that is highly correlated with castration-resistance, metastasis, and reduced overall survival in mCRPC patients. In this DDR gene signature homologous recombination (HR) DNA repair genes and HR modulator (HRM) genes are highly represented. The relatively large percentage of HR/HRM genes in the DDR gene signature underscores the importance of this group of genes to prostate cancer progression. Our preliminary preclinical studies demonstrated that enzalutamide (ENZ), a 2nd-generation anti-androgen that blocks androgen from binding to the androgen receptor (AR), suppressed the expression of a majority of the HR/HRM genes and synergized with olaparib (OLA), a poly(ADP-ribose) polymerase 1 (PARP1) inhibitor in suppressing prostate cancer growth. Previously, OLA has been associated with synthetic lethality in multiple malignancies with BRCA1/2 or other HR gene deficiencies and its target, PARP1, plays a crucial role in base excision repair (BER) and was reported to function as an AR co-factor. In this project, we propose to test the hypothesis that targeting AR (ENZ) and PARP (OLA) in a “lead-in” strategy will generate synthetic lethality in mCRPC through ENZ-mediated downregulation of HR/HRM gene activity and OLA-mediated suppression of PARP’s enzymatic activity in BER and PARP’s cofactor role of AR transcriptional activity. The lead-in trial design will allow us to efficiently determine the clinical relevance of our biological findings by linking baseline to sequential modulation of target genes in individual cancers. We will test this hypothesis in three Specific Aims.
Aim 1. Characterize the HR/HRM gene signature in bone marrow biopsies of men with mCRPC treated with enzalutamide and/or abiraterone, novel inhibitors of androgen signaling.
Aim 2. Further characterize the synergistic potential of and identify predictive biomarkers of response to combination therapies that co-target AR (ENZ) and PARP function (OLA) using preclinical models.
Aim 3. Conduct a clinical trial of treating CRPC patients with ENZ followed by the addition of the PARP inhibitor OLA to achieve greater therapeutic response and to correlate an ENZ-regulated HR/HRM gene signature to the therapeutic responses.
Project 4: Mitochondria, MicroRNA, and Metabolism in Predicting Aggressive Prostate Cancer
Jian Gu, Ph.D., Scientific Co-Leader
John Davis, M.D., Clinical Co-Leader
Jianfeng Xu, M.D., Ph.D., Clinical Co-Leader, North Shore University
Prostate cancer is increasingly detected at early stages due to routine PSA screening, leading to a 5-year survival rate of nearly 100%. However, many screening-detected prostate cancer are indolent, yet about 90% of men with localized prostate cancer receive upfront aggressive treatments that often cause significant morbidity. Conversely, some patients with potentially aggressive prostate cancer who would benefit from early intervention may choose to delay treatment. This dilemma of overtreatment and undertreatment is particularly acute for patients with clinically defined intermediate risk. Clinical variables alone are not sufficient to accurately differentiate aggressive and indolent diseases. Biomarkers are urgently needed to refine risk stratification. In this project, we will focus on three promising biomarkers: mitochondrial DNA, microRNA, and metabolites. These multi-functional and interconnected molecules are related to obesity, an established risk factor to aggressive prostate cancer. Leveraging two of the largest prostate cancer patient cohorts in the U.S., this project will perform integrative analyses of these biomarkers with clinical variables to more precisely define aggressive prostate cancer. We will use knowledge gained from comparing extreme phenotypes at diagnosis (high-risk prostate cancer versus low-risk prostate cancer) to better stratify patients with clinically defined intermediate risk profiles. There are four specific aims:
Aim 1. To identify novel genetic susceptibility factors for aggressive prostate cancer at diagnosis. We will use a three-phase design: discovery, internal replication, and external validation. We have designed a custom array of about 20,000 single-nucleotide polymorphisms (SNPs), which include SNPs in miRNA regulatory pathways, SNPs in mtDNA, and obesity- and prostate cancer-predisposing SNPs.
Aim 2. To identify novel intermediate biomarkers, including the mtDNA copy number in peripheral blood leukocyte DNA, circulating miRNAs, and circulating metabolites as predictors of aggressive prostate cancer at diagnosis. We will again use a three-phase design.
Aim 3. To test the prognostic value of validated biomarkers in special patient populations, including GS 7 patients, localized patients receiving prostatectomy or radiotherapy, and a special population enrolled in an MD Anderson active surveillance study.
Aim 4. To construct multivariate prognostic nomograms that include epidemiological risk factors, clinical variables, and biomarkers from this project. We will refine clinical variables in predicting the prognosis in patients with GS of 7 and in localized patients receiving prostatectomy or radiotherapy. We will compare the predictive accuracy of our nomograms with existing ones that are based solely on clinical variables.
Christopher J. Logothetis, M.D., Director
Timothy C. Thompson, Ph.D., Director
Sue-Hwa Lin, Ph.D., Co-Director
The Administrative Core provides essential support to the Prostate Cancer SPORE PIs and investigators to maximize success. It is directed by Drs. Christopher J. Logothetis and Timothy C. Thompson and co-directed by Dr. Sue-Hwa Lin, who co-chair the Executive Committee and provide overall supervision of 4 Projects, 2 additional Cores, Developmental Research (DRP) and Career Enhancement (CEP) Programs, and scientific direction of the SPORE. The Core Directors and co-Director rely on the extensive broad-based scientific, research, and SPORE experience of the Advisory Boards in critical decision-making. Success of the complex interdisciplinary research in the SPORE depends in part on integration of diverse prostate cancer research approaches. The Core will overcome barriers to interdisciplinary collaboration and data sharing and ensure a unified translational research effort. The SPORE is founded on planning, integration, and translational research efforts supported by this Core. Its leadership and staff will be responsible for monitoring/planning scientific activities; providing scientific direction; ensuring emphasis on translational research; ensuring interdisciplinary and inter-SPORE integration with major prostate programs within/outside MD Anderson and other broad translational research activities; and providing administrative and fiscal management (eg, personnel, budgets, office oversight, communication, organization of meetings, manuscript preparation, and progress and other reports to the NCI and SPORE committees, and support of Cores and Programs). Specific responsibilities of the Administrative Core are to: monitor research activity and provide stable and continuous leadership and direction; promote integration, communication, and collaboration among the SPORE and collaborating investigators at MD Anderson and other Texas Medical Center institutions; monitor scientific integrity and ensure overall compliance with all institutional, state, federal, and NCI regulations and requirements, as well as assurance for data quality control for the Biostatistics and Bioinformatics and Biospecimen and Pathology Cores; provide oversight for completion of DRP and CEP goals; convene, staff, and manage all necessary meetings; oversee expenditures and maintain budgets; communicate and consult with the NCI Translational Research Program Director and staff, including reports; increase awareness of prostate cancer research and patient advocacy in the community; address ongoing needs of minority and underserved communities in Houston and Harris County (Texas); and encourage and facilitate translational prostate cancer research by extramural groups within the region and throughout the US.
Core 1: Biostatistics and Bioinformatics Core
Kim-Anh Do, Ph.D., Director
Kevin Coombes, Ph.D., Co-Director
The research proposed in The Prostate Cancer SPORE encompasses a broad range of activities, including studies of cell lines and animal models and clinical trials. These studies will generate many different types of data, including clinical, epidemiological, biochemical, immunohistochemical, pharmacokinetic, genotypic, and immunologic data. The Biostatistics and Bioinformatics Core for the Prostate Cancer SPORE has been a comprehensive resource for the biostatistic and bioinformatic needs that arise within the SPORE. This resource has the flexibility to match personnel with the evolving needs of the SPORE projects. We are able to incorporate sound experimental design principles within each project to enhance the interpretability of the study results, carry out data analyses using appropriate statistical methodology, and contribute to the interpretation of results via written reports and frequent interaction with project investigators. We can match core personnel with the expertise required in a specific area of a SPORE project to efficiently meet the ongoing needs of the multiple components of the projects.
Aim 1. Provide guidance in the design and conduct of clinical trials and other experiments (including high-dimensional genomic and proteomic studies) arising from the ongoing research of the SPORE.
Aim 2. Provide innovative and tailored statistical modeling, simulation techniques, and data analyses as needed for the main projects, developmental research and career development projects, and other cores to achieve their specific aims.
Aim 3. Ensure that the results of all projects are based on well-designed experiments and are appropriately interpreted.
Aim 4. Provide guidance in the design and use of an information system to store appropriate data generated by all projects; develop integrated computational libraries and tools for producing documented, reproducible statistical and bioinformatic analyses; and support the use of these tools for analyses conducted by and on behalf of the projects.
Core 2: Biospecimen and Pathology Core
Patricia Troncoso, M.D., Director
The Biospecimen and Pathology Core will provide the infrastructure, biorepository, xenograft facility, pathological and technical expertise, and informatic infrastructure required to support the projects of the Prostate Cancer SPORE and ensure the achievement of their goals. These goals are: 1) to develop predictive tools to better inform prostate cancer patients with low-risk disease to make evidence-based decisions and thereby eliminate overtreatment; 2) to develop a clear understanding of the molecular mechanisms of resistance to currently available, diverse therapies for castrate-resistant prostate cancer (CRPC), including 2nd generation inhibitors of androgen signaling, immunotherapy, chemotherapy, and bone-homing radiopharmaceuticals and to develop combination therapies to overcome these resistance mechanisms; and 3) to develop novel therapeutic options for men with CRPC and treatment-refractory prostate cancer.
With its dedicated personnel, facilities, unique biospecimen resource, and prostate cancer patients derived xenografts (PDXs), this Core will provide the Prostate Cancer SPORE investigators with the critical support required to conduct their translational research.
Effective interaction among the Core personnel and Prostate Cancer SPORE investigators facilitates the planning, conduct, and analysis of translational experiments to optimally use limited biospecimen resources. The participation of the Core pathologists in the selection of specimens and interpretation of tissue-based studies promotes effective collaboration among basic researchers and clinical investigators as well as facilitates the uniform interpretation of the analyses. This support exists not only for Prostate Cancer SPORE investigators but also for investigators at collaborating institutions and in other SPOREs and the broader networks of collaborating investigators dedicated to addressing the challenge of prostate cancer.
The Core’s Prometheus informatics system provides the infrastructure required to integrate clinical, pathological, and translational data, facilitating interactions with the Biostatistics and Bioinformatics Core and projects and interpretation of the results of the various analyses. The essential functions of the Biospecimen and Pathology Core are reflected in four specific aims.
Aim 1. Collect, process, annotate, characterize, store, and distribute human biospecimens related to prostate cancer.
Aim 2. Create well-characterized and quality-controlled tissue derivatives (including patient-derived xenografts) for translational research and conduct selected tissue-based studies.
Aim 3. Provide investigators with expertise to optimally select and use biospecimen resources, analytical techniques, and interpretation of tissue-based studies.
Aim 4. Provide an informatics solution (Prometheus) that tightly integrates biospecimen acquisition, annotation, and analysis workflows with clinical data in a secure and accessible manner.