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Last Updated: 10/10/18

Northwestern University Prostate Cancer SPORE

Principal Investigator:
William Catalona, M.D.

Principal Investigator Contact Information

William J. Catalona, M.D.
Professor in Urology
Northwestern University
NMH/Galter Room 20-150
675 N. Saint Clair
Chicago, IL 60611
Phone: (312) 695-4471
Fax: (312) 695-7030
Email: wcatalona@nmff.org

Overview

The overall objective of our SPORE is to conduct studies that impact the outcome and overall quality of life of patients diagnosed with PC. Over the last five years we have personally experienced the loss of both of our original SPORE advocates to PC. We are therefore dedicated to honoring these men and all men suffering from this disease, conducting studies that will enable us to identify and treat tumors that will follow an aggressive course and developing novel therapies for men with castrate-resistant disease to prevent others from suffering this fate. We have three overarching, highly translational specific aims: 1) To identify patients who have aggressive prostate cancer versus those who have indolent disease through population genetic studies; 2) To develop innovative therapies for castration-resistant prostate cancer (CRPC), such as combination therapy to re-sensitize patients to androgen deprivation or novel molecular therapeutic approaches and 3) To develop and validate biomarkers that will avoid overtreatment of patients who receive a diagnosis of PC. All together these projects address the major questions of PC, with one project on early diagnosis and three projects on CRPC.

Our SPORE is a collaboration between Northwestern University’s Robert H. Lurie Comprehensive Cancer Center, the University of Chicago’s Comprehensive Cancer Center, NorthShore University HealthSystem, with contributions from the University of California San Francisco, the University of Pittsburgh and the University of Southern California. The SPORE first received funding from the NCI in 2001. A renewal application was funded by NCI in February 2009 and in August 2015 we received a new 5-year award from the NCI. Our work has contributed to implementation of unique clinical trials, FDA approval of a more accurate PSA assay, participation in inter-SPORE and DOD national clinical trials, contributions to the field of prostate cancer genetics, and involvement in national active surveillance initiatives. In this SPORE, we propose four research projects:

PROJECT 1: Impact of germline genetic variants on failure of active surveillance for prostate cancer

Project Co-Leaders:
W. Catalona
J. Witte
B. Helfand

Active surveillance (AS) is an important option for prostate cancer (PC) patients to avoid overtreatment, but better biomarkers are needed to avoid recommending AS to someone who may harbor aggressive disease. The rationale for AS is that PC is diagnosed in 14% of men, of whom ~80% have clinically localized disease, >80% undergo early treatment, but only ~3% ultimately die of PC. As treatment may have side effects, AS is an alternative option that may reduce overtreatment. Men with low-risk PC are monitored, and treatment is usually recommended when the patient withdraws from AS. However, within 10 years, up to ~60% of men withdraw from AS protocols. The majority of patients who “fail AS” have undiagnosed clinically-significant disease from the beginning rather than disease that “progresses” from low to high grade. In addition, many of the patients who go on definitive therapy do so because of “PSA anxiety.” In fact, 20-40% of AS patients are eventually found to have clinically significant disease, and the impact of delayed diagnosis remains to be determined. After delayed treatment up to 50% of patients have PSA recurrence. Some of these men develop metastases and die of PC. PC has a strong genetic component, and genome-wide association studies (GWAS) have now identified >100 single nucleotide polymorphisms (SNPs) associated with PC risk, together explaining >35% of the inherited risk. Some PC risk SNPs also have been associated with PC aggressiveness, but results have been inconsistent. We aim to clarify such results by studying germline genetic variants and AS failure. Specifically, this proposal addresses the hypotheses that: 1) AS candidates carry germline variants associated with AS failure; 2) genotyping with higher-density SNP and exome arrays will allow us to identify PC-associated variants that also impact AS failure; and 3) knowledge of germline variants in men with low-risk PC may affect treatment decisions. Our preliminary studies examine candidate germline variants associated with PC in a large set of men enrolled in AS protocols using the latest SNP and whole exome array technology. Our proposed studies leverage resources of the SPORE Genetics and AS working groups and non-SPORE AS studies as well as many non-SPORE investigators working in this field. Specific aim 1 will entail statistical analyses of the genotyping data. Specific aim 2 will validate these variants in independent AS cohorts. Specific aim 3 will use in silico approaches to map validated variants on cell signaling pathways as possible pharmaceutical targets and also will entail functional analyses of the relevant genes. Specific aim 4 will develop algorithms to identify men more likely to fail AS. This work will have translational implications, ultimately leading to 1) new biomarkers for screening and treatment decisions, 2) identifying the signaling pathway(s) involved in aggressive disease, 3) identifying pharmaceutical targets for new treatments and possibly PC prevention, and 4) advancing our understanding of genetic factors that influence PC aggressiveness.

PROJECT 2: GR transcriptional activity and the evolution of enzalutamide resistant CRPC

Project Co-Leaders:
S. Conzen
D. Vander Griend
R. Szmulewitz

In the United States, castration-resistant prostate cancer (CRPC), is the second leading cause of male cancer-related deaths. Although there are new and highly potent androgen receptor (AR) targeted therapies for the treatment of metastatic CRPC (e.g. enzalutamide), tumor resistance develops in most patients. We have recently shown that under the selective pressure of systemic AR blockade, tumor glucocorticoid receptor (GR) expression increases and GR activity sustains pro-cell survival gene expression thereby enabling CRPC progression. The role of GR activity in prostate cancer (PC) is therefore dynamic and complex; initially when AR signaling is intact, GR activation appears to be mainly anti-proliferative and only later, in the context of sustained AR antagonism, does GR signaling contribute to tumor progression. The goal of this project is to determine how GR’s pro-cell survival activity develops over time as a function of AR activation state, and whether novel GR antagonists can mitigate GR activity thereby decreasing enzalutamide-resistance (Enz-R). Our central hypothesis is that following therapeutic AR blockade, the GR transcriptome shifts from predominantly anti-proliferative gene expression to one promoting cell survival. We therefore predict that an increasing percentage of Enz-R CRPC tumor cells will demonstrate significant GR expression that will in turn, undergo cytotoxicity with the addition of GR antagonism. Three aims are proposed to address this hypothesis. In Aim 1, we will analyze GR transcriptional function in PC over time before, during and after AR blockade. In Aim 2, we will investigate intratumoral heterogeneity of GR expression to test the hypothesis that focal (clonal) areas of high GR expression evolve exhibit GR-activation and enzalutamide resistance. Aim 3 is a translational aim in which we will investigate a novel SGRM in a phase I clinical trial in combination with enzalutamide as a treatment strategy for Enz-R CRPC. In addition, patient samples will be collected in the context of this trial to characterize AR and GR expression within circulating tumor cells (CTCs) from patients before and after treatment with enzalutamide and the SGRM. This work will help clarify the mechanisms by which GR activation contributes to PC progression and will inform strategies for blockade of GR-mediated pro-tumorigenic signaling pathways in patients.

PROJECT 3: EPHB4 receptor kinase as a target in PC

Project Co-Leaders:
S. Abdulkadir
P. Gill
W. Stadler

A major clinical problem in the management of prostate cancer is the difficulty associated with treating aggressive cancers, especially those that are highly castration resistant. The androgen signaling pathway remains a key therapeutic target for advanced prostate cancer but resistance to agents targeting this pathway is common, highlighting the need to develop novel therapeutic approaches. Mouse prostate cancer modeling has elucidated molecular pathways of aggressive, castration-resistant prostate cancer (CRPC) which include loss of the tumor suppressors PTEN and TP53 and overexpression of the MYC oncogene. Using these spontaneous mouse models of prostate cancer we have identified Ephrin receptor EphB4 as a potential therapeutic target. EPHB4 is a receptor tyrosine kinase that with its ligand ephrin B2, is not expressed in normal prostate gland, but is expressed in a majority of human prostate cancers. EPHB4 is induced by multiple pathways important for CRPC development, including loss of PTEN and TP53 as well as activation of the PI3K pathway downstream of EGFR and IGF1R. In turn, EPHB4 activation engages multiple signaling pathways, including the PI3 kinase/AKT and MAPK pathways known to modulate the androgen receptor and drive CRPC development. To test the significance of EphB4, we generated conditional EphB4 knockout mouse. We found that genetic deletion of EphB4 or its inhibition using a soluble antagonist (sEPHB4) profoundly inhibited prostate tumorigenesis driven by loss of Pten and led to the regression of established tumors in transgenic mice. This was associated with inhibition of PI3K/AKT signaling and apoptosis. Notably, sEpBh4 antagonist and EphB4 knockdown led to markedly lower levels of androgen receptor (AR) protein. These functional genetic data lead us to hypothesize that EPHB4 is a novel pharmacologic target with high therapeutic potential in prostate cancer, including CRPC. We will explore this hypothesis by targeting EphB4 in genetically complex mouse models (loss of Pten, Tp53 and Myc over-expression) and human xenograft models of prostate cancer and CRPC, singly or in combination with AR-targeted therapy (including enzalutamide, abiraterone). We will examine human prostate tumor samples including metastases and CRPCs for the expression of EphB4, EphrinB2, and downstream markers. A soluble decoy EPHB4 receptor — human serum albumin fusion protein (sEPHB4HSA) antagonist is in early human trials in other tumors, and has been found to be remarkably safe in Phase I study. We will therefore implement a feasibility clinical trial of sEPHB4HSA aimed at determining the therapeutic efficacy of targeting EPHB4 in men with CRPC. Successful completion of the preclinical and early clinical studies we propose in this application could lead to a rapid translation of soluble EPHB4 antagonist as a treatment for advanced prostate cancer.

PROJECT 4: Targeting FOXA1 downstream pathways: a novel therapeutic strategy for CRPC

Project Co-Leaders:
T. Kuzel
J. Yu

Prostate cancer (PC) is the most commonly diagnosed non-skin cancer in American men. Androgen deprivation therapies (ADT) that target the androgen receptor (AR) are the mainstay treatment for metastatic PC. New-generation anti-androgen enzalutamide (Enz) has been effective in prolonging patient life for almost a full year and yet resistance develops rapidly. Importantly, castration-resistant PC (CRPC) is driven primarily by aberrant activation of the AR in the milieu of low androgen. The AR exerts its tumorigenic roles mainly through genomic regulation of target gene expression. This genomic action is tightly regulated by a number of cofactors, one of which is FOXA1. FOXA1 is traditionally known as an AR co-activator in androgen-stimulated AR signaling. However, biomarker studies have reported controversial results regarding FOXA1 as a positive or negative outcome predictor, suggesting context- or treatment-dependent roles. In addition, recurrent, loss-of-function mutations of FOXA1 have been found in PC indicating tumor suppressive roles. We recently found that although FOXA1 is slightly up-regulated in localized PC relative to benign tissues, it is dramatically down-regulated in CRPC. Mechanistic studies revealed that FOXA1 has dual roles in its regulation of AR signaling. In the presence of androgen, FOXA1 enhances AR signaling and induces cell growth. However, in the absence of androgen, FOXA1 suppresses residual AR activity and as such FOXA1 loss leads to androgen-independent AR activation and castration-resistant PC cell growth. Moreover, we found that FOXA1 loss also turns on TGFΒ/slug pathway contributing to cell migration and invasion. Further, TGFΒ/slug pathway is also activated in Enz-resistant CRPC cells. We thus hypothesize that clinically available ALK5 inhibitors that target TGFΒ/slug signaling may suppress CRPC progression and overcome Enz-resistance in combinatorial therapies. To test this hypothesis, three specific aims are proposed. In Aim 1 we will elucidate the roles of FOXA1 in suppressing CRPC progression in vitro and most importantly in xenograft tumors in vivo. Aim 2 will characterize the downstream pathways of FOXA1 in CRPC cells and PC specimens. In Aim 3 we will investigate the efficacy of Enz in combination with ALK5 inhibitor in CRPC cell lines and xenografts. Aim 4 will develop a phase I clinical trial of combinatorial Enz and ALK5 inhibitor treatment of metastatic CRPC.

Core A: Administrative, Leadership Development and Advocacy Core

Co-Leaders:
W. Catalona
W. Stadler
R. Leikin
S. Abdulkadir
A. Murphy
D. Shevrin

The Administrative, Leadership Development and Advocacy Core is responsible for oversight of SPORE projects and Cores. This leadership team works to promote the highest quality scientific research, effectively communicates SPORE activities through web sites and other written materials and supports advocacy (D. Shevrin) and outreach activities. New to the SPORE we will implement a leadership development program (S. Abdulkadir) to help junior faculty attain senior academic research positions and a diversity in men’s health committee (A. Murphy) to coordinate outreach activities focused on minority populations.

Core B: Biostatistics and Bioinformatics Core

Core Directors:
B. Jovanovic
R. Davuluri

The Biostatistics and Bioinformatics Core provides comprehensive expertise in biostatistical analysis, research design and informatics to all participants of the Northwestern University/University of Chicago/NorthShore University Prostate SPORE. The specific aims of the Core are:

  • To maintain and enhance the pre-clinical, clinical and tissue databases of the SPORE
  • To provide state of the art experimental design, epidemiological and biostatistical expertise to all of the SPORE projects
  • To conduct data collection and data analysis for SPORE projects
  • To provide infrastructure and expertise for inter-SPORE and other scientific collaborations.

Core C: Biospecimen Pathology Core

Core Directors:
K. Kaul
JJ. Wei

The Biospecimen Pathology Core oversees the procurement of human prostate tissue and other biologic specimens including serum, plasma, urine, prostatic fluid, prostate needle biopsies, etc at Northwestern Memorial Hospital and NorthShore/UC. We propose to link the University of Chicago in the new grant period (M. Lingen). The Core fully supports SPORE projects by providing well annotated specimens and a full range of services that includes construction of tissue microarrays and other specialized services such as laser capture microscopy, DNA and RNA preparation and immunohistochemical analysis of human and mouse tissues. In this grant period the Core will develop novel technologies for detection of circulating tumor cells (R. Szmulewitz). Requests for biologic specimens are entered into an electronic system, Disburser, and specimens may be disseminated after thorough review by the Tissue Review and Disbursement Committee. The biospecimen database is linked electronically to a fully annotated SPORE clinical database that is maintained by the Biostatistics/Bioinformatics Core.

Career Enhancement Program

Director:
M. Hussain

The Career Enhancement Program (CEP) is intended to recruit and train junior faculty investigators at Northwestern University and the University of Chicago for careers in prostate cancer translational research through strong mentoring and career guidance. Career development investigators are selected after careful review of their credentials and potential to develop an independent career in prostate cancer research. Drs. Conzen and Lee assign each (CEP) investigator a primary mentor, with whom he/she meets monthly, and a secondary mentor who meets with the career development investigator quarterly. Special efforts have been made to emphasize the recruitment of women and minorities to the SPORE Career Enhancement Program. CEP investigators who are making significant progress after the first year are eligible for an additional year of funding.

For additional information, contact:

Robin Leikin, PhD
Scientific Program Director, Lurie Cancer Center
reikin@northwestern.edu

Developmental Research Program

Directors:
W. Catalona
R. Leikin

The Developmental Research (pilot) Program supports innovative research initiatives by providing seed money through the funding of pilot projects. On an annual basis the SPORE solicits innovative translational research projects from investigators at Northwestern University, University of Chicago and NorthShore University Health System in all areas of prostate cancer with the ultimate goal of improving outcomes in prostate cancer patients. The SPORE funds five to six projects for a period of one year, with the option to extend funding for a second year if the research is successful and an extension is justified.

To learn more or to apply for a pilot, please contact:

Robin Leikin, PhD
Scientific Program Director, Lurie Cancer Center
reikin@northwestern.edu