Prostate Cancer

Research Description

Our laboratory focuses on understanding the molecular mechanisms that drive prostate cancer initiation, progression and recurrence with the ultimate goal of developing therapeutic strategies that target these processes. Our approach includes the genomic analysis of human tumors, cell culture studies and the use of genetically engineered mouse models. We have a strong interest in genomics and gene regulation, oncogenic kinases as potential molecular therapeutic targets and the use of in vivo lineage tracing to define the fates of specific cell populations in tumorigenesis.

Specific projects include:

The role of the oncogenic serine/threonine kinase PIM1 in prostate cancer - PIM1 is coexpressed with c-MYC and dramatically enhances c-MYC-driven prostate tumorigenesis in a kinase-dependent manner. Notably, PIM1 is induced in tumors by hypoxia, radiation and treatment with docetaxel, a common but largely ineffective option for patients with advanced castration-resistant prostate cancer. PIM1 induction by hypoxia/radiation/docetaxel promotes prostate cancer cell survival and therapeutic resistance. Therefore, PIM1 may represent a valuable therapeutic target in prostate cancer. We are using new mouse models of prostate cancer for testing the efficacy of novel PIM1 kinase inhibitors in treating prostate cancer and reversing therapeutic resistance. We have also identified novel candidate PIM1-interacting proteins in prostate epithelial cells. Among the proteins identified are a MYC transcriptional cofactor and a prostate stem cell marker/regulator. We are investigating how PIM1 promotes prostate tumorigenesis by phosphorylating these substrates involved in regulating MYC transcriptional activity and stem cell function.

Cellular and molecular determinants of prostate cancer recurrence - A major clinical problem in prostate cancer is that of tumor recurrence following initial apparently successful therapy. Recurrent tumors may arise from a small number of "cancer stem-like cells" that survive the initial therapeutic intervention and have the capacity to regenerate the tumor. We are using lineage tracing to examine the competence of specific prostate epithelial cell types to regenerate tumors following therapy in mice.

Targeting lethal prostate cancer – We are using our mouse model of lethal prostate cancer based on alterations in Myc, Pten and Tp53 to develop new targeted therapies. One current project involves the targeting of EphB4 receptor tyrosine kinase using an antagonist as a therapeutic strategy.

For more information, see Dr. Abdulkadir's faculty profile.

Publications

See Dr. Abdulkadir's publications in PubMed.

Contact

Dr. Abdulkadir
Lab Telephone: 312-503-5031

Research Description

For more than 25 years, Dr. Catalona’s research has contributed significantly to the areas of early detection, treatment and cures for prostate cancer. His research aims to provide genetic insights into the causes of prostate cancer. He has discovered several new regions of the human genome statistically associated with prostate cancer. His current research is studying genetic variants associated with aggressive disease in men enrolled in active surveillance protocols from around the country.

Publications

Gaylis FD, Cooperberg MR, Chen RC, Malin J, Loeb S, Witte JS, Carroll PR, Cohen ES, Dato PE, Lin DW, Zheng Y, Seibert TM, Setzler C, Wilt W, Gomez SL, Chan JML, Catalona WJ. Defining Quality Metrics for Active Surveillance: The Michigan Urological Surgery Improvement Collaborative Experience. Letter. J Urol. 2021 Jul; 206(1): 171-172.

Lopes Vendrami C, McCarthy RJ, Chatterjee A, Casalino D, Schaeffer EM, Catalona WJ, Miller FH. The Utility of Prostate Specific Antigen Density, Prostate Health Index and Prostate Health Index Density in Predicting Positive Prostate Biopsy Outcome is Dependent on the Prostate Biopsy Methods. Urology. July 2019.

Giri VN, Knudsen KE, Kelly WK, Abida W, Andriole GL, Bangma CH, Bekelman JE, Benson MC, Blanco A, Burnett A, Catalona WJ, et al.  Role of genetic testing for inherited prostate cancer risk: Philadelphia prostate cancer consensus conference 2017. Journal of Clinical Oncology. February 2018.

Loeb S, Shin SS, Broyles DL, Wei JT, Sanda, M, Klee G, Partin AW, Sokoll L, Chan DW, Bangma CH, van Schaik RHN, Slawin KM, Marks LS, Catalona WJ. Prostate Health Index improves multivariable risk prediction of aggressive prostate cancer. BJU International. July 2017.

Contact

For contact information, see Dr. Catalona's faculty profile.

Research Description

Polycomb group (PcG) proteins help to regulate gene expression in normal cells. Research shows that this family of proteins is associated with prostate cancer initiation, disease progression and metastasis. The Cao lab is particularly interested EZH2, a specific protein within the PcG family. The lab’s previous research identified EZH2 as a biomarker for aggressive breast cancer as well as characterized EZH2 as an oncogene which represses multiple tumor suppressors in breast and prostate cancer.  This work has demonstrated EZH2 as a valuable therapeutic target in cancer, and several pharmaceutical companies are developing EZH2- or BMI1- specific inhibitors for cancer therapy.

The Cao lab is also working to identify miRNAs targeting Polycomb group proteins and other oncogenes in cancer. Using bioinformatics, they identified the miRNAs, which target EZH2, EED, BMI1, and RING1B, in cancer. This research suggested that genomic loss of miR-101 leads to the overexpression of EZH2 in cancer. In addition, PRC2 complex represses a set of miRNAs, including miR-181a,b, miR-200b,c and miR-203, which, in turn, repress BMI1 and RING1B. In advanced cancer, loss or epigenetic repression of these miRNAs leads to upregulation of PRC1 proteins BMI1 and RING1B, epithelial-mesenchymal transition regulators ZEB1 and ZEB2, and histone methyltransferase MMSET. This study suggests these miRNAs may serves as therapeutic targets for advanced cancer patients.

 

Publications

Yi Y, Li Y, Li C, Wu L, Zhao D, Li F, Fazli L, Wang R, Wang L, Dong X, Zhao W, Chen K, Cao Q. Methylation-dependent and -independent roles of EZH2 synergize in CDCA8 activation in prostate cancer. Oncogene. 2022 Mar;41(11):1610-1621.

Yi Y, Li Y, Meng Q, Li Q, Li F, Lu B, Shen J, Fazli L, Zhao D, Li C, Jiang W, Wang R, Liu Q, Szczepanski A, Li Q, Qin W, Weiner AB, Lotan TL, Ji Z, Kalantry S, Wang L, Schaeffer EM, Niu H, Dong X, Zhao W, Chen K, Cao Q.  A PRC2-independent function for EZH2 in regulating rRNA 2'-O methylation and IRES-dependent translation. Nat Cell Biol. 2021 Apr; 23(4): 341-354.

Zhu S, Zhao D, Li C, Li Q, Jiang W, Liu Q, Wang R, Fazli L, Li Y, Zhang L, Yi Y, Meng Q, Wang W, Wang G, Zhang M, Zu X, Zhao W, Deng T, Yu J, Dong X, Chen K, Cao Q. BMI1 is directly regulated by androgen receptor to promote castration-resistance in prostate cancer. Oncogene. 2020 Jan.

Liu, Q., Wang, G., Li, Q., Jiang, W., Kim, J. S., Wang, R., Zhu, S., Wang, X., Yan, L., Yi, Y., Zhang, L., Meng, Q., Li, C., Zhao, D., Qiao, Y., Li, Y., Gursel, D. B., Chinnaiyan, A. M., Chen, K. & Cao, Q. Polycomb group proteins EZH2 and EED directly regulate androgen receptor in advanced prostate cancer.  Int J Cancer. 2019 Jan 10.

Zhu, S., Zhao, D., Yan, L., Jiang, W., Kim, J. S., Gu, B., Liu, Q., Wang, R., Xia, B., Zhao, J. C., Song, G., Mi, W., Wang, R. F., Shi, X., Lam, H. M., Dong, X., Yu, J., Chen, K. & Cao, Q. BMI1 regulates androgen receptor in prostate cancer independently of the polycomb repressive complex 1. Nat Commun. 2018 Feb 5;9(1):500.

Contact

For contact information, see the faculty profile of Qi Cao, PhD.

Research Description

Dr. Murphy's group investigates etiologies and modifiable risk factors for health disparities in prostate cancer. They study the biological and environmental mediators of serum vitamin D deficiency and prostate cancer risk. Dr. Murphy's group also assesses the role of HIV infection on the incidence and treatment of prostate cancer. Finally, they evaluate barriers of prostate cancer screening for African American men using community-based participatory research methods.

Publications

• Meza J, Babajide R, Saoud R, Sweis J, Abelleira J, Helenowski I, Jovanovic B, Eggener S, Miller FH, Horowitz JM, Casalino DD, Murphy AB. Assessing the accuracy of multiparametric MRI to predict clinically significant prostate cancer in biopsy naïve men across racial/ethnic groups. BMC Urol. 2022 Jul 18;22(1):107. 
• Murphy AB, Abern MR, Liu L, Wang H, Hollowell CMP, Sharifi R, Vidal P, Kajdacsy-Balla A, Sekosan M, Ferrer K, Wu S, Gallegos M, King-Lee P, Sharp LK, Ferrans CE, Gann PH. Impact of a Genomic Test on Treatment Decision in a Predominantly African American Population With Favorable-Risk Prostate Cancer: A Randomized Trial. J Clin Oncol. 2021 May 20;39(15):1660-1670. 

• Murphy AB, Carbunaru S, Nettey OS, Gornbein C, Macias V, Sharifi R, Kittles RA, Yang X, Kajdacsy-Balla A, Gann P, Dixon MA. A 17-Gene Panel Genomic Prostate Score Has Similar Predictive Accuracy for Adverse Pathology at Radical Prostatectomy in African American and European American Men. Urology. 2020 Jan.

• Carbunaru S, Nettey OS, Gogana P, Helenowski IB, Jovanovic B, Ruden M, Hollowell CMP, Sharifi R, Kittles RA, Schaeffer E, Gann P, Murphy AB. A comparative effectiveness analysis of the PBCG vs. PCPT risks calculators in a multi-ethnic cohort. BMC Urology. November 2019.

• Murphy AB, Nyame YA, Batai K, Kalu R, Khan A, Gogana P, Dixon M, Macias V, Kajdacsy-Balla A, Hollowell CMP, Catalona WJ, Kittles R. Does prostate volume correlate with Vitamin D deficiency among men undergoing prostate biopsy? Prostate Cancer and Prostatic Disease. October 2017.

Contact

For contact information, see the faculty profile of Adam B Murphy, MD, MBA.

Research Description

Ashley Ross MD, PhD, is an active clinician and surgeon scientist with expertise in prostate cancer, genomics, immunology, targeted therapies and clinical trials.  His research is focused on improving the diagnosis and treatment of clinically significant prostate cancer, including the development of prognostic and predictive biomarkers in prostate cancer and the initiation of clinical trials. 

Dr. Ross is an expert in the design and conduct of early phase clinical trials. He has conducted clinical trials utilizing novel therapeutic approaches to lethal prostate cancer including use of immunotherapies, targeted oncogenic pathway inhibitors, and the use of more potent androgen deprivation.

In this video, Dr. Ross describes the biomarker-driven clinical trials that are showing promise for prostate cancer and other future research directions in the field.

In this podcast, Dr. Ashley Evan Ross, MD, PhD, and Brittany Szymaniak, PhD, CGC, an expert researcher in Cancer Genetics discuss Germline genetic testing and prostate cancer.

Dr. Ross and his lab team have developed nomogram MRI Risk Calculator to assess the likelihood of prostate cancer and clinically significant disease based on a combination of clinical and imaging characteristics. The nMRIsk calculator calculates the probability of a patient having clinically significant prostate cancer, which based on age, race, highest PIRADS score on prostate MRI, prostate volume, and serum markers based on their availability.

Publications

View a full list of publications by Ashley Ross on PubMed.

Contact

For contact information, see the faculty profile of Ashley E Ross, MD, PhD.

Research Description

The laboratory of Edward Schaeffer, MD, PhD, conducts groundbreaking prostate cancer research focused on at-risk populations, diagnosis, treatment outcomes, and the molecular biology of lethal prostate cancer.  As Chair of the Department of Urology at Northwestern Medicine and Program Director of the Genitourinary Oncology Program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Dr. Schaeffer is championing leading-edge explorations that are advancing scientific and clinical care pathways in prostate cancer.

Molecular biology of prostate development and prostatic disease: Dr. Schaeffer proposed the concept that the lineage of a prostate epithelial cell is established early, upon exposure to androgen, and that this lineage affects subsequent re-activation of embryonic growth pathways in pathologic prostatic conditions including BPH and prostate cancer.  This body of work has resulted in an international recognition as a prostate embryologist and established the paradigm of “lineage addiction” of the prostate epithelial cell to androgen signaling.  

Clinical and molecular biology of high risk prostate cancer: Dr. Schaeffer’s clinical and molecular work has brought international recognition to the previously under appreciated observation that aggressive (high risk), localized prostate cancer is frequently lethal and often undertreated. His research  on the clinical-biologic features of men with high risk disease and the molecular underpinnings driving prostate cancers defined a new subset of the particularly lethal cancer, outlined the molecular basis driving them and begun to lead clinical trials designed to improve the oncologic outcomes for these men.

The impact of race on the biology of prostate cancer: African American men with prostate cancer are twice as likely to develop metastasis and die of the disease than Caucasian men. Dr. Schaeffer’s work demonstrated a more aggressive biologic subset of cancers in African American men. His other discoveries include: (1) distinctive anatomic locations of African American tumors, (2) molecular expression signatures of African American cancers that demonstrate decreased reliance on androgen signaling, (3) novel solid tumor gene fusions and (4) divergent biomarkers panels signaling aggressive disease. 

In this video, Dr. Schaeffer shares some of the exciting developments underway at Northwestern to better understand racial disparities in prostate cancer.

Tools to aid in clinical decision-making: One of the greatest challenges in prostate cancer management is identifying patients that will progress to advanced disease following treatment. The Schaeffer lab has developed and validated a genomic signature to predict response to anti-androgen therapies in order to guide treatment selection. The lab is currently refining this analysis to broaden our understanding of the molecular features of those who do and do not respond to treatment. In this video, he shares details about and future directions of this work.

Publications

Weiner AB, Yu CY, Kini M, Liu Y, Davicioni E, Mitrofanova A, Lotan TL, Schaeffer EM. High intratumoral plasma cells content in primary prostate cancer defines a subset of tumors with potential susceptibility to immune-based treatments. Prostate Cancer Prostatic Dis. 2022 May 14.

Weiner AB, Li EV, Desai AS, Press DJ, Schaeffer EM. Cause of death during prostate cancer survivorship: A contemporary, US population-based analysis. Cancer. 2021 Aug; 127(16): 2895-2904.

Weiner AB, Liu Y, McFarlane M, Bawa PS, Li EV, Zhao X, Li Z, Hammoud T, Hazime M, Karnes RJ, Davicioni E, Reichert ZR, Chinnaiyan AM, Lotan TL, Spratt DE, Schaeffer EM. A transcriptomic model for homologous recombination deficiency in prostate cancer. Prostate Cancer Prostatic Dis. 2021 Jul.

Weiner AB, Vidotto T, Liu Y, Mendes AA, Salles DC, Faisal FA, Murali S, McFarlane M, Imada EL, Zhao X, Li Z, Davicioni E, Marchionni L, Chinnaiyan AM, Freedland SJ, Spratt DE, Wu JD, Lotan TL, Schaeffer EM. Plasma cells are enriched in localized prostate cancer in Black men and are associated with improved outcomes. Nat Commun. 2021 Feb 10;12(1):935.

Faisal FA, Murali S, Kaur H, Vidotto T, Guedes LB, Salles DC, Kothari V, Tosoian JJ, Han S, Hovelson DH, Hu K, Spratt DE, Baras AS, Tomlins SA, Schaeffer EM, Lotan TL. CDKN1B Deletions are Associated with Metastasis in African American Men with Clinically Localized, Surgically Treated Prostate Cancer. Clin Cancer Res. 2020 Jan 22.

Spratt DE, Alshalalfa M, Fishbane N, Weiner AB, Mehra R, Mahal BA, Lehrer J, Liu Y, Zhao SG, Speers C, Morgan TM, Dicker AP, Freedland SJ, Karnes RJ, Weinmann S, Davicioni E, Ross AE, Den RB, Nguyen PL, Feng FY, Lotan TL, Chinnaiyan AM, Schaeffer EM. Transcriptomic Heterogeneity of Androgen Receptor Activity Defines a de novo low AR-Active Subclass in Treatment Naïve Primary Prostate Cancer.Clin Cancer Res. 2019 Nov 15;25(22):6721-6730. 

Refer to PubMed for a full list of publications. 

Contact

For contact information, see the faculty profile of Edward Schaeffer, MD,PhD.

Research Description

Dr. Wu's goal to better understand prostate cancer and cancer in general and to find a better treatment for the untreatable terminal diseases, her current research focuses on the following aspects:  

1. Understanding the universal mechanisms of cancer immune evasion and development of novel cancer immunotherapy with specific focus on the NKG2D signaling pathways; 
2. Understanding why immunotherapy is not effective in prostate cancer and how to make it work with understanding underlying mechanisms of resistance; 
3. Discovering biomarkers to distinguish progressive vs. indolent prostate cancer to direct clinical decision making on treatment options; 
4. Understanding mechanism underlying immunotherapy (specifically, immune checkpoint inhibitor-therapy) induced toxicity and developing mechanism-direct personalized treatment for cancer patients to alleviate toxicity and to improve clinical outcomes.  

For more information please view the faculty profile of Jennifer Wu, PhD.

Publications

Dhar P, Basher F, Ji Z, Huang L, Qin S, Wainwright DA, Robinson J, Hagler S, Zhou J, MacKay S, Wu JD. Tumor-derived NKG2D ligand sMIC reprograms NK cells to an inflammatory phenotype through CBM signalosome activation. Commun Biol. 2021 Jul; 4(1): 905-.

Basher F, Dhar P, Wang X, Wainwright DA, Zhang B, Sosman J, Ji Z, Wu JD. Antibody targeting tumor-derived soluble NKG2D ligand sMIC reprograms NK cell homeostatic survival and function and enhances melanoma response to PDL1 blockade therapy. J Hematol Oncol. June 2020.

Zhang J, Larrocha PS, Zhang B, Wainwright D, Dhar P, Wu JD. Antibody targeting tumor-derived soluble NKG2D ligand sMIC provides dual co-stimulation of CD8 T cells and enables sMIC + tumors respond to PD1/PD-L1 blockade therapy. J Immunother Cancer.  August 2019.

View a full list of publications by Jennifer Wu at PubMed.

Contact

Email Jennifer Wu, or phone at 312-503-1521.