Resistance and Response Mechanisms to Prostate Cancer Therapy

Summary

Principal Investigator: TOMASZ BEER
Abstract: The prognosis for men with prostate cancer extending beyond the anatomic boundaries of the prostate gland is poor due to early dissemination of disease that cannot be eradicated by currently available systemic therapies. Understanding the mechanisms leading to therapy resistance is a prerequisite to the development of effective treatments. These mechanisms remain poorly understood and progress has been stymied by the limitations of currently available pre-clinical models coupled with the inability to evaluate mechanisms of resistance in vivo due to lack of pre- post-therapy tumor specimens. Molecular studies of prostate cancer involving the analysis of gene expression profiles have demonstrated remarkable heterogeneity in the genetic make-up of primary and advanced prostate cancers that could lead to substantial inter-individual variation in response or resistance to therapy, based on intrinsic characteristics of the tumor. This proposal is based on the hypothesis that tumor response and resistance mechanisms can be identified through the comparative analyses of in vivo gene expression profiles acquired before and after the administration of cytotoxic drugs. Once identified, these tumor resistance mechanisms can be exploited through the design of combination therapies targeted toward circumventing these pathways. We further hypothesize that pretreatment gene expression profiles will be indicative of response to specific therapies, such that individualized treatments can be selected for optimal efficacy. This proposal will overcome previous obstacles by using tissue and clinical data from a unique prospective clinical trial of neoadjuvant cytotoxic chemotherapy in patients with high-risk prostate adenocarcinoma to identify molecular alterations correlating with clinical and pathological indicators of tumor response. The functional relevance of the molecular targets will then be examined in in vitro systems and effects of targeting these specific drug-resistance mechanisms on tumor response to chemotherapy will be examined using in vitro and in vivo. We seek to identify novel treatment targets by comparing cancer cells that survived chemotherapy to those collected prior to treatment in patients treated in a unique study of pre-operative chemotherapy for prostate cancer. We will test the effectiveness of novel treatments that exploit newly discovered targets in the laboratory and lay the foundation for human trials to develop effective prostate cancer treatment.
Funding Period: 2006-05-01 - 2010-03-31
more information: NIH RePORT

Top Publications

  1. pmc Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B
    Yu Sun
    Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
    Nat Med 18:1359-68. 2012
  2. pmc Malate dehydrogenase 2 confers docetaxel resistance via regulations of JNK signaling and oxidative metabolism
    Qiong Liu
    Oregon Health and Science University Knight Cancer Institute, Portland, OR, USA
    Prostate 73:1028-37. 2013
  3. pmc Genetic profiling to determine risk of relapse-free survival in high-risk localized prostate cancer
    Christine M Barnett
    Authors Affiliations Knight Cancer Institute Department of Public Health and Preventive Medicine Knight Diagnostic Laboratories, Oregon Health and Science University Portland VA Medical Center, Portland, Oregon and Puget Sound Oncology Consortium, Seattle Cancer Care Alliance, University of Washington, Seattle, Washington
    Clin Cancer Res 20:1306-12. 2014
  4. pmc Phase 1/2 study of preoperative docetaxel and mitoxantrone for high-risk prostate cancer
    Mark Garzotto
    Division of Urology, Oregon Health and Science University, Portland Veterans Administration Medical Center, Portland, Oregon, USA
    Cancer 116:1699-708. 2010
  5. pmc Histologic changes associated with neoadjuvant chemotherapy are predictive of nodal metastases in patients with high-risk prostate cancer
    Catherine O'Brien
    Oregon Health and Science University, Portland, 97239, USA
    Am J Clin Pathol 133:654-61. 2010
  6. pmc ID1 enhances docetaxel cytotoxicity in prostate cancer cells through inhibition of p21
    Hao Geng
    Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon 97239, USA
    Cancer Res 70:3239-48. 2010
  7. ncbi Molecular alterations in prostate carcinomas that associate with in vivo exposure to chemotherapy: identification of a cytoprotective mechanism involving growth differentiation factor 15
    Chung Ying Huang
    Division of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98105 1024, USA
    Clin Cancer Res 13:5825-33. 2007
  8. pmc Prostate cancer-associated gene expression alterations determined from needle biopsies
    David Z Qian
    Division of Hematology and Medical Oncology, Oregon Health and Science University, OR, USA
    Clin Cancer Res 15:3135-42. 2009
  9. pmc CCL2 is induced by chemotherapy and protects prostate cancer cells from docetaxel-induced cytotoxicity
    David Z Qian
    Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon 97239, USA
    Prostate 70:433-42. 2010

Detail Information

Publications9

  1. pmc Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B
    Yu Sun
    Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
    Nat Med 18:1359-68. 2012
    ..These results delineate a mechanism by which genotoxic therapies given in a cyclical manner can enhance subsequent treatment resistance through cell nonautonomous effects that are contributed by the tumor microenvironment...
  2. pmc Malate dehydrogenase 2 confers docetaxel resistance via regulations of JNK signaling and oxidative metabolism
    Qiong Liu
    Oregon Health and Science University Knight Cancer Institute, Portland, OR, USA
    Prostate 73:1028-37. 2013
    ..Molecular alterations in the metabolic pathways are associated with cancer development; however, the role of these alterations in chemotherapy efficacy is largely unknown...
  3. pmc Genetic profiling to determine risk of relapse-free survival in high-risk localized prostate cancer
    Christine M Barnett
    Authors Affiliations Knight Cancer Institute Department of Public Health and Preventive Medicine Knight Diagnostic Laboratories, Oregon Health and Science University Portland VA Medical Center, Portland, Oregon and Puget Sound Oncology Consortium, Seattle Cancer Care Alliance, University of Washington, Seattle, Washington
    Clin Cancer Res 20:1306-12. 2014
    ..We examined the prevalence of potentially therapeutically actionable mutations in patients with high-risk clinically localized prostate cancer...
  4. pmc Phase 1/2 study of preoperative docetaxel and mitoxantrone for high-risk prostate cancer
    Mark Garzotto
    Division of Urology, Oregon Health and Science University, Portland Veterans Administration Medical Center, Portland, Oregon, USA
    Cancer 116:1699-708. 2010
    ..Secondary endpoints included safety, pathologic effects of chemotherapy, and predictors of disease recurrence...
  5. pmc Histologic changes associated with neoadjuvant chemotherapy are predictive of nodal metastases in patients with high-risk prostate cancer
    Catherine O'Brien
    Oregon Health and Science University, Portland, 97239, USA
    Am J Clin Pathol 133:654-61. 2010
    ..In multivariable logistic regression analysis, only intraductal pattern (P = .007) predicted lymph node metastases. Intraductal and cribriform histologic features apparently predict postchemotherapy outcome...
  6. pmc ID1 enhances docetaxel cytotoxicity in prostate cancer cells through inhibition of p21
    Hao Geng
    Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon 97239, USA
    Cancer Res 70:3239-48. 2010
    ..Taken together, it shows that ID1 expression has a novel therapeutic role in prostate cancer chemotherapy and prognosis...
  7. ncbi Molecular alterations in prostate carcinomas that associate with in vivo exposure to chemotherapy: identification of a cytoprotective mechanism involving growth differentiation factor 15
    Chung Ying Huang
    Division of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98105 1024, USA
    Clin Cancer Res 13:5825-33. 2007
    ..To identify molecular alterations associating with in vivo exposure of prostate carcinoma to chemotherapy and assess functional roles modulating tumor response and resistance...
  8. pmc Prostate cancer-associated gene expression alterations determined from needle biopsies
    David Z Qian
    Division of Hematology and Medical Oncology, Oregon Health and Science University, OR, USA
    Clin Cancer Res 15:3135-42. 2009
    ....
  9. pmc CCL2 is induced by chemotherapy and protects prostate cancer cells from docetaxel-induced cytotoxicity
    David Z Qian
    Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon 97239, USA
    Prostate 70:433-42. 2010
    ..Metastatic prostate cancer is either inherently resistant to chemotherapy or rapidly acquires this phenotype after chemotherapy exposure. In this study, we identified a docetaxel-induced resistance mechanism centered on CCL2...