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2019 PCF Challenge Award

Joshua Lang, MD, MSc

Discovering drivers of treatment response and resistance in the multi-focal prostate tumor microenvironment

Principal Investigators: Joshua Lang, MD, MSc (University of Wisconsin), Steve Cho, MD (University of Wisconsin), Kenneth Pienta, MD (Johns Hopkins University), David Jarrard, MD (University of Wisconsin), David Quigley, PhD (University of California, San Francisco)

Co-Investigators: David Beebe, PhD (University of Wisconsin), John Denu, PhD (University of Wisconsin), Shane Wells, MD (University of Wisconsin), Wei Huang, MD (University of Wisconsin), Alejandro Roldán-Alzate, PhD (University of Wisconsin), Tyler Bradshaw, PhD (University of Wisconsin), Irene Ong, PhD (University of Wisconsin), David Kosoff, MD (University of Wisconsin), Sarah Amend, PhD (Johns Hopkins University)

Description:

  • The men at greatest risk of progressing to castration resistance prostate cancer (CRPC) and death are those that initially present with multiple high-grade primary prostate tumors (“multi-focal”), and/or with distant metastases.
  • Joshua Lang and team hypothesize that tumor heterogeneity (molecular and genomic diversity of the tumor cell population) and support from non-tumor cells in the tumor microenvironment, are two major factors that enable multi-focal primary prostate cancer to develop resistance to therapy.
  • In this project, Dr. Lang and team will investigate the mechanisms that give rise to multi-focal, treatment-resistant prostate cancer.
  • The team will conduct a clinical trial testing a combination of docetaxel + hormonal therapy prior to prostatectomy in men diagnosed with high-risk non-metastatic prostate cancer or with limited numbers of distant metastases. Patients on this trial will first undergo PSMA-PET + MRI imaging to identify sites of disease at diagnosis and after receiving treatment with docetaxel + hormonal therapy. Thereafter, patients will undergo radical prostatectomy. Patients will undergo a third PSMA-PET/MRI scan at the time of PSA progression or 12 months post-prostatectomy, whichever occurs first.
  • The team will investigate whether any PSMA-PET/MRI imaging features are able to predict treatment response vs. resistance. Other new imaging technologies will also be tested in a subset of patients.
  • Prostatectomy specimens will be dissected using a special “3D-mold” methodology, which enables the tumor sites evaluated to be mapped to the PSMA-PET/MRI scans. Different sites of primary prostate cancer corresponding to those that responded vs. were resistant to therapy (as determined by pre- vs. post-treatment PSMA-PET/MRI scans), will be dissected and evaluated for distinguishing genomic alterations, gene expression patterns, and the types and activities of non-tumor cells present.
  • The team will also evaluate the types and activities of different populations of immune cells from tumor sites that responded vs. progressed on therapy.
  • If successful, this team will identify mechanisms and biomarkers of high-risk primary prostate cancers that respond vs. develop resistance to treatment with docetaxel + hormonal therapy. This will enable better identification of patients who have higher-risk disease, as well as lead to new therapeutic concepts.

What this means for patients: Men diagnosed with high risk prostate cancer present a treatment dilemma that needs clarity. Dr. Joshua Lang and team will combine advanced imaging, 3-dimensional reconstruction of the prostate and associated cancer, biology and medical intervention to improve outcomes for patients with this subtype of prostate cancer. Funding this research project could prevent or slow metastatic prostate cancer in as many as 10,000 patients per year.