Disentangling the origin of chemical differences using GHOST
The Big Picture for Mechanisms of Resistance in Prostate Cancer
1. Basic/Translational Perspective
The Big Picture for Mechanisms of
Resistance in Prostate Cancer
SBUR/SUO Joint Meeting
May 4, 2019
Nima Sharifi, M.D.
Director, Genitourinary Malignancies Research Center
Professor and Kendrick Family Chair for Prostate Cancer Research, Cleveland Clinic
3. Session Goal:
Discuss best systemic therapy advances
including androgen annihilation and ADT plus
chemotherapy in the mHRpc, and introduce the
concept of oligometastatic treatment
4. Advanced Prostate Cancer
(mCRPC, CSPC, nmCRPC, etc.)
ADT
Docetaxel
Cabazitaxel
Abiraterone
Enzalutamide
Apalutamide
(Darolutamide)
Registration Trials
No biologic distinction made among patients
May 4, 2019
Nima Sharifi
5. What is the question for
mechanisms of resistance?
Question: How do we move the
needle for advanced castration-
sensitive prostate cancer?
My opinion: We have to know what
treatment will add benefit and for
which patients.
Nima Sharifi
6. We need to change our model
Tumor Patient/Host
Nima Sharifi
8. Boiling down mechanisms of resistance
for treatment intensification
Androgens and prostate cancer
treated with castration
1) Does the tumor need it?
2) Does the tumor get it?
AR
T/DHT
Nima Sharifi
9. Does the tumor need it (androgens)?
Signature derived from NE and ARS genes
(distinguish tumors that do vs. don’t need it)
Rb1 / p53 loss
(tumors truly androgen indifferent)
Nima Sharifi
10. Does the tumor get it (androgens)?
DHEA T/DHT
3βHSD1 (1st step)
AR
Crude Oil Refined Oil
Can’t use Can use
Nima Sharifi
11. HSD3B1 (gene) → 3βHSD1 (enzyme)
-Required for all pathways to T/DHT synthesis (adrenal and de novo)
-Common germline variant with protein coding change
-Differs by race
HSD3B1(1245A)
Rapidly degraded protein (↓)
DHEA → DHT (slow)
Chang, et al. Cell 2013
Adrenal restrictive
genotype
Adrenal permissive
genotype
Low DHT
HSD3B1(1245C)
Stable protein (↑)
DHEA → DHT (fast)
High DHT (from adrenals)
Nima Sharifi
12. HSD3B1 Genotype CRPC
Adrenal restrictive
HSD3B1
Adrenal permissive
HSD3B1
DHT CRPC
-Cleveland Clinic Hearn, et al., Lancet Onc. 2016
-Mayo (non-metastatic)
-Mayo (metastatic)
-Utah Hahn, et al. JAMA Onc. 2017
-Dana-Farber Hearn, et al., JAMA Onc. 2018
-Japan Shiota, et al. JAMA Open 2019
-Spain Gil, et al. Eur J Onc Phar. 2018
CHAARTED data coming - ASCO 2019
Nima Sharifi
14. Is knowledge of tumor-intrinsic AR-
dependency enough?
Treatment Selection
Is knowledge of patient-dependent
androgen metabolism enough?
NOT IDEAL
(but retrievable in germline)
NOT IDEAL
It takes two
Ideally you want to know both
Nima Sharifi
16. Conclusions
1) Under ADT treatment, PCa extragonadal DHT supply
and AR-dependence are 2 critical and separable issues
2) HSD3B1 = germline predictive biomarker of extragonadal
DHT supply and CRPC outcomes
3) Ideally you want to know both for treatment of advanced
disease and oligo met trials (e.g. local therapy) with
curative intent
4) We need to get beyond this
Nima Sharifi
17. Laboratory
Current Members
Mohammad Alyamani, PhD – DOD Early Invest. Award
Erik Hedrick, PhD – Cancer Biology T32
Ziqi Zhu, PhD – DOD Postdoctoral Fellowship
Hyun-Kyung Ko, PhD
Mehdi Baratchian, PhD
Liang Qin, PhD
Navin Sabharwal
Jianneng Li, PhD – DOD Postdoctoral Fellowship
Mona Patel
Mike Berk
Jeff McManus, PhD
Kelsey Bohn, PhD – DOD Early Invest. Award
Aimalee Hardaway, PhD – NIH Diversity Suppl. Fellowship
Yijing Dai, PhD
Xiuxiu Li, PhD
Mishka Gidwani
Susan Taylor
JJ Zhang, MD
Lewis Thomas, MD
Former Members
Kai-Hsiung Chang, PhD – National Health Research Institute
Zhenfei Li, PhD – SIBCB, Chinese Academy of Sciences
Jason Hearn, MD – University of Michigan
Andrew Bishop, PhD – Assistant Prof, Wake Forest
Ghada AbuAli, PhD – Angle PLC (London)
Chad Reichard, MD – MD Anderson (Urologic Onc Fellow)
Nima Almassi, MD – MSKCC (Urologic Onc Fellow)
Charles Dai, MD – MGH (Internal Medicine Resident)
Dan Hettel, MD – Cleveland Clinic Urology Resident
Collaborators
Eric Klein, MD – Glickman Urological and Kidney Institute
Jorge Garcia, MD – Taussig Cancer Institute
Brian Rini, MD – Taussig Cancer Institute
Richard Auchus, MD, PhD – University of Michigan
Mary-Ellen Taplin, MD – Dana-Farber Cancer Institute
Steven Balk, MD, PhD - Harvard
Robert Dreicer, MD – University of Virginia
Manish Kohli, MD – Moffitt
Terry Friedlander, MD – UCSF
Charles Ryan, MD – University of Minnesota
Phil Kantoff – MSKCC
Patients and Families
Funding
Prostate Cancer Foundation
National Cancer Institute – R01CA190289, R01CA172382
and R01CA168899
American Cancer Society Research Scholar Award
Harrington Discovery Institute
Kendrick Family Endowment
