Pharmacodynamic and pharmacokinetic neoadjuvant study of hedgehog pathway inhibitor Sonidegib (LDE-225) in men with high-risk localized prostate cancer undergoing prostatectomy

Autor: Stephanie Glavaris, Jeffrey J. Tosoian, Ashley E. Ross, Carolyn Chapman, Trinity J. Bivalacqua, Ping He, Tanya Skelton O'Neal, Paula J. Hurley, Emmanuel S. Antonarakis, Nicole M. Anders, Kamyar Ghabili, Angelo M. DeMarzo, Rana Harb, Michelle A. Rudek, Robert M. Hughes, Mohamad E. Allaf, Edward M. Schaeffer, Luigi Marchionni, Alan W. Partin
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Zdroj: Oncotarget
ISSN: 1949-2553
Popis: // Ashley E. Ross 1, 2, 3, * , Robert M. Hughes 1, 2, 3, * , Stephanie Glavaris 1, 2, 3 , Kamyar Ghabili 1, 2, 3 , Ping He 3, 4 , Nicole M. Anders 3, 4 , Rana Harb 3 , Jeffrey J. Tosoian 1 , Luigi Marchionni 2, 3 , Edward M. Schaeffer 1, 2, 3 , Alan W. Partin 1, 2, 3 , Mohamad E. Allaf 1, 2, 3 , Trinity J. Bivalacqua 1, 2, 3 , Carolyn Chapman 1, 2, 3 , Tanya O’Neal 1, 2, 3 , Angelo M. DeMarzo 1, 3, 5 , Paula J. Hurley 1, 2, 3 , Michelle A. Rudek 3, 4, 6 and Emmanuel S. Antonarakis 1, 2, 3 1 James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA 2 Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA 3 Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA 4 Analytical Pharmacology Core Laboratory, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA 5 Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA 6 Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD, USA * These authors have contributed equally to this work Correspondence to: Emmanuel S. Antonarakis, email: eantona1@jhmi.edu Keywords: prostate cancer; Hedgehog; Sonidegib (LDE-225); GLI1 ; clinical trial Received: July 21, 2017 Accepted: September 15, 2017 Published: October 26, 2017 ABSTRACT Purpose: To determine the pharmacodynamic effects of Sonidegib (LDE-225) in prostate tumor tissue from men with high-risk localized prostate cancer, by comparing pre-surgical core-biopsy specimens to tumor tissue harvested post-treatment at prostatectomy. Methods: We conducted a prospective randomized (Sonidegib vs. observation) open-label translational clinical trial in men with high-risk localized prostate cancer undergoing radical prostatectomy. The primary endpoint was the proportion of patients in each arm who achieved at least a two-fold reduction in GLI1 mRNA expression in post-treatment versus pre-treatment tumor tissue. Secondary endpoints included the effect of pre-surgical treatment with Sonidegib on disease progression following radical prostatectomy, and safety. Results: Fourteen men were equally randomized (7 per arm) to either neoadjuvant Sonidegib or observation for 4 weeks prior to prostatectomy. Six of seven men (86%) in the Sonidegib arm (and none in the control group) achieved a GLI1 suppression of at least two-fold. In the Sonidegib arm, drug was detectable in plasma and in prostatic tissue; and median intra-patient GLI1 expression decreased by 63-fold, indicating potent suppression of Hedgehog signaling. Sonidegib was well tolerated, without any Grade 3-4 adverse events observed. Disease-free survival was comparable among the two arms (HR = 1.50, 95% CI 0.26–8.69, P = 0.65). Conclusions: Hedgehog pathway activity (as measured by GLI1 expression) was detectable at baseline in men with localized high-risk prostate cancer. Sonidegib penetrated into prostatic tissue and induced a >60-fold suppression of the Hedgehog pathway. The oncological benefit of Hedgehog pathway inhibition in prostate cancer remains unclear.
Databáze: OpenAIRE
Externí odkaz: