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Hormone Responsive Cancers

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Hormone Responsive Cancers Hormone Responsive Cancers Hormone Molecular & Responsive Structural Biology Cancers Maryland State Council on Cancer Control Viral Amy Fulton, Ph.D. Experimental Oncology December 5, 2012 Therapeutics Tumor Immunology and Immunotherapy Discovery & Development of a Multi-mechanistic Agent VN/124-1 (TOK-001 or Galeterone) for Prostate Cancer Therapy Inventors: Vincent C. O. Njar, Ph.D., Professor & Angela M. H. Brodie, Ph.D., Professor Department of Pharmacology & Center for Biomolecular Therapeutics (CBT) Prostate Cancer • Most common cancer in males worldwide • Advanced prostate cancer remains incurable despite significant advances in treatment options • Identification of new strategies (prevention and therapy) are needed Prostate Cancer & Androgens • ~ 90% Prostate cancers are androgen-dependent • Blockage of androgen action = Effective treatment strategy • Surgical castration/use of GnRH (LHRH) = current “gold standard” for therapy – Eliminates testosterone production from testes but not from adrenals • Combination therapy: GnRH + antiandrogens – more effective Androgens • Steroids (testosterone and DHT) that stimulate male characteristics • Implicated in prostate cancer progression OH OH 5-Reductase O NADPH NADP+ O H (DHT) TESTOSTERONE (T) 5-DIHYDROTESTOSTERONE PCA Recurrence Following Anti-Hormonal Therapy • Reasons advanced for PCA recurrence – Androgen receptor (AR) mutation – AR gene amplification and/or over expression – Androgen independent activation of AR • However, anti-hormonal therapies produce most beneficial responses in multiple settings in PCA patients Steroidal Biosynthetic Pathway Cholesterol Aldosterone (-) Pregnenolone Progesterone Corticosterone - - - - - - - CYP17 - - - - - - - - (17-Hydroxylase)x 17-Hydroxy- 17-Hydroxy- Cortisol Pregnenolone Progesterone - - - - - - - CYP17 - - - - - - - - (17,20-Lyase)x DHEA Androstenedione Testosterone DHT Relative Binding Affinity Casodex, VN/124-1 & Abiraterone to Androgen Competitive Binding to the Androgen ReceptorReceptor (Wild-type) 130 120 110 100 90 80 70 Casodex 60 Abiraterone 50 40 VN/124-1 % of Control 30 20 10 0 -10 -9 -8 -7 -6 -5 -4 -3 Log Concentration [M] N N VN/124-1 N Abiraterone Casodex H OH O F3C N S O O HO HO NC F Antitumor Studies – Human LAPC4 Tumors in MaleLTLC SCID cells Mice (5.0x106 cells/site), s.c. Ovariectomized • Wild type androgen receptors (AR) • Mice inoculated with LAPC4 cells/2 sites (n = 5 per group) • Tumors ~ 300 mm3 Vehicle treated control, s.c. 4A (100 g/day), s.c. Let (10 g/day ) + • Treated with 50 mg/kg,From sc Day(x1 0or x2) for 28 daysFrom Day 0 4A (100 g/day), s.c. From Day 0 VN/14-1 (20mg/kg/d), s.c. After tumor development Tumor growth is independent of estrogens produced by the aromatization of 4A Tumors are insensitive to nonsteroidal aromatase inhibitor (letrozole) Effects of Castration, VN/85-1 & VN/124-1 on Formation & Growth of LAPC4 Tumor Xenografts 1000 40 900 Castration g/mg 30 VN/85-1 twice daily 800 in Control 5 700 20 600 10 500 of Concentration 0 Tumor(g/ml) Liver(g/ml) Testis(g/ml) 400 300 VN/124-1 200 twice daily % Change in mean tumor in volume mean % Change 100 * ** 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Duration of Treatment (weeks) VN/124-1 Unlike Casodex Induces AR Degradation in LNCaP & LAPC-4 Cells AR Expression in LNCaP cells after 24 h treatments AR Protein Expression in LNCaP Cells Treated with VN/124-1 and Casodex 130 120 110 100 90 80 70 60 50 40 % of Control 30 20 10 0 M M M M m m m m 1 5 1 5 10 1 10 15 Control VN/124-1 Casodex Treatment Vasaitis et al., Mol. Cancer Ther., 2008, 7: 2348-2357 Androgen Receptor (AR) Protein Expression from LAPC4 Tumors Following Various Treatments AR Protein Expression - LAPC4 Xenograft 3 2 1 Fold Fold Increase 0 Control Castration Bicalutamide VN/124-1 VN/124-1 + Castration Prevention AR 1 2.8 2.3 0.1 0.2 1.3 Beta Vasaitis et al., Mol. Cancer Ther., 2008, 7: 2348-2357 Actin Multiple Mechanisms of VN/124-1 Inhibition Along Androgen Axis 1 2 3 Effects of VN/124-1 & Abiraterone on Growth of LAPC-4 Tumors In Vivo 2000 LAPC4 In-Vivo Control 1500 Castration VN/124-1 ) 3 VN/124-1 Acetate 1000 Abiraterone (mm Abiraterone Acetate 500 Avg Tumor Avg Volume/Mouse 0 0 5 10 15 20 25 30 35 Days Bruno RD et al., Steroids, 2011, 76: 1268-1279 Androgen-dependent & -independent Mechanisms of Action of VN/124-1 VN/124-1 May be Effective Treatment at All Stages of PCA Development Radiation Therapy New Therapeutics Chemotherapy Radical Prostatectomy Proteasome inhibitors Docetaxel- (ARDA’s) based Castration metastatic localized recurrent metastatic refractory androgen- prostate cancer (rising prostate cancer (rising independent cancer serum PSA) cancer serum PSA) cancer N VN/124-1 N HO Development of VN/124-1 for the Treatment of Prostate Cancer: VN/124-1 Technology • Licensed to Tokai Pharmaceuticals Inc., Cambridge, Mass., USA - 2006 Discovery Pre-clinical Phase I/II Phase II-III 2003 2006 VN/124-1 4th quarter of 2012 November 5, 2009 Potent CYP17 inhibitor endowed with (Completed) multiple desirable anti-prostate cancer Tokai License activities of Technology Galeterone (TOK-001 or VN/124-1) • Oral small molecule for treatment of Castration Resistant Prostate Cancer (CRPC) • Tokai licensed technology from University of Maryland, Baltimore in 2006 – Inventors: Vincent C. O. Njar, Ph.D. & Angela M. H. Brodie, Ph.D. • Three Mechanisms of Action (MOA): Androgen Receptor (AR) CYP17 Lyase inhibitor Decrease AR levels antagonist Galeterone: ARMOR1 (Androgen Receptor Modulation Optimized for Response) - Design • Dose escalation trial in eight clinical centers – Standard dose escalation safety trial; 6 patients per group – Doses: 650 mg/day, 975 mg/day, 1300 mg/day, 1950 mg/day, 2600 mg/day – Single agent – Patient instructed to take galeterone with food • Dosing daily for 12 weeks (followed by optional continued dosing for eligible patients) • Single and Split oral dosing • With and without supplement • Entry Criteria – CRPC patients > 18 y.o. – Metastatic and non-metastatic disease – Chemotherapy and ketoconozole naive Maximal PSA Response: Waterfall Plot An increase in response rate was seen with higher doses Reduction in tumor size reported in 3 patients treated with high doses of Galeterone • Decrease in left pelvic lymphadenopathy • Corresponding 80% PSA reduction Baseline (2/9/2011): 3.9 x 2.9 cm 3 month (5/6/2011): 2.8 x 1.3 cm Summary of Clinical Trials & Further Development of Galeterone • Galeterone, well tolerated • Significant & long-term PSA responses observed • Excellent safety profile • Tumor reduction observed radiologically • Human proof-of-concept achieved: PSA reductions with soft tissue disease shrinkage • Undergone successful formulation optimization • Phase 2b trials planned for 4th quarter of 2012 On June 12, 2012 Galeterone (TOK-001 or VN/124-1) received Fast Track designation from the U.S. Food and Drug Administration (FDA) for the potential treatment of metastatic castration-resistant prostate cancer (CRPC) Thank You Vincent Njar, Ph.D Angela Brodie, Ph.D. Njar Laboratory Brodie Laboratory Members Members .
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