Challenges to Drug Development in Academia. Charles L. Sawyers, M.D.

Size: px

Start display at page:

Download "Challenges to Drug Development in Academia. Charles L. Sawyers, M.D."

Thomasine Glenn
5 years ago
Views:

1 Challenges to Drug Development in Academia Charles L. Sawyers, M.D. Chair, Human Oncology and Pathogenesis Program (HOPP) Investigator, Howard Hughes Medical Institute Memorial Sloan-Kettering Cancer Center; New York, NY

2 Disclosure I am a co-inventor of the drug MDV3100, now in a phase III clinical trial in prostate cancer, and I own stock in the company Medivation.

3 Two translational tales 1) Dasatinib (Sprycel) in chronic myeloid leukemia: serendipitous marriage of a discovery in academia that reshaped a pharma-driven drug development program 2) MDV3100 in prostate cancer: academia-based target validation and drug screening project that resulted in a biotech/pharma licensing deal for clinical development

4 The Ph Chromosome: t(9;22) Translocation 9 9 q + 22 Ph ( or 22q-) bcr bcr-abl abl Normal CML FUSION PROTEIN WITH TYROSINE KINASE ACTIVITY

5 Imatinib/STI571 (Gleevec) blocks BCR-ABL Goldman JM, Melo JV. NEJM. 344:

6 Blood counts of the first 6 patients who took 300 mg/day of Gleevec 100 WBC x Days on Gleevec

7 Gleevec is not a cure: Small numbers of CML cells are detected in patients who are in remission. Patients can relapse while taking Gleevec. Why?

8 A mutation isolated from patients who relapse on Gleevec blocks drug binding to BCR-ABL WILD-TYPE T315I MUTANT (MODEL) (Gorre et al Science, 2001)

9 BCR-ABL Kinase Domain Mutations Associated with Imatinib Resistance

10 Imatinib resistance mutations impair conformational flexibility of the ABL kinase Location of Mutations P loop Direct contact with drug hinge John Kuriyan, Bhushan Nagar (UC-Berkeley)

11 How do we deal with resistance? Problem: Over 50 different mutations can cause resistance to Gleevec Structural biology prediction: Mutations change the shape of BCR-ABL so that it favors the open conformation. Solution: Drugs that target the open conformation should work in patients with Gleevec resistance.

12 Dasatinib Gleevec

13 The SRC/ABL inhibitor dasatinib (BMS ) is active against all but one of the known mutations in BCR-ABL that confer imatinib resistance Normalized cell viability Shah et al Science, T315I F317L 0.4 wt BCR-ABL nm BMS BCR/ABL/WT M244V G250E Q252H Q252R Y253F Y253H E255K E255V T315I F317L M351T E355G F359V H396R F486S Ba /F3

14 BCR-ABL genotype predicts clinical response to dasatinib Talpaz.Sawyers, NEJM, 2006

15 Chronic Myeloid Leukemia: ) Imatinib has been frontline CML therapy -75% of patients achieve complete cytogenetic response -20% relapse within 5 years, usually with mutant BCR-ABL 2) Dasatinib and nilotinib were initially approved as 2 nd line therapy for imatinib-resistant CML (2006, 2007) 3) Upfront comparisons show than 2 nd generation compounds are superior to imatinib (Kantarjian et al NEJM 2010; Saglio et al NEJM 2010)

16 Inhibition of androgen receptor (AR) signaling testosterone hormone LHRH agonists AR kinases P AR Anti-androgens Bicalutamide* Flutamide* *Both drugs are partial agonists/antagonists Androgen receptor CoR vs Coactivators NCoR/HDAC Pol II P P AR AR ARE Transcription of AR target genes eg PSA Activation of TMPRSS/ERG fusion

17 Typical Response to Hormone Therapy Disease Burden Hormone Therapy Time Discontinue Antiandrogen

18 Primary Mechanism of Resistance to Castration and/or Current Antiandrogens 1) AR is overexpressed in castration resistant sublines of multiple prostate cancer xenograft models (and in patients) 2) Forced AR overexpression confers castration-resistance 3) AR knockdown impairs castration-resistant growth 4) AR antagonists act as agonists when AR levels are high (Chen et al Nature Med, 2004)

19 AR is required to maintain castrate resistance in vivo Lentivirus vector AR shrna GFP 5 LTR U6 AR RNAi Term. CMV GFP 3 LTR Tumor volume (mm 3 ) Vector AR shrna * * * * Vector * * AR shrna 100 * 50 * * LAPC4/CR Time (days) LNCaP/CR Growth of castrate resistant xenografts in castrate male mice

20 Primary Mechanism of Resistance to Castration and/or Current Antiandrogens 1) AR is overexpressed in castration resistant sublines of multiple prostate cancer xenograft models (and in patients) 2) Forced AR overexpression confers castration-resistance 3) AR knockdown impairs castration-resistant growth 4) AR antagonists act as agonists when AR levels are high (Chen et al Nature Med, 2004) Second generation anti-androgens must: be effective in cells expressing high levels of androgen receptor AND overcome the problem of antagonist/agonist conversion

21 Cell-based screen for compounds with greater antagonism and no agonism ( pure antagonists ) Design tools: - Crystal structure - Homology modeling - Binding affinity High AR binding affinity (Ka = 20 nm for human AR) But with agonistic activity H - b o n d i n t e r a c t i o n R i g i d i t y H y d r o p h o b i c i n t e r a c t i o n N C F 3 C Binding affinity to AR O N S Antagonist Activity Samedy Ouk, Michael Jung (UCLA Department of Chemistry) N R 1 R 2 Hydrophobic interactions with AR R Jung et al, J Med Chem, 2010

22 RD162 and MDV3100 do not display agonism in AR overexpressing cells PSA TMPRSS2 Veh Bic RD162 MDV3100 Veh Bic RD162 MDV3100 and have more potent antagonist activity Veh Bic RD162 MDV3100 Veh Bic RD162 MDV3100 Tran et al, Science 2009

bicalutamide Immunodeficient SCID castrate male mice.

23 RD162 (and MDV3100) are superior to bicalutamide in the castrate-resistant LNCaP-AR xenograft model bicalutamide Immunodeficient SCID castrate male mice. Tumor volume was measured in 3 dimensions. Tran et al, Science 2009

24 Androgen receptor activation and mechanism of antiandrogen action Androgen (R1881) Bicalutamide MDV3100 Revised from Lancet Oncol Oct;10(10):

Overlap among AR binding peaks in response to antagonists (determined by AR ChIP-Seq) R1881 (androgen) 42284 R1881

25 Overlap among AR binding peaks in response to antagonists (determined by AR ChIP-Seq) R1881 (androgen) R R1881+MDV 1793 MDV 451 Bicalutamide peaks found by MACS, p-value <10-5 R1881+Bicalutamide Ling Cai

26 A Phase 1-2 Multicenter First-in-Man Trial of MDV3100 in Castrate Resistant Prostate Cancer 1. Dose escalation, 3 patients per cohort, beginning at 30 mg/d to 600 mg/d 2. After safety was established at 60 mg/d, cohorts were expanded to 24 patients (12 chemo-naïve, 12 chemo failure) 3. First patient dosed in July, men enrolled at 5 centers (MSKCC, OHSU, U Wash, DFCI, MDACC) Scher et al Lancet, 2010

27 Waterfall Plot of Best Percent PSA Change from Baseline Chemotherapy- Naïve (N=65) Post- Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline

28 Radiographic Changes in Soft Tissue (N=59) and in Bone (N=109) Chemotherapy-Naïve Patients (N=65) Post-Chemotherapy Patients (N=75) Soft Tissue * (Best Response) Partial Response Stable Disease N=25 36% (9/25) 44% (11/25) N=34 12% (4/34) 53% (18/34) Bone Scan (Week 12) Stable Disease N=41 63% (26/41) N=68 51% (35/68) * 59 patients with evaluable soft tissue disease as defined by PCWG2 consensus J Clin Oncol 2008.

29 Time to PSA Progression For Preand Post-Chemotherapy Treated Patients Pre (Not reached) Post (186 days)

30 Summary 1. Castration resistant prostate cancer remains dependent on androgen receptor (AR) function. 2. Pure AR antagonists like MDV3100 can overcome clinical resistance to partial antagonists (bicalutamide). 3. MDV3100 likely induces an AR conformation that precludes DNA binding. 4. MDV3100 development has progressed to a phase III registration trial in castration resistant, chemotherapy resistant prostate cancer

31 CML/Abl Inhibitor Project Mercedes Gorre Neil Shah Ron Paquette Liz Haddad Mike Burgess John Nicoll BMS clinical trial Moshe Talpaz Art Decillis Claude Nicaise Eric Bleickardt Chris Tran Bhushan Nagar John Kuriyan (UC Berkeley) Frank Lee (BMS)

32 Prostate Cancer/Antiandrogen Project Charlie Chen Derek Welsbie John Wongvipat Chris Tran David Hung Medivation Nicola Clegg Michael Jung (Chemistry) Samedy Ouk (Chemistry)

The BCR-ABL1 fusion. Epidemiology. At the center of advances in hematology and molecular medicine

The BCR-ABL1 fusion. Epidemiology. At the center of advances in hematology and molecular medicine At the center of advances in hematology and molecular medicine Philadelphia chromosome-positive chronic myeloid leukemia Robert E. Richard MD PhD rrichard@uw.edu robert.richard@va.gov Philadelphia chromosome