Translational Platform for the Development of Targeted Therapeutics

Transcription

1 Translational Platform for the Development of Targeted Therapeutics Ondřej Kalous, MD Associate Project Scientist UCLA Translational Oncology Research Laboratories (TORL) Jonsson Comprehensive Cancer Center Los Angeles, CA, USA

2 UCLA/TORL Translational Cancer Research Program Aims to rapidly translate discoveries from the laboratory to the development of clinical studies (bench to bedside) Not just a one-way path Clinical observations, ideas, and samples from clinics are transferred to the laboratory (bedside to bench) Requires frequent communications between the laboratory and clinical sites Relies on translational thinking from both laboratory scientists and physicians

3 UCLA/TORL Components Proliferation assays conducted on a panel of ~ 600 cell lines Calculating outcome measures (i.e., IC50, IC100) Identification of sensitive and resistant histologies and histological subtypes Analysis of in vitro biomarkers using genotyperesponse and protein expression-response association screens In vivo testing using s.c. xenograft models of human cancer (selective) Preclinical data used to support clinical trials conducted by TRIO network

4 UCLA/TORL Panel of Cell Lines ~600 human cancer cell lines from 15 different cancer types Obtained from commercial vendors (ATCC, DSMZ, JCRB, ECACC) or established internally from patient samples Verified as unique via mitochondrial DNA sequencing STR profiling to match with online data sources

5 UCLA/TORL Cell Line Panel

6 UCLATORL Proliferation Assay Protocol

7 Summary of Outcome Measures Primary outcome measure: % generational inhibition Doublings from Baseline = log Avg Day5 Count log Avg Day0 Count log 2 % Inhibition = 1 doublings under treatment doublings without treatment 100% IC50 = dose of drug necessary to prevent 50% of cell population growth IC100 = dose of drug where cell population does not grow from baseline Dose response data condensed to single-value summary measures used to rank order cell lines by response

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10 Genomic and Proteomic Characterization Four main data sources: Whole-exome point mutation data from Cancer Cell Line Encyclopedia Copy number alteration data from comparative genomic hybridization arrays (UCLA/TORL) mrna expression by Agilent 44K microarrays (UCLA/TORL) Reverse phase protein array for total and phosphorylated protein (n = 225) levels (from MD Anderson)

11 % Change Body Weight Cell line and patient derived xenograft models representing each of the known cancer sub-types Our own dedicated vivarium with a capacity for carrying 1,400 animals managed by a team of experienced technologists and veterinarians Inform the design of patient clinical trials by determining the most active and safest single agent and drug combination strategies In vivo Program at UCLA-TORL Assessment of Drug Activity 10,00% Assessment of Drug Safety Tumor Volume mm ,00% 0,00% -5,00% -10,00% -15,00% ,00% 0 Days

12 TRIO network TRIO is a not-for-profit CRO that is dedicated to advancing translational cancer research by bringing forward innovative and targeted therapeutic concepts into the clinical trial setting TRIO offices are based in Canada, France and Uruguay International network of 2000 investigators and 450 cancer centers in over 45 different countries TRIO comes from the merger of CIRG (Cancer International Research Group) and TORI (Translational Oncology Research International), and the wide group of preclinical researchers at UCLA JCCC TRIO is developing from proof of concept up to registrational phase III trials in breast, ovary, GI and other cancers

13 UCLA TORL/TRIO Translational Platform PALBOCICLIB (PD ) CDK-4/6 INHIBITOR

14 Rb as Master-Regulator of the R-point palbociclib Richard Finn, AACR

15 Breast Cancer Research, 2009

16 Differentially Expressed Genes Between Sensitive and Resistance Cell Lines RB and cyclin D1 expression were higher and CDKN2A (p16) was lower in sensitive cell lines. Finn et al., Breast Cancer Research

17 Palbociclib Synergizes the Effects of Tamoxifen in ER+ Breast Cancer in vitro Finn et al., Breast Cancer Research 2009

18 Palbociclib + Letrozole Phase Ib Trial To test the safety of palbociclib in combination with letrozole (aromatase inhibitor) Oral palbociclib 125 mg once daily for 3 weeks followed by 1 week off treatment in a 28-day cycle, combined with letrozole 2.5 mg once daily The most common treatment-related adverse events were neutropenia, leucopenia, and fatigue

19 PALOMA-1/TRIO-18 Phase 2 Design Part 1 Part 2 ER+, HER2 BC R A N D O M I Z A T I O N 1:1 PD mg QD a + Letrozole 2.5 mg QD Letrozole 2.5 mg QD ER+, HER2 BC with CCND1 amp and/or loss of p16 R A N D O M I Z A T I O N PD mg QD a + Letrozole 2.5 mg QD 1:1 Letrozole 2.5 mg QD N = 66 N = 99 a Schedule 3/1. Stratification Factors Disease Site (Visceral vs Bone only vs Other) Disease-Free Interval (>12 vs 12 mo from end of adjuvant to recurrence or de novo advanced disease)

20 Progression Free Survival Probability (%) Progression-Free Survival (ITT) PAL + LET (N=84) LET (N=81) Number of Events (%) 41 (49) 59 (73) Median PFS, months (95% CI) Hazard Ratio (95% CI) 20.2 (13.8, 27.5) (0.319, 0.748) p-value (5.7, 12.6) Time (Month) Number of patients at risk PAL+LET LET Finn et al, Lancet Oncol 2015

21 Palbociclib Timeline Late 1990s: Parke Davis / Onyx /Pfizer develop a novel small molecule (PD ) that is potent and selective against Cyclin D-CDK4/6, no clear indication for use 2007: Pfizer contracts with UCLA/TORL for preclinical development 2009: UCLA/TORL publishes observation that ER+ breast cancers are uniquely sensitive to CDK4/6 inhibition 2010: Phase 1 trial shows hints of efficacy, with minimal toxicity 2011: TRIO begins biomarker-informed Phase : Interim analysis shows major improvement in PFS FDA grants Breakthrough Therapy status in April, 2013 TRIO begins enrollment in large Phase : Final analysis from Phase 2 confirms strong efficacy signal Phase 3 study is fully enrolled and ongoing

22 Dacomitinib (pan-her inhibitor) in Breast Cancer Dacomitinib has a strong antiproliferative activity in HER2-amplified breast cancer cell lines Dacomitinib maintains high activity in HER2- amplified cell lines with de novo and acquired resistance to trastuzumab and acquired resistance to lapatinib. Kalous et al., Mol Cancer Ther 2012

23 AMG 900 pan-aurora Kinase Inhibitor in Breast Cancer AMG 900 has potent anti-proliferative effects in breast cancer cell lines regardless of subtype Neither gene copy number changes nor expression of Aurora kinases A/B/C predicted for response to AMG 900 AMG 900 preferentially inhibits the proliferation of breast cancer cell lines with dysfunctional p53 and low protein expression of p21, a downstream target of p53 Kalous et al., Breast Cancer Res Treat, 2013

24 Translational component in cancer research Can identify sensitive subtypes within histologies and novel predictive markers of response Can help select the right patients for clinical trials Can speed up the development of targeted therapeutics Can save financial resources All to benefit our patients

25 Thank you Dennis Slamon Richard Finn Dylan Conklin Erika von Euw Neil O Brien UCLA/TORL staff