New Paradigms in Personalized Medicine and Drug Discovery for Cancer - PowerPoint PPT Presentation

New Paradigms in Personalized Medicine and Drug Discovery for Cancer d D Di f C Dan Theodorescu MD PhD University of Virginia Charlottesville, Virginia, USA

Cancer of the Bladder Cancer of the Bladder The Clinical Challenge of Metastatic Disease The Clinical Challenge of Metastatic Disease Overall Survival of 405 patients with T4b or N2-3 or M1 urothelial carcinoma randomized to Gem-Cis or MVAC www.mritutor.com www mritutor com von der Maase, H. et al. J Clin Oncol; 23:4602-4608 2005 von der Maase H et al J Clin Oncol; 23:4602 4608 2005 Metastatic disease = Death Visceral Metastasis curable only in ~5-7% Needs Individualize “personalize” therapy Individualize “personalize” therapy Better drugs / drug combinations www.tju.com

Challenges of Individualized cancer therapy Challenges of Individualized cancer therapy � We have prognostic markers of outcome � We don’t have predictive biomarkers of � We don t have predictive biomarkers of treatment response in majority of tumors � Could our single drugs or drug combinations that cure 5-10% of patients, if applied to th t 5 10% f ti t if li d t specific patient subsets this result in improved cure rates ? Treatment Treatment Chemotherapy Regimens Regimens MVAC Optimized Regimen Treatment Selection Tumor Response GC Sample Biomarkers Biomarkers In aggregate In aggregate Cures Likely >10% GT Cancer Cancer

Challenges of Drug Discovery Challenges of Drug Discovery Compound Success Rate in Drug Discovery Discovery 5,000 - 10,000 (2-10 Years) ( ) Screened Preclinical Testing Laboratory and animal testing Phase I 250 Determine safety and dosage Enter preclinical testing Enter preclinical testing Phase II Phase II Efficacy and side effects Phase III 5 Adverse reactions to long-term use Enter clinical testing FDA Review/Approval FDA R i /A l Additional Post-market Testing Years 0 0 2 2 4 4 6 6 8 8 10 10 12 12 14 14 16 16 1 1 Approved by FDA ~$880 million / successful drug ~$880 million / successful drug Time Time—12 years! 12 years!

Drug Discovery and Clinical Medicine Drug Discovery and Clinical Medicine The “Tumor “Tumor- -Drug Disconnect” Drug Disconnect” Common Problem Common Problem—The Drug Discovery and Development NCI-60 Cell Panel Human Cell Lines L Leukemia (6) Melanoma (7) Breast (8) k i (6) M l (7) B t (8) Ovarian (6) CNS (6) Lung (9) Prostate (2) Colon (7) Kidney (8). HTS Drugs Screening (eg. NCI) >100,000 chemical compounds Clinical Clinical results of 45K are available publically lt f 45K il bl bli ll Practice 2 3 1 2 3 1 575A Sensitive 1 3 2 1 1 1 1 3 2 3 2 Poor Predictability of Drug Action in Patients

Drug Disconnect” …..does …..does not not Classic Solution to the “Tumor Classic Solution to the “Tumor- -Drug Disconnect” help efficiency of drug discovery! help efficiency of drug discovery! Discovery (2-10 Years) Tumor Tumor Profiling Sample Taken Preclinical Testing Laboratory and animal testing 3 Drug Chemotherapy Phase I ase Regimen “ABC” Regimen ABC Determine safety and dosage Phase II Responders Non Responders Efficacy and side effects Biomarker Phase III Development Development Adverse reactions to long-term use Treatment Response FDA Review/Approval Biomarkers Additional Post-market Testing Post-market Testing Clinical Clinical Selection of patients Selection of patients Use of ABC that respond to ABC Biomarker Development Clinical use with Response Biomaker Years $$$$ $$$$ and 1 $$$$ and 1-2 yrs! $$$$ 2 yrs! y Limited utility Limited utility 0 2 4 6 8 10 12 14 16

Comprehensive solution to the “Tumor Comprehensive solution to the “Tumor- -Drug Disconnect” Drug Disconnect” Addressing Addressing both both Drug Discovery and Individualized Therapy Drug Discovery and Individualized Therapy Inspiration….The Rosetta Stone Hieroglyphic: script for important / religious documents Demotic Egyptian : common script of Egypt Greek: language of the rulers of Egypt Idea…. t Control 2 3 1 3 2 1 575A Sensitive 1 NCI-60 Panel Cell Lines NCI 60 Panel Cell Lines 3 3 2 2 Percent 1 1 3 2 3 2 Dose Gene expression profile Patient Bladder Tumor

The Idea: COXEN “CO The Idea: COXEN “ CO-e eX Xpression pression E Extrapolatio xtrapolatioN N” Uses in Drug Discovery and Individualized Therapy Uses in Drug Discovery and Individualized Therapy NCI-60 Cell Line Panel 2 3 1 2 3 1 575A Sensitive Expression IC50 for 45,345 1 3 2 Profiling Compounds 1 1 3 3 2 2 3 2 Human Bladder Bladder Cancer Cancer Cell Lines patient samples COXEN COXEN Gene Expression Model (GEM) for each Test Compound p ( ) p GEM Score Evaluation on Bladder Cancer patient tissues or cells 2 3 1 2 1 3 575A wth Sensitive Grow 1 1 High Score Hi h S 3 2 1.0 High Score 1 1 Predicted responders 3 2 COXEN Score 3 2 Fraction Disease-Free 0.8 COXEN Score for each drug 0.6 2 3 for each patient 1 3 2 1 575A across all Growth Sensitive 0.4 Predicted non-responders for specific drug 1 3 2 patients 0.2 (P-value = 0.021) (p-value = 0.021) 1 1 3 Low Score 2 Low Score Low Score 3 2 3 2 0.0 0 0 50 100 150 Time (months) Survival time [Drug] Individualized Therapy Drug Discovery

The Idea: COXEN “ The Idea: COXEN “CO CO-e eX Xpression pression E Extrapolatio xtrapolatioN N” Uses in Drug Discovery and Individualized Therapy Uses in Drug Discovery and Individualized Therapy COXEN COXEN Discovery (2-10 Years) Preclinical Testing Laboratory and animal testing Phase I Determine safety and dosage Phase II Efficacy and side effects Phase III Adverse reactions to long-term use FDA Review/Approval FDA Review/Approval Additional Post-market Testing Biomarker Development Clinical use with Response Biomaker Years 0 2 4 6 8 10 12 14 16

COXEN Applied to COXEN Applied to Individualized Therapy Individualized Therapy COXEN provides treatment response biomarkers without the need for tissue from patients treated with COXEN COXEN COXEN COXEN chemotherapy regimens! h th i ! Discovery - Uses in vitro data (2-10 Years) - Can develop biomarkers Preclinical Testing g f for any drug d Laboratory and animal testing combinations within Phase I Determine safety and dosage days with minimal Phase II effort ! Efficacy and side effects y Phase III Adverse reactions to long-term use FDA Review/Approval Additional Post-market Testing Biomarker Development Clinical use with Response Biomaker Years 0 2 4 6 8 10 12 14 16

Can COXEN predict effectiveness of cisplatin Can COXEN predict effectiveness of cisplatin and paclitaxel in and paclitaxel in Bladder cancer cells Bladder cancer cells ? Cisplatin (GI50) Cisplatin (GI50) Paclitaxel (GI50) Paclitaxel (GI50) BLA-40 Cell line Cisplatin normalized log(GI50) & MiPP prediction scores BLA-40 Cell line umuc9 htb9 crl2742 X253jp (p-value = 0.006) (p-value = 0.016) slt4p3 umuc2 X253jbv ku7 sensitive log(GI50) Sensitive: Actual GI50 sensitive log(GI50) sensitive log(GI50) X253jbv 53jb umuc14 umuc14 Sensitive: Actual GI50 Sensitive: Actual GI50 sensitive predicted iti di t d Sensitive: COXEN Prediction sensitive predicted scaber crl7833 Sensitive: COXEN Prediction resistent log(GI50) Resistant: Actual GI50 umuc6 fl3p10 resistent log(GI50) resistant Resistant: Actual GI50 resistent predicted Resistant: COXEN Prediction umuc1 ku7 resistent predicted Resistant: COXEN Prediction resistant X253jp umuc3 vmcub1 umuc3e jon rt4 cubIII crl7193 crl7193 crl2169 j82 ht1197 psi X575a bc16.1 cubIII ht1197 mghu3 rt4 jon kk47 kk47 umuc1 1 bc16.1 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 Standardized log(GI50) Standardized log(GI50) Standardized COXEN Score Standardized COXEN Score …..No bladder cell lines were on NCI60 panel

Conclusion: Conclusion: COXEN COXEN Predicts In Vitro Predicts In Vitro Chemotherapy Responses Chemotherapy Responses � But WAIT!.... ....most human cancers treated with combination chemotherapy � Can COXEN predict effectiveness of known chemotherapeutic drug combinations in bladder cancer cell lines? cell lines? � Can COXEN predict treatment responses of known drug combinations in bladder cancer patients?

Can COXEN Predict Combination Chemotherapy Can COXEN Predict Combination Chemotherapy Responses ? Responses ? � Approach � Use 40 bladder cancer cell lines (BLA-40) � Evaluate common “doublet” drug combinations used in patients NCI-60 Panel BLA-40 3 2 1 3 2 Cisplatin 1 575A Sensitive C 1 Gemcitabine 3 2 COXEN COXEN 1 1 Taxol Taxol 3 2 3 3 2 2 Validation of COXEN predictions on BLA-40 Validation of COXEN predictions on BLA-40 COXEN Scores of compare cisplatin + gemcitabine In vitro evaluation of cisplatin + paclitaxel combinations gemcitabine + paclitaxel g p in BLA-40 cells in BLA 40 cells activity in the BLA-40 IC50

Results: Results: COXEN predicts effectiveness of COXEN predicts effectiveness of combination combination therapy in therapy in bladder cancer cells bladder cancer cells ? Resistant 100 CIS + PAC Resistant 3 12 3 CIS + GEM 12 80 PAC + GEM 11 4 gate 50 Surrog Correct Class Correct Class 60 Misclassified 40 IC5 20 0 Sensitive Sensitive 0.0 0.2 0.4 0.6 0.8 1.0 COXEN Score COXEN Score Responder Non-responder