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Bench to Bedside Translation Patient Derived Xenograft (PDX) Models and Case Study S. S. Gail Eckhardt, M.D. University of Colorado Cancer Center September 2014 Schema: Patient Derived Xenograft Model (PDX) These are the logistical steps that need to be worked out: consenting patients and getting tumor from pathology in OR Note: Tumors are never grown on plastic Response of Colorectal PDX to a Range of Targeted Agents 150.00% 100.00% 50.00% IGF1Ri MEKi STI Pro-apoptotic 0.00% AurAi PLKi Irinotecan Cetuximab -50.00% -100.00% -150.00% GSI Individual Tumor Growth Curves Reveal Heterogeneity Drug A/2500 mm3 scale Drug A Drug B/2500 mm3 scale Drug A/600 mm3 scale Colorectal (CRC) PDX Preservation of histopathologic diversity Stromal evolution to mouse PDX (Similar to primary) ALU probe in situ hybridization stromal cells negative at 8th passage Julien S et al. Clin Cancer Res 2012;18:5314-5328 Circos plots for the 1° tumor, metastasis and xenograft genomes PDX and metastasis look similar Met PDX Ding L, et al Nature Vol 464 April 2010 Sorafenib in RCC PDX: Efficacy Recapitulated in PDX Models Yuen JSP et al BJC 2011 104: 941-947 Cetuximab (EGFR Ab) Treatment in Unselected Metastatic CRC Xenopatients: Prediction of KRAS Status Effect WT KRAS PDX responded (regression) If this had been known prior to phase III development, literally thousands of patients could have avoided ineffective and toxic therapy Bertotti A et al. Cancer Discovery 2011;1:508-523 ©2011 by American Association for Cancer Research Using PDX to Develop Rational Combinations Case Study: MEK Combination in CRC Synthetic Lethality: Functional Screen for Actionable Resistance Pathways Identifying genes which when suppressed potentiate cell death with Drug X WNT signaling pathway Legend SL genes GSEA core genes Common in GSEA and SL genes 3/5 R CRC PDX had >50% increase in FZD2 (Wnt receptor) post-treatment with a MEK inhibitor CUCRC006 CUCRC007 CUCRC012 CUCRC021 CUCRC027 4 2 1 CUCRC027 post-T CUCRC027 pre-T CUCRC021 post-T CUCRC021 pre-T CUCRC012 post-T CUCRC012 pre-T CUCRC007 post-T CUCRC007 pre-T CUCRC006 post-T 0 CUCRC006 pre-T relative expression 3 FZD2 PDX Models Enable Validation of Cell-Line Derived Hypotheses EOS End of treatment CUCRC006 3000 vehicle additional time point selumetinib CsA combo Rational Combination: selumetinib+CsA CsA+selumetinib MEK inhibitor + Wnt inhibitor Percent Day 1 2000 Tested in PDX model 1000 We were also able to test the robustness of the response and durability 0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 Days single agents vs combo combos vs vehicle regrowth Clinical Translation: NCI/CTEP Approved Trial Note: PDX will be utilized to determine which are the most effective biomarkers to assess in patient’s tumors on the study Three Dose Levels Dose Level -1 1 2 MTD No. Patients 3-6 3-6 3-6 20 AZD6244 (orally) 50 mg QD 50 mg BID 75 mg BID TBD Cyclosporin A (orally) 2 mg/kg BID 2 mg/kg BID 2 mg/kg BID TBD Treatment Plan (dose escalation) • In Cycle 1 (dose-escalation) – AZD6244 alone on Day -7 • plasma sampling at baseline, 0.5, 1, 2, 4, 8, and 24 hours – Cyclosporin A alone on Day -3, • plasma sampling at baseline, 0.5, 1, 2, 4, 8, and 24 hours • On Day 1 all patients will receive both AZD6244 and cyclosporin A with plasma sampling at baseline, 0.5, 1, 2, 4, 8, and 24 hours • Cyclosporin A levels will be checked 6-8 days later and at least every other week while patients are taking cyclosporin A • The dose of cyclosporin A will be adjusted accordingly for a goal of steadystate trough levels of 125 to 250 ng/mL Treatment Plan (dose expansion) • Total of 20 patients with CRC – all required to have a baseline tumor biopsy • A cohort of seven patients will have a 7-day AZD6244 alone run-in – Biopsy before AZD6244 and after the 7-day run-in – Assessing up-regulation of resistance (Wnt) pathway(s) – Biopsy at the time of progression • AZD6244 and Cyclosporin A will be given together on day 1 • No PKs in the expansion cohort This was the First activated Experimental Therapeutics – Clinical Trials Network (ET-CTN) (UM1) clinical trial! PETT Lab Program for the Evaluation of Targeted Therapy (PETT) Lab S. Gail Eckhardt, M.D. Aik-Choon Tan, Ph.D. John Tentler, Ph.D. Todd Pitts, M.S. Steve Leong, M.D. Jiyhe Kim, Ph.D. Jennifer Diamond, M.D. Anastasia Ionkina Stacey Bagby, BA, AAS, CVT Peter Klauck Lindsey Davis, M.D. Chris Lieu, M.D. Kit Wong, M.D.