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Bench to Bedside TranslationPatient 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
Drug A
Drug A/2500 mm3 scale Drug A/600 mm3 scale
Drug B/2500 mm3 scale
Individual Tumor Growth Curves Reveal Heterogeneity
Colorectal (CRC) PDXPreservation of histopathologic diversity
Stromal evolution to mouse
Julien S et al. Clin Cancer Res 2012;18:5314-5328
ALU probe in situ hybridization
stromal cells negative at 8th passage
PDX(Similar to primary)
Circos plots for the 1° tumor, metastasis and xenograft genomes
Ding L, et al Nature Vol 464 April 2010
PDX and metastasislook similar
Met
PDX
Sorafenib in RCC PDX:Efficacy Recapitulated in PDX Models
Yuen JSP et alBJC 2011 104: 941-947
Cetuximab (EGFR Ab) Treatment in Unselected Metastatic CRC Xenopatients: Prediction of KRAS Status Effect
Bertotti A et al. Cancer Discovery 2011;1:508-523
©2011 by American Association for Cancer Research
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
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
3/5 R CRC PDX had >50% increase in FZD2 (Wnt receptor) post-treatment with a MEK inhibitor
PDX Models Enable Validation of Cell-Line Derived Hypotheses
CUCRC006
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 2200
1000
2000
3000vehicle
selumetinib
CsA
combo
selumetinib+CsA
CsA+selumetinib
single agents vs combo combos vs vehicle regrowth
additional time point
EOS End of treatment
Days
Per
cen
t D
ay 1
Rational Combination:
MEK inhibitor + Wnt
inhibitor
Tested in PDX model
We were also able to test the
robustness of the response and
durability
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
Dose Level
No. Patients
AZD6244 (orally)
Cyclosporin A (orally)
-1 3-6 50 mg QD 2 mg/kg BID
1 3-6 50 mg BID 2 mg/kg BID 2 3-6 75 mg BID 2 mg/kg BID MTD 20 TBD TBD
Three Dose Levels
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 steady-state 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 Evaluationof Targeted Therapy (PETT)LabS. 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 IonkinaStacey Bagby, BA, AAS, CVTPeter KlauckLindsey Davis, M.D.Chris Lieu, M.D.Kit Wong, M.D.
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