Precision oncology through responses and resistance to anti-cancer therapies

Transcription

1 Precision oncology through responses and resistance to anti-cancer therapies Barry S. Taylor, Ph.D. Departments of Epidemiology/Biostatistics Medicine/Hematology-Oncology Helen Diller Family Comprehensive Cancer Center University of California, San Francisco

2 RE-CASTING DISCOVERY GENOMICS IN AN ERA OF TRANSLATIONAL SEQUENCING Bedside-to-bench-and-back-again Establishing the molecular genetic basis of observed phenotypes

3 TRANSLATIONAL GENOMICS FOR EXCEPTIONAL RESPONDERS Response to everolimus in metastatic bladder cancer patient Iyer G. et al. Science 2012

4 TRANSLATIONAL GENOMICS FOR EXCEPTIONAL RESPONDERS Whole genome sequencing in the clinical setting Iyer G. et al. Science 2012

5 TRANSLATIONAL GENOMICS FOR EXCEPTIONAL RESPONDERS Coincident TSC1 and NF2 mutations epistasis drives mtorc1 dependence Iyer G. et al. Science 2012

6 TRANSLATIONAL GENOMICS FOR EXCEPTIONAL RESPONDERS Biomarkers of mtorc1 inhibitor sensitivity? Iyer G. et al. Science 2012

7 GOOD AFTER BAD: MORE EFFICIENT AND EFFECTIVE TRIAL DESIGN Rational deployment of anti-cancer therapies in molecular defined populations

8 CURATIVE THERAPY FOR METASTATIC DISEASE? Combination therapy with AZD7762 and Irinotecan in small-cell cancer Al-Ahmadie H. et al. In revision

9 CURATIVE THERAPY FOR METASTATIC DISEASE? Combination therapy with AZD7762 and Irinotecan in small-cell cancer Al-Ahmadie H. et al. In revision

10 CURATIVE THERAPY FOR METASTATIC DISEASE? Combination therapy with AZD7762 and Irinotecan in small-cell cancer Al-Ahmadie H. et al. In revision

11 SYNTHETIC LETHALITY BETWEEN DDR DYSFUNCTION AND COMBINATION THERAPY RAD50 hypomorphism is synergistic with checkpoint inhibition MRN complex mutations are M.EX in cancer and affect ~4% of all human tumors Al-Ahmadie H. et al. In revision

12 NEW BIOMARKERS AND NEW TARGETS Utility of the genetic bases of rare but extreme responses anti-cancer therapy Durable ongoing CR (~3yrs on everolimus) Curative therapy with AZD7762+Irinotecan (NED ~2yrs after discontinuation of therapy) Iyer G. et al. Science 2012 Al-Ahmadie H. et al. In revision

13 EXPLOITING A PERENNIAL PROBLEM FOR ONCOLOGY Taking advantage of the design of typical phase II trials 1 Define the targets ^ Identify a drug 2 Cancer genome characterization 3 Identify the patients

14 INTERPRETING THE CLINICAL SIGNIFICANCE OF MUTATIONS IN CONSTANTLY EVOLVING DISEASE

15 FROM THE FRONT LINES OF RECURRENT GLIOMA Suffered a malignant progression from grade II to GBM after diagnosis B. Jonhson, Submitted

16 PRIMARY AND MATCHED RECURRENT GLIOMA LGG drivers present are generally clonal, early in nearest common progenitor B. Jonhson, Submitted

17 PRIMARY AND MATCHED RECURRENT GLIOMA Adjuvant TMZ induced catastrophic hypermutation at recurrence B. Jonhson, Submitted

18 PRIMARY AND MATCHED RECURRENT GLIOMA The disappearing act of the druggable BRAF V600E How do we interpret the clinical significance of such mutations at diagnosis? B. Jonhson, Submitted

19 ACKNOWLEDGEMENTS Taylor Lab Saurabh Asthana Tambu Shamu Oliver Zill UCSF Brett Johnson Tali Mazor Collin M. Blakely Luping Lin Matthew A. Gubens Kevan Shokat Boris Bastian Joseph Costello Trever G. Bivona Memorial Sloan-Kettering Cancer Center Gopa Iyer Marcel Hohl Hikmat Al-Ahmadie Aphrothiti J. Hanrahan Sasinya N. Scott Manickam Janakiraman Mono Pirun Chris Sander Nicholas D. Socci Agnes Viale Adriana Heguy Matthew I. Milowsky Bernard Bochner Dean F. Bajorin Michael F. Berger John H.F. Petrini David B. Solit