Genetic Research: Developments in prostate cancer Eliezer (Eli) Van Allen, MD Instructor in Medicine Dana-Farber Cancer Institute Broad Institute of MIT and Harvard May, 2014
About me • Born and raised in Los Angeles, CA • Studied Symbolic Systems (Stanford) – CS + linguistics + other – Camp Kesem
à Computers à Cancer
• Medical school (UCLA) • Residency (UCSF) à Prostate cancer • Fellowship and beyond (Dana-Farber) Big Question: Can we apply “big data” computer science to studying prostate cancer that will improve patient care?
Outline • • • •
Cancer genetics 101 Precision medicine and oncology Using tumor genetics in prostate cancer Future directions
Outline • • • •
Cancer genetics 101 Precision medicine and oncology Using tumor genetics in prostate cancer Future directions
The Big Question: How do our genes relate to (prostate) cancer?
Genomic Structure
AACR Annual Report 2013
Deciphering the Genetic Code
AACR Annual Report 2013
The Impact of Genetic Mutations
AACR Annual Report 2013
The scale of the problem • Big data in biomedical science: – 3 billion base pairs per genome – 1% in proteincoding regions ( “exome”)
• How to tackle this immense challenge?
Genomes as Big Data
The Broad Institute of MIT and Harvard Cambridge, MA
More = better Most places
Broad Institute
Genomes as Big Data
Illumina
Genomes as Big Data
Bioworld, 2013
Genomes as Big Data
Bioworld, 2013
From Big Data to Genetic Variants
Gad Getz, Broad Cancer Genome Analysis group
Mutations across cancers
Lawrence et al, Nature 2014
Acquired genetic mutations can drive prostate cancer
Barbieri, Baca et al, Nature Genetics 2014
Larger genomic “structural” changes in prostate tumors Normal
Prostate tumor
Baca et al, Cell 2013
Outline • • • •
Cancer genetics 101 Precision medicine and oncology Using tumor genetics in prostate cancer Future directions
ü The human genome is vast ü Cancers emerge from genomic errors ü “Industrial strength” sequencing is here ü The prostate cancer genome has been mapped
Outline • • • •
Cancer genetics 101 Precision medicine and oncology Using tumor genetics in prostate cancer Future directions
The Big Question: Can we use information about tumor genetics to guide patient care in oncology?
Precision oncology: A paradigm shift Past à Present Non-specific chemotherapy
Cancer Present à Future
Cancer
Test for tumorspecific genetic targets that can be “drugged” EGFR BCR-ABL ALK HER2 …
Targeted therapy
erlotinib imatinib crizotinib trastuzumab …
Path to precision oncology
Garraway JCO 2013
Early success stories
CML
BCR-ABL fusion
Imatinib
Very common
Unlikely
Breast cancer
Likely HER2 amplification Trastuzumab Very common (in metastatic disease)
Lung cancer
EGFR mutation
Erlotinib
Common
Almost universal
Evolution of precision oncology
2007
2010
2013
Single genes
OncoMap
OncoPanel
1-10 genes “10s” of data points
41 genes 100s of data points
2013+
Genome sequencing
300 genes 20,000 genes 1000s of >1,000,000,000s data points of data points
More needles… …but an (almost) infinitely larger haystack
Big data and clinical oncology Data points per patient WES, WGS Transcriptome
100,000
10,000
1,000 History and Physical Labs, Imaging Pathology…
SNaPShot OncoMap
100 10
Source: NHGRI
PHIAL Precision Heuristics for Interpreting the Alteration Landscape
“May it be a light to you in dark places, when all other lights go out.”1 1Galadriel,
in Tolkien, The Fellowship of the Ring
PHIAL
Van Allen, Wagle et al. in press, Nature Med.
Impact on clinical decision-making KRASA146V •
Rare activating alteration
David Barbie Leena Ghandi
Germline + integrative interpretation
Outline • • • •
Cancer genetics 101 Precision medicine and oncology Using tumor genetics in prostate cancer Future directions
ü Genomic data for clinic use is vast ü Using genomic technology in the clinic is achievable ü Genomics can directly impact patient care
Outline • • • •
Cancer genetics 101 Precision medicine and oncology Using tumor genetics in prostate cancer Future directions The Big Question: Does the precision medicine paradigm apply to prostate cancer?
Precision oncology for prostate cancer Metastatic advanced prostate cancer patient
PI3K inhibitor AKT inhibitor mTOR inhibitor
Tumor-only variants
Responds to cisplatin!
PHIAL
PARP inhibitor Platinum chemotherapy
Inherited (“germline”) variant BRCA2 K3326* nonsense
Five potential therapies for a patient who exhausted standard-of-care options!
“Long tail” and clinical relevance
Stand Up 2 Cancer Project Treatment with second generation ADT in mCRPC Pre-treatment Tumor & blood sample
Metastatic tumor biopsy & blood sample
WHOLE EXOME (DNA) AND TRANSCRIPTOME (RNA) SEQUENCING
Philip Kantoff
Levi Garraway
Outline • • • •
Cancer genetics 101 Precision medicine and oncology Using tumor genetics in prostate cancer Future directions
ü Precision oncology can be applied to prostate cancer ü Rare events may occur in anyone and are worth looking for ü Currently for metastatic disease
Outline • • • •
Cancer genetics 101 Precision medicine and oncology Using tumor genetics in prostate cancer Future directions
The Big Question: Where do we go from here?
Deciphering the Genetic Code, cont.
AACR Annual Report 2013
Future Directions • Pan-omic profiling – DNA – RNA – Protein – Other
• More patients, more trials, more everything • Larger preclinical testing
Future Directions: Which mutations matter?
Did not work in preclinical models Better predictions needed
Acknowledgements Garraway lab
Broad Institute
Levi Garraway
Gad Getz
Nikhil Wagle Gregory Kryukov Jean-Philippe Theurillat Eran Hodis Daniel Treacy Mahmoud Ghandi Aisha Townes Eva Goetz Steven Whittaker Craig Bielski Terence Wong Rajee Antony Jasmine Mu Ginevra Botta Ali Amin-Mansour Claudine Christoforides Frederick Wilson Sylvan Baca Dana-Farber/Partners Franklin Huang Cancer Care Judit Jane-Valbuena Robert J. Mayer Cory Johannessen Ann LaCasce David Konieczkowski Jennifer Temel Christine Kwon Alan D’Andrea Flora Luo Kent Mouw Sara Marlow Chengyin Min Jasmine Mu Chelsea Place Marius Pop
Scott Carter Amaro Taylor-Weiner Deborah Farlow Alexis Ramos Aaron McKenna Adam Keizun Pablo Tamayo Michael Lawrence Kristian Cibulskis Jeffrey Gentry Nils Gehlenborg David DeLuca Andrey Sivachenko Yotam Drier Nils Gehlenborg Stacey Gabriel Sheila Fisher William Hahn Matthew Meyerson Todd Golub Eric Lander …
The patients
DeCOG
Dirk Schadendorf Antje Sucker Many clinicians
MSKCC Jonathan Rosenberg Ilana Garcia-Grossman Philip Kim
Funding DFCI Leadership Council Friends of DFCI NIH/NHGRI Starr Prostate Cancer Foundation American Cancer Society