Genetic Research: Developments in prostate cancer

Genetic Research: Developments in prostate cancer Eliezer (Eli) Van Allen, MD Instructor in Medicine Dana-Farber Cancer Institute Broad Institute of M...
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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