New uses of drugs from a trillion points of data

Atul Butte, MD, PhD

Chief, Division of Systems Medicine, Department of Pediatrics, Genetics,and by courtesy, Medicine, Pathology, and Computer Science

Center for Pediatric Bioinformatics, LPCH

Stanford University

abutte@stanford.edu

@atulbutte

Disclosures• Scientific founder and

advisory board membership– Genstruct– NuMedii– Personalis– Carmenta

• Past or present consultancy– Lilly– Johnson and Johnson– Roche– NuMedii– Genstruct– Tercica– Ecoeos– Ansh Labs– Prevendia– Samsung– Assay Depot– Regeneron– Verinata– Geisinger

• Honoraria– Lilly– Pfizer– Siemens– Bristol Myers Squibb– AstraZeneca

• Corporate Relationships– Aptalis– Thomson Reuters

• Speakers’ bureau– None

• Companies started by students– Carmenta– Serendipity– NuMedii– Stimulomics– NunaHealth– Praedicat– MyTime– Flipora

Over 1.2 million microarrays available

Doubles every 2-3 years

Butte AJ. Translational Bioinformatics: coming of age. JAMIA, 2008.

Public big data = retroactive crowd-sourcing

Available Cancer Types # Cases Shipped by BCR # Cases with DataDate Last Updated (mm/dd/yy)

Acute Myeloid Leukemia [LAML] 200 200 6/24/2013

Adrenocortical carcinoma [ACC] 80 0

Bladder Urothelial Carcinoma [BLCA] 201 184 7/5/2013

Brain Lower Grade Glioma [LGG] 296 271 7/3/2013

Breast invasive carcinoma [BRCA] 1007 961 7/5/2013

Cervical squamous cell carcinoma and endocervical adenocarcinoma [CESC] 163 163 7/5/2013

Colon adenocarcinoma [COAD] 439 425 6/28/2013

Esophageal carcinoma [ESCA] 63 63 7/5/2013

Glioblastoma multiforme [GBM] 514 510 6/28/2013

Head and Neck squamous cell carcinoma [HNSC] 427 376 7/3/2013

Kidney Chromophobe [KICH] 66 66 7/5/2013

Kidney renal clear cell carcinoma [KIRC] 512 512 7/3/2013

Kidney renal papillary cell carcinoma [KIRP] 158 144 6/28/2013

Liver hepatocellular carcinoma [LIHC] 152 128 7/3/2013

Lung adenocarcinoma [LUAD] 500 499 7/3/2013

Lung squamous cell carcinoma [LUSC] 500 494 7/5/2013

Lymphoid Neoplasm Diffuse Large B-cell Lymphoma[DLBC] 18 18 7/3/2013

Mesothelioma [MESO] 0 0

Ovarian serous cystadenocarcinoma [OV] 572 570 7/5/2013

Pancreatic adenocarcinoma [PAAD] 71 62 7/3/2013

Pheochromocytoma and Paraganglioma [PCPG] 0 0

Prostate adenocarcinoma [PRAD] 248 201 7/5/2013

Rectum adenocarcinoma [READ] 169 168 6/28/2013

Sarcoma [SARC] 111 75 7/5/2013

Skin Cutaneous Melanoma [SKCM] 357 336 7/5/2013

Stomach adenocarcinoma [STAD] 343 325 7/3/2013

Testicular Germ Cell Tumors [TGCT] 0 0

~300 Diseases and Conditions

20k+ Genes

Blue: gene goes down in diseaseYellow: gene goes up in disease

Human Disease Gene Expression Collection

Butte AJ, Kohane IS. Nature Biotechnology, 2006, 24:55.Butte AJ, Chen R. Proc AMIA Fall Symposium, 2006.Chen R, Butte AJ. Nature Methods, 2007.Dudley J, Tibshirani R, Deshpande T, Butte AJ. Molecular

Systems Biology, 2009.Shen-Orr S, ... Davis MM, Butte AJ. Nature Methods, 2010.

5,178 compounds· 1,300 off-patent FDA-approved drugs· 700 bioactive tool compounds· 2,000+ screening hits (MLPCN and others)3,712 genes (shRNA + cDNA)· targets/pathways of FDA-approved drugs (n=900)· candidate disease genes (n=600)· community nominations (n=500+)15 cell types· Banked primary cell types· Cancer cell lines· Primary hTERT immortalized· Patient derived iPS cells· 5 community nominated

Lamb J, ..., Golub TR. Science, 2006. Sirota M, Dudley JT, ..., Sweet-Cordero A, Sage J, Butte AJ.

Science Translational Medicine, 2011.

Marina SirotaJoel Dudley

Validation methods are increasingly commoditized

Candidate anti-seizure drug against inflammatory bowel disease

Marina SirotaJoel Dudley

Sirota M, Dudley JT, ..., Sweet-Cordero A, Sage J, Butte AJ. Science Translational Medicine, 2011.

Anti-seizure drug works against a rat model of inflammatory bowel disease

Dudley JT, Sirota M, ..., Pasricha J, Butte AJ. Science Translational Medicine, 2011.

Marina SirotaJoel Dudley

Mohan M Shenoy Jay Pasricha

Rat colonoscopy Rat with Inflammatory Bowel Disease

Inflammatory Bowel Disease

After Anti-seizure Drug

Dudley JT, Sirota M, ..., Pasricha J, Butte AJ. Science Translational Medicine, 2011.

Anti-seizure drug works against a rat model of inflammatory bowel disease

Anti-ulcer drug works for lung adenocarcinoma

• Human lung adenocarcinoma cell lines explanted into mouse models

• Followed growth 11 days

• Positive-control doxorubicin grew to 2x original volume

• Tumors in mice treated with vehicle grew to 3.25x original volume

• Not only did our compound work statistically better than control, it worked in a dose-dependent manner

• Tumors in mice treated with 50 mg/kg/day grew 2.8x

• Those treated with 100 mg/kg/day grew only 2.3x.

Joel DudleyMarina Sirota

Julien SageSirota M, Dudley JT,..., Sage J, Butte AJ. Science Translational Medicine, 2011,

Control With Cimetidine

Anti-depressant Imipramine Shows Significant Activity Against Small Cell Lung Cancer

Vehicle control Imipramine

p53/Rb/p130triple knockoutmodel of SCLC

Mice dosed after tumor formation

Joel DudleyNadine Jahchan

Julien SageJoel NealNuMedii

Cancer Discovery, 2013.

Drug development

NuMedii lands 1st deal to spin drug data into product gold San Francisco Business Times by Ron Leuty, Reporter

Date: Wednesday, October 3, 2012, 5:30am PDT - Last Modified: Wednesday, October 3, 2012, 6:27am PDT

Ron LeutyReporter- San Francisco Business Times

NuMedii Inc. is looking to make a big difference in drug

development with Big Data.

The Mountain View company co-founded by Stanford

University’s Atul Butte and his wife, former Affymetrix

executive Gini Deshpande, said Wednesday that it inked a

deal to help drug developer Aptalis Pharma Inc. find new

treatments for gastrointestinal disorders and cystic fibrosis.

Stanford University professor and NuMedii

co-founder Atul Butte.

October 3, 2012 4:02 pm by Deanna Pogorelc | 1 Comments

Pairing existing drugs with new disease applications, using not wet labs but

computers, has landed a Stanford startup its first contract with a pharmaceutical

company.

Using data to find new drug-disease matches wins startup NuMedii its first pharma deal

108 million substances x650,000 assays

1 billion points of data within a grid of 70 trillion cells

Five Lessons Learned• Public molecular data has incredible utility

– All public-funded data should eventually become publicly-available

– Consider mechanisms to promote secondary uses and computation

• Sufficient high quality data already exists to impact medicine

– More is better, but no reason to wait for more data

– Should never wait for perfect data, experiment, conditions

– Requiring perfection can even slow secondary use

• It’s not just about infrastructure, it’s about using it

– Too many tools. Those who build platforms use them too!

• Need to train students to initiate science with data

– High school higher education career changers

– Scaling through students

• Entrepreneurship from public-funded data is not a dirty word!

– Academics and industry can coexist and thrive together

Collaborators• Jeff Wiser, Patrick Dunn, Mike Atassi / Northrop Grumman

• Ashley Xia and Quan Chen / NIAID

• Takashi Kadowaki, Momoko Horikoshi, Kazuo Hara, Hiroshi Ohtsu / U Tokyo

• Kyoko Toda, Satoru Yamada, Junichiro Irie / Kitasato Univ and Hospital

• Shiro Maeda / RIKEN

• Alejandro Sweet-Cordero, Julien Sage / Pediatric Oncology

• Mark Davis, C. Garrison Fathman / Immunology

• Russ Altman, Steve Quake / Bioengineering

• Euan Ashley, Joseph Wu, Tom Quertermous / Cardiology

• Mike Snyder, Carlos Bustamante, Anne Brunet / Genetics

• Jay Pasricha / Gastroenterology

• Rob Tibshirani, Brad Efron / Statistics

• Hannah Valantine, Kiran Khush/ Cardiology

• Ken Weinberg / Pediatric Stem Cell Therapeutics

• Mark Musen, Nigam Shah / National Center for Biomedical Ontology

• Minnie Sarwal / Nephrology

• David Miklos / Oncology

Support

• Lucile Packard Foundation for Children's Health

• National Institutes of Health

• March of Dimes

• Hewlett Packard

• Howard Hughes Medical Institute

• California Institute for Regenerative Medicine

• Scleroderma Research Foundation

• Clayville Research Fund

• PhRMA Foundation

• Stanford Cancer Center, Bio-X

• Tarangini Deshpande

• Kimayani Butte

Admin and Tech Staff

• Susan Aptekar

• Rhonda Pisk

• Alex Skrenchuk