Curing Cancer 2015 update

Jesse S. Boehm, Ph.D.

Associate Director, Broad Institute Cancer Program

2003 20132015 2023

Empiric(organ)

Precise(gene)

Personalized(patient)

Two decades of cancer medicine

2015: A unprecedented moment in the history of cancer

Before BRAF drug 6 weeks later

Example: BRAF-mutant melanoma

2015: Explosion of excitement around using the immune system to fight cancer

• NYT: “Is the cure for cancer inside you?”

• Amazing, unprecedented long term successes, never before seen!

• 60% of patients with late stage melanoma now alive at 18 months, vs. <5% previously

• Scientists are working to better predict which patients will respond

MSKCC

2015: The culture of science is changing – we are all becoming part of a cancer-curing ecosystem

Most tumor samples have not been readily available for study

Technology, social media, and cultural changes now provide a

new opportunity to engage cancer patients and

directly partner withthem in this research

We are launching new approaches to directly engage cancer patients in research

Only 5% of U.S. cancer patients are enrolled in

clinical trials

85% of U.S. cancer patients are treated in community

settings

A model of collaborative science

Broad as a horizontal connector across multiple institutions

Broad Cancer Program

• Is another cancer research effort really needed?

• Potent synergy between innovation and scale; harnessing creativity of academia with the professional, goal-oriented focus of industry

• Collaborative, team-oriented approach (200+ scientists) to tackle what industry deems scientifically or financially “impossible;”

• New organizational model focused on community impact and public good; pilot projects (that won’t be solved by industry) catalyze worldwide effort

2015: A unprecedented moment in the history of cancer

Before BRAF drug 6 weeks later

Example: BRAF-mutant melanoma

How did this happen?

• Identification in 2002 that the BRAF protein is mutated in melanoma

• Develop a powerful drug that blocks the BRAF protein

• Launch a focused clinical trial by enrolling only patients with molecular biomarker that predicts response

• Understand relationship between having the mutation and responding to therapy

• Clinical trials are thus smaller, faster and cheaper

• See amazing clinical success (~2009) and FDA approval (2011)

What is Cancer?

• An uncontrolled growth of cells

newscenter.cancer.gov

An Uncontrolled Growth of Cells

• Healthy cells turn into the enemy• divide too quickly or abnormally• become abnormal shapes and sizes• grow in all directions

• Cells stop listening to the body, which is telling them to stop!

.. ... .. ... .. .... . .. ... .. .. .. . .. ..... ..

structuralsupport

dividing cells

non-dividing cells

normalskin

skin cancer

What is Cancer?

• An uncontrolled growth of cells

• A family of similar diseases

newscenter.cancer.gov

A family of similar diseases

• Leukemias and Lymphomas:

from cells in the blood andimmune system

• Sarcomas: from cells in supportive tissue

• Carcinomas: from cells which protect the body from air and internal fluidsnewscenter.cancer.gov

What is Cancer?

• An uncontrolled growth of cells

• A family of similar diseases

• A genetic disease caused by mutations

newscenter.cancer.gov

Cancer is a genetic disease

Normal Cells Cancer Cells

.. ... .. ... .. .... . .. .

• Cancer cells harbor genetic alterations

• Point mutations• Chromosomal deletions or amplifications

Common causes of cancer

• Chemicals (e.g. tobacco, asbestos)

• Certain viruses and bacteria (e.g. HPV)

• Radiation from the sun

• What do all of these have in common?

Common causes of cancer

• Chemicals (e.g. tobacco, asbestos)

• Certain viruses and bacteria (e.g. HPV)

• Radiation from the sun

• What do all of these have in common?

• They all lead to MUTATIONS in the DNA of your cells

Remarkable advances in cancer prevention

Prevent nearly all cervical cancers!

Common causes of cancer

• Chemicals (e.g. tobacco, asbestos)

• Certain viruses and bacteria (e.g. HPV)

• Radiation from the sun

• What do all of these have in common?

• They all lead to MUTATIONS in the DNA of your cells

• Can also be predisposed to getting cancer by inheriting mutations from parents

• Most of the known genes associated with cancer have been found by:

Studying familial cancer syndromes (pedigrees)

• 1969 Li-Fraumeni Syndrome = mutated p53• 1980s Retinoblastoma = mutated RB• 1990 Neurofibromatosis = mutated NF1• 1990s Breast Cancer = mutated BRCA1/2• 1996 Cowden Syndrome = mutated PTEN

Finding key genes that cause cancer (1969-2000)

2001: Sequence of the human genome

• Could now analyze cancer genomes from tumors and look for differences!

germline

somaticCharacterization (Individual) Interpretation (Population)

Using genomics to build the world’s first map of all genes that cause cancer

B) Which genome alterations are statistically significant in the population (occur more than expected by chance)?

A) What is the full set of genome alterations within each tumor?

Discovering Cancer Geneswhere we are now

• Mapping cancer genes highlights potential drug targets

• First cancer genome decoded in 2009

• 2015: Broad has mapped over 15,000 cancer genomes across >25 tumor types, produced computational tools widely used across the globe

• We will soon have the complete map of common mutations in every major cancer type

• Major discoveries in nearly every cancer type; genome-guided medicine becoming reality for patients

2015: Rise of “precision cancer medicine”

patient tumor clinical sequencing and

pathology

mutations(10-150)

cancer drugs that each target

one of the mutations

Many cancer patients are now having their cancer genome sequenced to help predict which drugs to

take!

Converting genome information into cancer therapeutics: two challenges• Drugs exist today that block only 10% of the

mutated genes

• Challenge 1: For another 20% we know that we need to block the gene, but these targets have been called “undruggable”

• Challenge 2: For the remaining 70% we’re not sure what to do; we don’t yet know the relationships between the genetics of cancer and how to kill cancers

Converting genome information into cancer therapeutics: two challenges• Drugs exist today that block only 10% of the

mutated genes

• Challenge 1: For another 20% we know that we need to block the gene, but these targets have been called “undruggable”

• Challenge 2: For the remaining 70% we’re not sure what to do; we don’t yet know the relationships between the genetics of cancer and how to kill cancers

• SOLUTION 1: AGGREGATE CLINICAL DATA ON GENETICS LINKED TO DRUG RESPONSES (GLOBAL ALLIANCE FOR GENOMICS AND HEALTH)

Can also learn information right from patients!Use genome to demystify “exceptional responders”

• Resurrect “failed” drugs by finding genes that allowed rare patients to respond!

Converting genome information into cancer therapeutics: two challenges• Drugs exist today that block only 10% of the

mutated genes

• Challenge 1: For another 20% we know that we need to block the gene, but these targets have been called “undruggable”

• Challenge 2: For the remaining 70% we’re not sure what to do; we don’t yet know the relationships between the genetics of cancer and how to kill cancers

• SOLUTION 1: AGGREGATE CLINICAL DATA ON GENETICS LINKED TO DRUG RESPONSES (GLOBAL ALLIANCE FOR GENOMICS AND HEALTH)

• SOLUTION 2: BUILD A CANCER DEPENDENCY MAP IN THE LABORATORY

Can grow cancers in the lab

Peds002TW: Wilms Tumor

AAO2: Pancreatic adenocarcinoma BT584: Brain metastasis of colon cancer

JL16: Anaplastic thyroid cancer

Map genetics of lab models: Cancer Cell Line Encyclopedia

1000 cancer cell lines

Barretina et al, Nature 2012

www.broadinstitute.org/ccle

Turn each gene off one at a time and assess cancer cell survival via RNAi or CRISPR/Cas9

• Discovery in early 2000s that “RNA interference” could be used to silence genes; however, not very specific

• Discovery in 2013 of the amazing new “CRISPR” gene editing technique; has revolutionized biomedicine

• Can use these technologies to systematically turn off each gene in the genome and study effects on cancer survival

CRISPR in action

Steven Dixon

RNAi/CRISPR/small molecule

assessments of essentiality

genetic/molecularfeatures

Have the feature

Do not have the feature

Degree of vulnerability

Feature status

Towards a Complete Cancer Dependencies Map

high low

• Make all data available to empower the scientific community

• Use statistical analyses to extract relationships

Work to develop a cancer drug and deliver to right patients

Curing disease is no longer something that only scientists do: in 2015 we are all becoming scientists

• Patients may hold the keys to curing disease within their genome and can partner with scientific teams in new ways

• Crowd-sourcing challenges lower barriers to participation invite smart (young) people to solve big problems

• Can propel science through careers in policy, law, counseling, advocacy, communication/marketing, technology, etc (in addition to research/medicine)

• If you go to the doctor, take medicine, vote, use internet or social media to source health information, you are already part of the scientific ecosystem!