Curing Carcinoid From genes to drugs: Finding the genes Matthew Meyerson, M.D., Ph.D. Dana-Farber Cancer Institute Boston, Massachusetts
Dec 25, 2015
Curing Carcinoid
From genes to drugs:Finding the genes
Matthew Meyerson, M.D., Ph.D.Dana-Farber Cancer Institute
Boston, Massachusetts
Conflicts of interest
Research and consulting support from Novartis (manufacturer of Gleevec)
Research support from Genentech(manufacturer of Tarceva)
Inventor of patent on using EGFR gene for cancer diagnosis
Cancer-causing genes:why do we care?
Because cancer is caused by changes in genes and in the genome—more later
To understand what causes cancer—so we can think in the right wayThis may affect prevention, surgery, even nutrition
To treat cancer by blocking the activity of cancer-causing genesThis has worked for many diseases:
Imatinib for chronic myeloid leukemia with ABL activation
Trastuzumab for breast cancer with ERBB2 activation
Erlotinib/gefitinib for lung cancer with EGFR activation
The promise of gene-targeted cancer therapy
The needCancer kills over 500,000 Americans each year and millions of people world-wideCytotoxic chemotherapy is non-selective and highly toxic
The hopeSelective therapies against altered cancer-causing genes can be highly effective and can exert fewer side effects
Example: a patient with lung cancer, with an EGFR mutation in her tumor ( thanks to Bruce Johnson, M.D., DFCI)
Before treatment
After 2 months erlotinib treatment
What is a gene?
Genes are instructions to make proteins……and proteins perform the activities of cells
…and billions of cells make up our bodies
Genes are stretches of DNA, our genetic code…and are used to make RNA and then protein
Genes are units of inheritance…passed from parent to child, and from cell to cell
DNA and the genome
DNA is the genetic codeFour “letters”: A, C, G, T
Some DNA stretches code for proteins, some DNA for chromosome structure, some DNA stretches control when or where proteins are made
Our genome is made of 6 billion DNA “letters”3 billion from our mother, 3 billion from our father
Organized in 46 chromosome “strings”
Including around 20,000 genes
What is a cell?
Cells are units of function in the bodyHighly specialized—blood cells, muscle cells, brain cells,
germ cells (egg and sperm), skin cells, …
Each cell contains a complete genome—6 billion letters of DNA
Around 100 trillion cells in the human body
Some cells can divide and make daughter cells, in a highly controlled manner, others can’t
This is a picture of cells, with the DNA stained green and the “membrane” covering stained red
How is a cancer cell different?
• Cancer cells are partly like other cells– Still have certain features (shapes, proteins, …) of
related cells– For example, stomach cancer cells still look related to
the stomach lining, while carcinoid cells are related to other neuroendocrine cells that secrete hormones
• Cancer cells have different growth patterns– Cancer cells divide when they shouldn’t, and grow in
places where they shouldn’t
How is the cancer genome different?
The genome of cancer cells is different from normal cells– Almost all cells in our bodies have the same DNA– The DNA of cancer cells is different from the normal cells in the
same person, or “mutated”– A “mutation” means a change in DNA sequence or structure and
implies a functional significance– The genomes of cancer cells can change as disease gets more
severe or patients become resistant to drugs
Cancer patients may be born with DNA sequence variations– Such variations affect the whole body (“germ-line”)– These variations may be inherited from parents or may be new
mutations in the patient– These variations may increase the risk of cancer
Genomic causes of cancer
Mutation
GGTGly GAT
Asp
GCTAla
GTTVal
AGTArg
CGTCys
TGTSer
Amplification/deletion
Translocation
Infection
Because the cancer genome is different from the normal genome, cancer cells have different survival requirements from normal cells.
So, in principle, we can find drugs that kill cancer cells but have much less effect on normal cells
Two kinds of cancer genes
OncogenesPromote cancer growth
Become hyperactive in cancer
Effective drugs that target oncogenes (imatinib)
Tumor Suppressor GenesSuppress cancer drug
Lose activity in cancer
No effective drugs yet for this class
Two kinds of cancer genes: a cartoonOncogenes Tumor suppressors
Wild-type proto-oncogene
Activated oncogene
Wild-type
Inactivated
The Carcinoid Genome Project
Goals of the carcinoid genome project
• Read the DNA sequence of 2000 genes in 48 carcinoid tumors and matched blood from the same patients
• Evaluate the presence of cancer-specific mutations in this DNA
• Perform experimental studies of these cancer-specific mutations to determine whether they are targets for drug therapy
Carcinoid genome project: why now?
1. Technology revolution in genome analysis
2. Carcinoid sample banks
3. Hope for finding new drugs
Technology revolution in genome analysis
Moore’s law: integrated circuits get twice as powerful every two years
Genome analysis: Moore’s law in the dust! Better than 2-fold improvement per year, now maybe 10-fold
Next-generation sequencing allows us to read millions of DNA sequences at once
Digital, not analog
Can discover:Mutations--in thousands of genesCopy number alterationsTranslocationsInfections
Carcinoid samples
• Thanks to CFCF and other support…• Physicians and scientists have been building
collections of frozen carcinoid tumors• International network for the carcinoid genome
project– Drs. Matthew Kulke and Ramesh Shivdasani, Dana-
Farber Cancer Institute, Boston– Drs. James Yao and Asif Rashid, M.D. Anderson
Cancer Center, Houston– Dr. Sylvia Asa, Princess Margaret Hospital, Toronto
Hope for finding new drugs
• Our DNA sequencing efforts are focused on genes that are known drug targets
• We will test mutated genes to see whether they promote cancer
• We will look for mutations that might predict response to known drugs
• We will make our data publicly available so that all physicians and scientists have a chance to build on our results to make further discoverie
Special thanks…to the Caring for
Carcinoid Foundation