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 way This may affect prevention, surgery, even nutrition To treat cancer by blocking the activity of cancer- causing genes This 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 need Cancer kills over 500,000 Americans each year and millions of people world-wide Cytotoxic chemotherapy is non-selective and highly toxic The hope Selective 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 code Four “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 body Highly 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 GGT Gly GAT Asp GCT Ala GTT Val AGT Arg CGT Cys TGT Ser 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 Oncogenes Promote cancer growth Become hyperactive in cancer Effective drugs that target oncogenes (imatinib) Tumor Suppressor Genes Suppress cancer drug Lose activity in cancer No effective drugs yet for this class

Two kinds of cancer genes: a cartoon OncogenesTumor 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 genes Copy number alterations Translocations Infections

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