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Curing Carcinoid From genes to drugs: Finding the genes Matthew Meyerson, M.D., Ph.D. Dana-Farber Cancer Institute Boston, Massachusetts.

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Cancer-causing genes: why do we care?

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Cancer causing genes why do we care

Curing CarcinoidFrom genes to drugs:Finding the genesMatthew Meyerson, M.D., Ph.D.Dana-Farber Cancer InstituteBoston, Massachusetts


Cancer causing genes why do we care

Conflicts of interestResearch 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

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 promise of gene-targeted cancer therapy

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)

After 2 months erlotinib treatment

Before treatment


What is a gene

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 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

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

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

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

Genomic causes of cancer

Amplification/deletion

Infection

AGT

Arg

CGT

Cys

Mutation

TGT

Ser

Translocation

GGT

Gly

GAT

Asp

GCT

Ala

GTT

Val


Cancer causing genes why do we care

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

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

Oncogenes

Tumor suppressors

Two kinds of cancer genes: a cartoon

Wild-type

Wild-type proto-oncogene

Inactivated

Activated oncogene


The carcinoid genome project

The Carcinoid Genome Project


Goals of 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

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

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

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

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

Special thanks…to the Caring for Carcinoid Foundation


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