Broad Institute of Harvard and MIT Cancer: Are we closer to a cure? Jesse Boehm, Ph.D. Broad Institute of Harvard and MIT Cambridge, MA

Cancer is a huge public health problem

Overall mortality rates have not changed for cancer… * Age-adjusted to 2000 US standard population. Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised. 2001 Mortality Data–NVSR-Death Final Data 2001–Volume 52, No. 3. http://www.cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_03.pdf

But we have made HUGE advances in some cancers!!!! Before Iressa treatment After 3 months of Iressa treatment Image provided by B. Johnson

We have made HUGE advances in prevention!!!!

The Fundamentals of Cancer What is cancer? Molecular causes of cancer How faulty genes are involved How a cancer cell becomes dangerous

What is Cancer? An uncontrolled growth of cells A genetic disease A family of similar diseases newscenter.cancer.gov

An Uncontrolled Growth of Cells normal skin skin cancer non-dividing cells . . dividing cells structural support 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!

A Genetic Disease Normal Cells Cancer Cells . Mutations in DNA can make normal cells become cancerous These can be inherited or spontaneous

A Family of Similar Diseases Carcinomas: from cells which protect the body from air and internal fluids Sarcomas: from cells in supportive tissue Leukemias and Lymphomas: from cells in the blood and immune system newscenter.cancer.gov

The Fundamentals of Cancer What is cancer? Molecular causes of cancer How faulty genes are involved How a cancer cell becomes dangerous

Common causes of cancer Chemicals (e.g. tobacco, asbestos) Viruses (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 They are called MUTAGENS Can also be predisposed to getting cancer by inheriting mutations from parents newscenter.cancer.gov

Smoking and Alcohol Cigarette smoking causes 87 percent of lung cancer deaths and is responsible for most cancers of the larynx, oral cavity and pharynx, esophagus, and bladder Tobacco smoke contains thousands of chemical agents, including over 60 substances that are known to cause cancer. Alcohol use has been implicated in the development of a number of cancers Risk increases >1 drink for women or 2 drinks for men/day

What are mutations and how do they cause normal cells to become Causes of Cancer What are mutations and how do they cause normal cells to become cancer cells? Cancer Cells

How Could a Mutant Protein Make Cells Divide Out of Control? mutant DNA mutant protein cancer cells

What Happens Normally? Normal DNA A T C G A T A T C G G C A T G C A T DNA Bases C G A T A T C G G C A T G C A T

What Happens Normally? Normal DNA mRNA A T A DNA is transcribed (copied) to RNA C C G A A T A A T C G C G C G A T A G C G A T A

What Happens Normally? Normal DNA mRNA A T A Normal Protein C C G A A amino acids A A T C G C G C G Translation: Proteins are made from mRNA A T A G C G A T A

A Mutation Occurs Changed DNA A T C G A T DELETION C G G C A T G C A T

A Mutant Protein is Made Changed DNA Changed mRNA Normal Protein A T A C C G A A T DELETION A C G C G C G A T A Abnormal/ Mutant Protein G G C A A T A A T

A Mutant Protein is Made Changed DNA A T Normal Protein C G A T C G G C A T G C Abnormal/ Mutant Protein A T A T

How Could a Mutant Protein Make Cells Divide Out of Control? mutant protein cancer cells

The Cell Cycle Controls Cell Division Cells divide (mitosis) Growth Cell Cycle Growth DNA Synthesis

The Cell Makes Sure That There are no Problems Did division go correctly? Cell Cycle Am I ready to divide? Am I big enough? Is my DNA copied correctly?

The Cell Cycle Has Checkpoints Did division go correctly? Cell Cycle Am I ready to divide? Am I big enough? Is my DNA copied correctly?

The Normal Protein Functions at a Cell Cycle Checkpoint Is my DNA copied correctly?

The Mutant Protein Allows The Cell to Divide Out of Control Cell Cycle Normal Protein go! Abnormal/ Mutant Protein I can’t stop and check if the DNA has been copied correctly!!!

The Fundamentals of Cancer What is cancer? Molecular causes of cancer How faulty genes are involved How a cancer cell becomes dangerous

How Faulty Genes are Involved Not every gene leads to cancer when mutated Mutations in two specific categories of genes can lead to cancer Tumor-Suppressor Genes Oncogenes

How Faulty Genes are Involved Not every gene leads to cancer when mutated Mutations in two specific categories of genes can lead to cancer Tumor-Suppressor Genes Oncogenes

Inactivated Tumor Suppressor Genes Lead to Cancer Tumor Suppressor (TS) genes normally inhibit cell growth Mutations in TS genes may inactivate them, so that they cannot stop cell-growth TS genes include p53 and BRCA1/2 cell TS gene

How Faulty Genes are Involved Not every gene leads to cancer when mutated Mutations in two specific categories of genes can lead to cancer Tumor-Suppressor Genes Oncogenes

Activated Oncogenes Lead to Cancer Oncogenes normally promote cell growth carefully Mutations in oncogenes may over-activate them, so that they always promote cell-growth One well-known oncogene is called RAS cell oncogene

Mutations in Specific Genes Turn a Normal Cell into a Cancer Cell Mutate tumor suppressor genes, turning these genes OFF Mutate oncogenes, turning these genes ON p53 RAS 1 2 3 4 5 6….. mutations normal cell cancer cell

The Fundamentals of Cancer What is cancer? Molecular causes of cancer How faulty genes are involved How a cancer cell becomes dangerous

Benign vs. Malignant Benign: A non-malignant tumor lacking the ability to invade surrounding normal tissue Malignant: A tumor that tends to grow, has the capacity to invade nearby tissue and spreads through the blood stream adapted from “Concise Dictionary of Biomedicine and Molecular Biology,” Pei-Show Juo, 1996

How cancer cells become dangerous A cancer cell on its own will not cause you harm To become the disease “Cancer” the cell must: 1) Form a tumor (at least) 2) Recruit a blood supply = angiogenesis (solid tumors only) 3) Spread to other parts of the body = metastasis (advanced stages)

Metastasis Cancer cells enter blood vessels Cells travel through the blood stream to distant sites Cells then invade new tissues, and begin to grow

Cancer treatment Heart Lung Tumor

There are different types of treatments Drugs (chemotherapy) Radiation Surgery

Cancer can be local or metastatic local (one primary tumor) metastatic (secondary tumors)

Cancer therapy: local and systemic Rx LOCAL: surgery and radiation SYSTEMIC: chemotherapy, etc.

Why need targeted therapy? The problem of Selectivity of chemotherapy and radiation normal cells cancer cells

Why need targeted therapy? The problem of Selectivity of chemotherapy and radiation normal cells cancer cells

Why need targeted therapy? The problem of Selectivity of chemotherapy and radiation normal cells cancer cells

Killing a fly with a cannon ball?

We can kill the fly but…

Problem with selectivity leads to side effects hair follicles: hair loss bone marrow:  immune defense, anemia, clotting problems gut lining: diarrhea skin: flaky/scaly skin normal cells cancer cells

How can we improve cancer therapy? Pick a better TARGET! Normal cell Cancer cell

Points to remember Cancer is a family of similar diseases, not just one! Different cancers have different causes, treatments and outcomes Cancer is caused by MUTATIONS Prevent your exposure to mutagens! A tumor causes a patient harm by becoming malignant and metastasizing By learning more about cancer we are developing new, “smarter” cancer drugs More effective Fewer side effects

Thank you!