cancer: are we closer to a cure? jesse boehm, ph.d. broad institute of harvard and mit cambridge, ma

Cancer:Are we closer to a cure?

Jesse Boehm, Ph.D.

Broad Institute of Harvard and MITCambridge, MA

Cancer is a huge public health problem

Overall mortality rates have not changed for cancer…

586.8

193.9245.8

194.4

0

100

200

300

400

500

600

700

Heart Disease Cancer

Deaths per 100,000 people

1950

2001

* 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

Before Iressa treatment After 3 months of Iressa treatment

But we have made HUGE advances in some cancers!!!!

Image providedby 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

•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

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 andimmune system



What is cancer?




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


Smoking and AlcoholCigarette 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

Causes of Cancer

Cancer Cells

What are mutations and how do they cause normal cells to become

cancer cells?

How Could a Mutant Protein Make Cells Divide Out of Control?

mutant protein cancer cells

?

mutant DNA

What Happens Normally?

DNA Bases

Normal DNA

A T

C G

CG

A T

CG

A T

C G

A

A

T

T

Normal DNA


A T

C G

CG

A T

CG

A T

C G

A

C

G

A

G

A

C

mRNA

DNA is transcribed (copied) to RNA

A

A

T

T

A

A


Normal Protein

mRNA

Translation: Proteins are made from mRNA

aminoacids

Normal DNA

A T

C G

CG

A T

CG

A T

C G

A

C

G

A

G

A

C

A

A

T

T

A

A

A T

C G

CG

A T

CG

Changed DNA

A T

C G

DELETION

A Mutation Occurs

A T

Changed DNA

A Mutant Protein is Made

A T

C G

CG

A T

CG

A T

C G

A

C

G

A

G

A

C

Changed mRNA

DELETION

Normal Protein

Abnormal/ Mutant Protein

A T

A

A

AA T

A Mutant Protein is Made

Normal Protein

Changed DNA

A

T

C G

CG

A T

CG

C G

A

T


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

Cell Cycle

Cells divide (mitosis)

DNA Synthesis

Growth

Growth

The Cell Makes Sure That There are no Problems

Cell Cycle

Did division go correctly?

Is my DNA copied

correctly?

Am I big enough?

Am I ready to divide?

The Cell Cycle Has Checkpoints

Cell Cycle

Did division go correctly?

Is my DNA copied

correctly?

Am I big enough?

Am I ready to divide?

The Normal Protein Functions at a Cell Cycle Checkpoint

Cell Cycle

Normal Protein

Is my DNA copied correctly?

The Mutant Protein Allows The Cell to Divide Out of Control

Cell Cycle

I can’t stop and check if the DNA has been copied

correctly!!!

Normal Protein


go!


What is cancer?




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

normal cell cancer cell

mutations

1 2 3 4 5 6…..


What is cancer?




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

Cells then invade new tissues, and

begin to grow

Cells travel through the blood stream to

distant sites

Cancer cells enter blood vessels

Cancer treatment

Tumor

Lung

Heart

Surgery

Radiation

Drugs (chemotherapy)

There are different types of treatments

Cancer can be local or metastatic

local (one primary

tumor)

metastatic (secondary

tumors)

Cancer therapy: local and systemic

LOCAL: surgery and

radiation

SYSTEMIC: chemotherapy,

etc.

Rx

The problem of Selectivity of chemotherapy and radiation

Why need targeted therapy?

cancer cellsnormal cells

Killing a fly with a cannon ball?

We can kill the fly but…

Problem with selectivity leads to side effects

SIDE EFFECTS!

• hair follicles: hair loss • bone marrow: immune defense,

anemia, clotting problems• gut lining: diarrhea• skin: flaky/scaly skin

cancer cellsnormal cells

How can we improve cancer therapy?

Pick a better TARGET!

Normal cell Cancer cell

Points to rememberCancer 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!

cancer: are we closer to a cure? jesse boehm, ph.d. broad institute of harvard and mit cambridge, ma

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