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Cancer:Are we closer to a cure?
Thanks to: 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…
De
ath
s p
er
100
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0 p
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Year
CDC Mortality Data
2015: A unprecedented moment in the history of cancer
Before BRAF drug 6 weeks later
Example: BRAF-mutant melanoma
2015: A unprecedented moment in the history of cancer
How did this happen?
•Identification in 2002 that the BRAF protein is mutated in melanoma
•Develop a powerful drug that blocks the BRAF protein
•Launch a focused clinical trial by enrolling only patients with molecular biomarker that predicts response (sequence tumor)
•Understand relationship between having the mutation and responding to therapy•Clinical trials are thus smaller, faster and cheaper
•See amazing clinical success (~2009) and FDA approval (2011)
Before Iressa treatment After 3 months of Iressa treatment
We have made HUGE advances in other cancers!!!!
Image providedby B. Johnson
2003 2011 2015 2023
Empiric/Experimental
(organ)
Precise/Targeted
(gene)
Personalized(patient)
Progress/The Future: Two decades of cancer medicine
Discovering Cancer Geneswhere we are now
• Mapping cancer genes highlights potential drug targets
• Human genome mapped in 2001• First cancer genome decoded in 2009
• 2014: Broad has mapped over 15,000 cancer genomes across >25 tumor types, produced the world’s standard computational tools
• We will soon have the complete map of common mutations in every major cancer type
• Major discoveries in nearly every cancer type; genome-guided medicine becoming reality for patients
Many cancer patients today are having their tumor genomes sequenced to predict treatments
patient tumor clinical sequencing and pathology
mutations(10-150)
cancer drugs that each target one of
the mutations
We don’t have all of the drugs yet, but now that we know what proteins to block, drug companies are developing
successful cancer drugs at a much faster pace!
We have also 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
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
Facts: 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
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
What Happens Normally?
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
What Happens Normally?
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
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
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
Abnormal/ Mutant Protein
go!
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
normal cell cancer cell
mutations
1 2 3 4 5 6…..
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
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 cells
normal cells
The problem of Selectivity of chemotherapy and radiation
Why need targeted therapy?
cancer cells
normal cells
The problem of Selectivity of chemotherapy and radiation
Why need targeted therapy?
cancer cells
normal 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
Goal: Discover new drugs that attack most important mutations
Example: MCL1 gene helps cells survive
Progress: Discovery of new early stage drugs that block MCL1 in cancer cells
normal breast cancer
MCL1 gene
ALIVE DEAD
Turn off MCL1 in lab
Goal: Discover new drugs that attack most important mutations
Example: MCL1 gene helps cells survive
Want to explore this further? Check this out:
Progress: Discovery of new early stage drugs that block MCL1 in cancer cells
500,000 chemicals robotics
http://www.hhmi.org/biointeractive/bcr-abl-cancer-protein-structure-function
2015 Revolution in Cancer Therapy #1: Using the immune system to fight cancer
• Amazing, unpredecented successes (2013-2015), never before seen!
• A revolution in cancer therapy
2015 Revolution in Cancer Therapy #2: Resurrect “failed” drugs by finding genes that allowed rare patients to respond!
Can you have an impact on cancer? He did!
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