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Cancer:
Are we closer to a cure?
Thanks to: Jesse Boehm, Ph.D.
Broad Institute of Harvard and MIT
Cambridge, MA
Cancer is a huge public health problem
Deaths per 100,000 people
Overall mortality rates have not
changed for cancer…
Year
CDC Mortality Data
2015:
2015: AAunprecedented
unprecedentedmoment
moment
ininthe
thehistory
historyofofcancer
cancer
Example: BRAF-mutant melanoma
Before BRAF drug
6 weeks later
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)
We have made HUGE advances
in other cancers!!!!
Before Iressa treatment
After 3 months of Iressa
treatment
Image provided
by B. Johnson
Progress/The Future: Two decades of
cancer medicine
2003
Empiric/
Experimental
(organ)
2011 2015
Precise/
Targeted
(gene)
2023
Personalized
(patient)
Discovering Cancer Genes
where 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
non-dividing
cells
dividing cells
normal
skin
.. .. .. .. ..
.....
skin cancer
.... .... . ... ...
..
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
newscenter.cancer.gov
Can also be predisposed to getting
cancer by inheriting mutations from
parents
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
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
What Happens Normally?
Normal DNA
mRNA
A
T
A
C
G
C
A
T
A
A
T
A
C
G
C
G
C
G
A
T
A
G
C
G
A
T
A
DNA is transcribed
(copied) to RNA
What Happens Normally?
Normal DNA
mRNA
A
T
A
C
G
C
A
T
A
A
T
A
C
G
C
G
C
G
A
T
A
G
C
G
A
T
A
Normal
Protein
amino
acids
Translation:
Proteins are made
from mRNA
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
A
T
Changed mRNA
A
C
G
C
A
T
A
DELETION
Normal
Protein
A
C
G
C
G
C
G
A
T
A
G
C
G
A
T
A
A
T
A
Abnormal/
Mutant
Protein
A Mutant Protein is Made
Changed DNA
A
T
C
G
A
T
C
G
G
C
A
T
G
C
A
T
A
T
Normal
Protein
Abnormal/
Mutant
Protein
How Could a Mutant Protein Make
Cells Divide Out of Control?
?
mutant protein
cancer cells
The Cell Cycle Controls Cell Division
Cells divide
(mitosis)
Cell
Cycle
Growth
DNA
Synthesis
Growth
The Cell Makes Sure That There are no
Problems
Did division
go correctly?
Am I ready
to divide?
Cell
Cycle
Am I big
enough?
Is my DNA
copied
correctly?
The Cell Cycle Has Checkpoints
Did division
go correctly?
Am I ready
to divide?
Cell
Cycle
Is my DNA
copied
correctly?
Am I big
enough?
The Normal Protein Functions at a
Cell Cycle Checkpoint
Cell
Cycle
Is my DNA
copied correctly?
Normal
Protein
The Mutant Protein Allows The Cell
to Divide Out of Control
Cell
Cycle
Normal
Protein
go!
I can’t stop and
check if the DNA
has been copied
correctly!!!
Abnormal/
Mutant
Protein
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
cell
•Mutations in TS genes may inactivate them,
so that they cannot stop cell-growth
•TS genes include p53 and BRCA1/2
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
cell
oncogene
•Mutations in oncogenes may over-activate them,
so that they always promote cell-growth
•One well-known oncogene is called RAS
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
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 then invade
new tissues, and
begin to grow
Cells travel through
the blood stream to
distant sites
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
 SIDE EFFECTS!
normal cells
•
•
•
•
cancer cells
hair follicles: hair loss
bone marrow:  immune defense,
anemia, clotting problems
gut lining: diarrhea
skin:
flaky/scaly skin
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
normal
breast cancer
MCL1 gene
Turn off
MCL1 in
lab
ALIVE
DEAD
Goal: Discover new drugs that attack
most important mutations
Example: MCL1 gene helps cells survive
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500,000 chemicals
robotics
Want to explore this further? Check this out:
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 (20132015), never before
seen!
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 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