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Bishop and Varmus
We Are Making Quite a Progress in Cancer Detection
And we need to remember detection when it comes
to “survival rates”.
Cancer Therapy
Traditional Therapy
chemotherapy; radiation
Targeted Therapy
passive immunization; biology-targeted drugs
Personalized Therapy
Traditional Therapy
The logic: kill proliferating cells
All proliferating cells will react, but cancer cells
will have a reduced capacity to repair the
damage induced by chemotherapy agents.
Mustard Nitrogen
From warfare to therapy
Mustard Nitrogen
From warfare to therapy
-cytotoxic effects by binding covalently to DNA
-sulfur mustard gas; war fare agent: topical burns, lungs, mucosa and aplasia of
BM, lymphoid tissue, GI ulcerations
United Kingdom against the Red Army in 1919;
Spain against Rif insurgents in Morocco in 1921-1927;
Italy in Libya in 1930;
Soviet Union in Xinjiang, China in 1934 and 1936-1937;
Italy in Abyssinia (now Ethiopia) in 1935-1940;
Poland against Germany in 1939 during an isolated incident, British product;
Germany against Poland and the Soviet Union in a few erroneous uses during WWII;
Japan against China in 1937-1945;
Egypt against North Yemen in 1963-1967;
Iraq against Iran in 1981 and 1983-1988;
Iraq against Kurds in 1988;
Possibly Sudan against insurgents in the civil war, in 1995 and 1997
chemotherapy
alkylating agents: crosslink DNA (e.g. cisplatin)
anti-metabolites: inhibit nucleotides synthesis (e.g. MTX)
alkaloids: inhibit microtubules (e.g. Taxol)
And other chemicals that affect DNA replication,
transcription, anything that would arrest proliferation.
Example:
Methotrexate
(MTX)
The first designed drug
1948
Methotrexate (MTX) was the first
designed drug.
Acts as a Folate antagonist.
Sydney Farber
We treat cells with MTX, in combination with leucovorin,
to achieve a leucovorin rescue
Leucovorin (folinic acid)
but... cancer cells have a response
Drug Resistance
Chemotherapy works, but is not very efficient.
Knowing what we know today about cancer biology, how can
we improve cancer therapy (more efficient, less harmful)?
Targeted Therapy
How can we kill cancer cells without affecting normal cells?
Targeted Therapy
passive immunization
drugs against specific proteins
other biological-active targets (e.g. angiogenesis)
example #1:
Herceptin
EGFRs
HER2 is an orphan receptor
Valberga, Anals. Oncogene 07
Lodish 05
Gene Amplification: the main
mechanism of HER2 oncogenesis.
Figure 20-34a Molecular Biology of the Cell (© Garland Science 2008)
Figure 20-34b Molecular Biology of the Cell (© Garland Science 2008)
HER2 is Amplified in 30% of Breast Cancer Cases
HER2 normal
HER2 amplified
Kim et al, JKMS 08
Herceptin: a monoclonal antibody that targets HER2
(Trastuzumab)
Figure 15.1b The Biology of Cancer (© Garland Science 2007)
Figure 15.37c The Biology of Cancer (© Garland Science 2007)
Herceptin can inhibit HER2 by several mechanisms
Herceptin is not the only antibody.
Rituxan is used for treating lymphomas.
Figure 15.40 The Biology of Cancer (© Garland Science 2007)
Targeted Drugs
Which are the good candidates?
Hanahan and Weinberg, Cell 100:57-70 (2000)
example #1: Gleevec and Bcr-Abl
How does Bcr-Abl cause cancer?
c-Abl
myristate
Actinbinding
SH2
SH3
F
G
F
G
kinase
Bcr-Abl
Bcr
Gleevec blocks the ATP binding site of the kinase domain
STI571
example #2: Iressa, Tarceva and the EGFR
low-molecular weight (easy
to penetrate big tumors)
can act on receptors w/o
extra-cellular domains
much cheaper than
antibodies
Four second generation EGFR inhibitors
are now entering clinical trials
EKB-569, HKI-272, CI-1033, and ZD6474
•
Covalently bind EGFR
•
Target multiple kinases including HER2 and VEGFR
The Oncologist, Vol. 12, No. 3, 325-330, March 2007
The key property of a drug: be effective but not harmful
(aka Therapeutic Index= efficacy Vs. toxicity).
Testing a new drug and finding the Therapeutic Index
in vitro studies
in vivo studies
clinical trials
Phase I
Testing safety and adverse effects that occur as dosage levels are increased;
contains selected patients that respond badly to the standard treatment and are
in an advanced state of the disease; takes several months; 70% of experimental
drugs pass this initial phase of testing.
Phase II
Testing efficacy and safety; several hundred patients; several months to two
years; 30% of experimental drugs pass Phases I and II.
Phase III
Testing effectiveness, benefits, and the range of possible adverse reactions;
several thousands patients; 70%-90% success for drugs that entered this phase.
The Post-Genomic Era
Personalized Therapy
Microarrays can be used as a
personal genetic signature.
We are making progress!!
The big questions in the future might not be the
technological ones but the social ones
The Viral Transforming Functions Reside in a Single Viral
Gene: src
Let’s label the src gene and follow its dynamics inside the host
cell, after infection.
A Cellular src Exists, Even Before Infection
Bishop and Varmus
Nobel prize in
physiology and
medicine 1989
The Transforming Oncogene is Ras
human RAS
mouse RAS
Der et al. PNAS 82
Channing Der, UNC
We turned to model organisms to understand
the cellular and molecular machinery of cancer
The RTK Pathway
Rb, tumor suppressor genetein
regulates the cell cycle
Retinoblastoma is Associated with
Loss of Heterozygosity (LOH) at the RB Locus
~40% of the time the
Wild type allele is mutated
4% of these are deletions
R. Weinberg, Cancer Biology
Cancer develops through gradual changes
in cell morphology and properties.
benign tumor
malignant tumor
Cells Move During Development
David Shook
Bob Goldstein
Ray Keller
Turner, Giacoletti and Kaufman
Dave McClay
cancer cells metastasize after
undergoing EMT induced by
stromal cells
major changes: cell adhesion,
cell shape changes, and
secretion of MMPs
Figure 14.19c The Biology of Cancer (© Garland Science 2007)