bishop and varmus. we are making quite a progress in cancer detection
TRANSCRIPT
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 Therapychemotherapy; radiation
Targeted Therapy
Personalized Therapy
passive immunization; biology-targeted drugs
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.
Traditional Therapy
Mustard NitrogenFrom 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
Mustard NitrogenFrom warfare to therapy
alkylating agents: crosslink DNA (e.g. cisplatin)
alkaloids: inhibit microtubules (e.g. Taxol)
anti-metabolites: inhibit nucleotides synthesis (e.g. MTX)
And other chemicals that affect DNA replication, transcription, anything that would arrest proliferation.
chemotherapy
Example: Methotrexate
(MTX)
The first designed drug
Methotrexate (MTX) was the first designed drug.
Acts as a Folate antagonist.
1948
Sydney Farber
Leucovorin (folinic acid)
We treat cells with MTX, in combination with leucovorin, to achieve a leucovorin rescue
but... cancer cells have a response
Drug Resistance
Targeted Therapy
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)?
How can we kill cancer cells without affecting normal cells?
passive immunization drugs against specific proteins
other biological-active targets (e.g. angiogenesis)
Targeted Therapy
EGFRs
example #1: Herceptin
Valberga, Anals. Oncogene 07 Lodish 05
HER2 is an orphan receptor
Figure 20-34a Molecular Biology of the Cell (© Garland Science 2008)
Gene Amplification: the main mechanism of HER2 oncogenesis.
Figure 20-34b Molecular Biology of the Cell (© Garland Science 2008)
Kim et al, JKMS 08
HER2 amplified
HER2 normal
HER2 is Amplified in 30% of Breast Cancer Cases
Figure 15.1b The Biology of Cancer (© Garland Science 2007)
Herceptin: a monoclonal antibody that targets HER2(Trastuzumab)
Figure 15.37c The Biology of Cancer (© Garland Science 2007)
Herceptin can inhibit HER2 by several mechanisms
Figure 15.40 The Biology of Cancer (© Garland Science 2007)
Herceptin is not the only antibody. Rituxan is used for treating lymphomas.
Targeted DrugsWhich are the good candidates?
Hanahan and Weinberg, Cell 100:57-70 (2000)
c-Abl
SH3F G
SH2
kinase
Actin-binding
F GBcr
Bcr-Abl
myristate
How does Bcr-Abl cause cancer?
example #1: Gleevec and Bcr-Abl
STI571
Gleevec blocks the ATP binding site of the kinase domain
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
The Oncologist, Vol. 12, No. 3, 325-330, March 2007
• Covalently bind EGFR
• Target multiple kinases including HER2 and VEGFR
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 vivo studies
Phase III
Phase II
Phase I
in vitro studies
clinical trials
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.
Testing efficacy and safety; several hundred patients; several months to two years; 30% of experimental drugs pass Phases I and II.
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
Bishop and Varmus
Let’s label the src gene and follow its dynamics inside the host cell, after infection.
Nobel prize in physiology and medicine 1989
A Cellular src Exists, Even Before Infection
Der et al. PNAS 82
The Transforming Oncogene is Ras
Channing Der, UNC
mouse RAS
human RAS
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 theWild type allele is mutated4% of these are deletions
R. Weinberg, Cancer Biology
Cancer develops through gradual changesin cell morphology and properties.
benign tumor
malignant tumor
Cells Move During Development
David Shook
Turner, Giacoletti and Kaufman
Bob Goldstein
Ray Keller
Dave McClay
Figure 14.19c The Biology of Cancer (© Garland Science 2007)
cancer cells metastasize after undergoing EMT induced by
stromal cells
major changes: cell adhesion, cell shape changes, and
secretion of MMPs