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