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 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 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 ; Italy in Libya in 1930; Soviet Union in Xinjiang, China in 1934 and ; Italy in Abyssinia (now Ethiopia) in ; 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 ; Egypt against North Yemen in ; Iraq against Iran in 1981 and ; Iraq against Kurds in 1988; Possibly Sudan against insurgents in the civil war, in 1995 and 1997 Mustard Nitrogen From 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 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 The Biology of Cancer (© Garland Science 2007) Herceptin is not the only antibody. Rituxan is used for treating lymphomas.

Targeted Drugs Which are the good candidates? Hanahan and Weinberg, Cell 100:57-70 (2000)

c-Abl SH3 FG SH2 kinase Actin- binding FG Bcr 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, , 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 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 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