Targeted Therapy in Cancer

Xanit Hospital InternacionalAvenida de los Argonautas s/n, 29630, Benalmádena, Málaga. Tlf: 952 367 190 - Fax: 952 367 191 - www.xanit.net

Xanit Oncology InstituteXanit Oncology InstituteTargeted Therapy in CancerTargeted Therapy in Cancer

Dr Rafael Trujillo Vilchez

Area de Oncología

Hospital Xanit Internacional

Chemotherapy vs Targeted Therapy

• Chemotherapy:– Drugs that effect cells that are doubling– Not very specific– Mostly intravenous, some oral agents– Cytotoxic

• Targeted therapy:– Drugs that inhibit a more specific target in cells– Many are oral agents– Mixture of cytostatic and cytotoxic

Chemotherapy vs Targeted Therapy

• If we use the analogy of pesticides: empiric therapy would be “Raid” while targeted therapy is the “Roach Hotel.”

Dr. David Gandara

• A “smart” bomb versus a “cluster” bomb.Dr. Nevin Murray

What is Targeted Therapy?

Structural variants•Translocations•Fusions•Inversion

Copy number alterations•Amplifications•Deletions•LOH

Point mutations & indels•Missense•Nonsense•Splice site•Frameshift

Gene expression•Outlier expression•Isoform usage•Pathways & signatures

Wild type AGTGAMutant AGAGA

Adapted from: Roychowdhury et al. Sci Transl Med; 20122

The Origins of CML

Gleevec

BRAF Mutation in Melanoma

Traditional View of Lung Cancer

AdenocaSmallCellLarge Cell

Squamous

EGFR Gene Mutations in Adenocarcinoma Lung Cancer

N=170

n = 345

Therascreen ®EGFR (29) RGQ PCR Kit

Presentation• EGFR mutations

– RADIANT adjuvant results in EGFR mutations– Uncommon EGFR mutations– Resistance in EGFR mutations (+) patients

• ALK gene rearrangements– Resistance in ALK gene rearrangement (+) patients

• BRAF mutations• Other mutations, fusions and amplifications

Locations and Types of the 134 EGFR Gene Mutations Detected in Lung Cancers

Shigematsu H et al. JNCI J Natl Cancer Inst 2005;97:339-346Journal of the National Cancer Institute, Vol. 97, No. 5, © Oxford University Press 2005, all rights reserved.

L858R

Del 19

T790M

EML4-ALK Mutation in Lung Cancer

• Present in 3-5% of non-small cell lung cancer, usually adenocarcinoma

• Mutation leads to formation of a fusion gene that codes for an abnormal tyrosine kinase receptor

~250 kb ~300 kb

t(2;5) ALK genebreakpoint region

2p23 regionTelomere Centromere

3’ 5’

FISH Assay for ALK Rearrangement*

Break-apart FISH assay for ALK-fusion genes1

ALK 29.3

EML4 42.3

ALK break-apart FISH assay[Courtesy John Iafrate, Massachusetts General Hospital]

1Shaw AT et al. J Clin Oncol 2009;27:4247–4253

q36.1q36.3q37.2

q34

q32.1

q32.3

q33.2

q31.3

q24.3

q24.1q23.2q22.2q22.1q21.2q14.3

q14.1

q12.3q12.1

p12

p13.2p14p16.1p16.3

p22.1

p23.2p22.3

p24.1p24.3

p25.2

q36.1q36.3q37.2

q34

q32.1

q32.3

q33.2

q31.3

q24.3

q24.1q23.2q22.2q22.1q21.2q14.3

q14.1

q12.3q12.1

p12

p13.2p14p16.1p16.3

p22.1

p23.2p22.3

p24.1p24.3

p25.2

Split signalNon-split signal

*Assay is positive if rearrangements can be detected in ≥15% of cellsFISH = fluorescence in situ hybridization

Response to crizotinib in patients with EML-ALK NSCLCA

Drugs in the Pipeline for ALK

Her-2/neu• About 25% of breast cancer cases are associated

with a amplification of the genes coding for a cell surface receptor called Her-2/neu

• These cells may a 1000 fold increase in the number of these receptors over normal breast cells

• Associated with rapid growth

Herceptin

There Are Multiple Agents Already Available

Non-Hodgkin Lymphoma

Antibody-Drug Conjugates

A New Agent in Hodgkin's Disease

Stimulating an Immune Response

New Agent in Melanoma Therapy

Pushing Immune Cells to Recognize Cancer Cells

Provenge in Prostate Cancer

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