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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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