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Non-Small-Cell Lung Cancer
• Leading cause of cancer-related mortality in the
US
• Current Therapies:
– “Despite great efforts, only minor gains” Traynor
et al. 2004
– Combination of Chemo/Surgery/Radiotherapy:
Platinum Doublets favored, in combo with other chemo
reagent.
• Future Therapies: 166 ongoing clinical trials
– EGFR over expressed in 40 to 80 % of cancers
Peptide Vaccine
• Phase I Study of EGFRvIII Peptide
Vaccine With Sargramostim (GM-CSF)
Versus Keyhole Limpet Hemocyanin as
Adjuvant in Patients With EGFRvIIIExpressing Cancer
Epidermal Growth Factor Receptor VIII Peptide
Vaccination Is Efficacious against Established
Intracerebral Tumors
Heimberger et al. 2003
Vaccine Based Immunotherapy to
L523S
– Phase I: Safety and Immunogenicity of
Recombinant DNA and Adenovirus Expressing
L523S Protein in Early Stage Non-Small Cell
Lung Cancer The purpose of this trial is to
examine the safety and immunogenicity of a
therapeutic vaccine regimen with recombinant
DNA and adenovirus expressing L523S protein in
patients with early stage non-small cell lung
cancer. The vaccine regimen will consist of two
fixed doses of recombinant DNA (pVAX/L523S)
followed by two doses of recombinant adenovirus
(Ad/L523S). The trial will evaluate the dose
escalation of Ad/L523S through three cohorts of
patients.
EGFR Schematic
Sordella et al. 2004
Gefitinib:
• Targeting the proliferative signals in cancer cells -> EGFR
– 1) In-Vitro Proof of Concept
• ZD1839 Synthesized/Screened --1994-2001
– 2) Animal Models
– Mouse Xenografts: Success Not Dependant on Level of
Expression of EGFR ---2002
– 3) Initial Clinical Trials: 2001-2
• Limited Tox
• Response in only 10-19% of chemo-refractory advanced NSCL
cancers
• R Bailey et al. 2003 --> EGFR Expression not an effective
predictor of response to gefitinib
– 4) Molecular explanation???
• Factors that favor Gefitinib sensitivity:
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Woman
Non-Smoker
Japenese
Adenocarcinoma
» Paez et al. 2004
A highly significant
effect in sensitive
patients
So What are the Mutations?
•
•
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•
Extract DNA
Amplify Gene of Interest (28 exons)
PCR
Sequence (Sense + Antisense)
What do these mutations tell us?
• 1) Hypothesis: Improved stability for binding of
ATP and Gefitinib
– Modified ATP binding pocket.
• 2) Hypothesis: Mutation plays a key role in the
development of this cancer.
– Somatic
– Heterozygous ---> Dominance
– Sequenced 95 primary tumors, 108 cancer-derived cell
lines. No EGFR mutants
What does this all mean?
• Marker for the success of gefitinib?
– Is this a good clinical test?
– If there is no toxicity, can you add drug on top of
standard therapy despite low probability of success?
• Why the insensitivity with W.T. gefitinib?
– 1) Kinetics: Bioavailability poor, (KD too high)
• Find a better way to knock out Kinase
– 2) The Mutant Kinase is more important to the cancer,
than the wild type.
• Overexpression does not mean functionality is key. In-vitro
models have to be interpreted carefully.
Science, August 20th 2004.