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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: – – – – Woman Non-Smoker Japenese Adenocarcinoma » Paez et al. 2004 A highly significant effect in sensitive patients So What are the Mutations? • • • • 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.