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Non-Small-Cell Lung Cancer

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.

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Non-Small-Cell Lung Cancer

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  1. 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

  2. Peptide Vaccine • Phase I Study of EGFRvIII Peptide Vaccine With Sargramostim (GM-CSF) Versus Keyhole Limpet Hemocyanin as Adjuvant in Patients With EGFRvIII-Expressing Cancer Epidermal Growth Factor Receptor VIII Peptide Vaccination Is Efficacious against Established Intracerebral Tumors Heimberger et al. 2003

  3. 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.

  4. EGFR Schematic Sordella et al. 2004

  5. 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???

  6. Factors that favor Gefitinib sensitivity: • Woman • Non-Smoker • Japenese • Adenocarcinoma • Paez et al. 2004

  7. A highly significant effect in sensitive patients

  8. So What are the Mutations? • Extract DNA • Amplify Gene of Interest (28 exons) • PCR • Sequence (Sense + Antisense)

  9. 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

  10. 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.

  11. Science, August 20th 2004.

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