Relating Activating K-Ras Mutations to Small Molecule Sensitivity in Non-Small-Cell Lung Cancer - PowerPoint PPT Presentation

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Title: Relating Activating K-Ras Mutations to Small Molecule Sensitivity in Non-Small-Cell Lung Cancer


1
Relating Activating K-Ras Mutations to Small
Molecule Sensitivity in Non-Small-Cell Lung
Cancer
  • Flavian D. Brown
  • Carleton College
  • Class of 2009

2
Lung Cancer
  • Leading cause of death from cancer in the world
  • Over 90 of NSCLC contain mutations in EGFR,
    BRAF and K-Ras
  • Discovery of Gefitnib

3
Ras Signaling
Oncogenic Mutation
?
?
Oncogenic Mutation
?
Schubbert et al. (2007) Hyperactive Ras in
developmental disorders and cancer. Nature Review
of Cancer, Vol. 7 295-307.
4
Hypothesis
  • NSCLC tumors are genetically sensitized due to
    changes in cellular state secondary to activating
    K-Ras mutations.
  • - Different drug targets
  • - Oncogene Addiction

5
Small Molecule Screens

6
Hits From Primary Screen
A549 Hits Highlighted Color coding on the
images Red unbiased commercial compound Forma
setGreen bioactives (including kinase
inhibiting drugs)Magenta HDAC biased DOSBlue
commercial kinase biased (CBkinase)Yellow
analyticon purified natural productsBlack DMSO
control plateGray con dose plate
7
Assay Development
8
Small Molecule Sensitivity
9
Small Molecule Sensitivity
10
Small Molecule Sensitivity
11
Structural Activity Relationship
Aromatic group at the opposite end of structures
Carbon spacer can be rigid or flexible
Hydroxamic acids attached to a 4 or 5 carbon chain
12
Future Investigations
  • Analyze signaling downstream of the activating
    mutation
  • -Immunofluorescence
  • -Western Blotting
  • Target Identification
  • - Pull down assay
  • Correlate phenotypic data with genetic data
  • - SNP copy number

13
Impact
  • Genotype specific inhibitors for K-Ras mutants
  • Paradigm for investigating genotype-phenotype
    relationships in other malignancies
  • - WGAS for somatic alterations
  • Molecularly targeted cancer therapeutics.

14
Acknowledgements
  • Principle Investigator
  • Stuart L.Schreiber, Ph.D
  • Mentor
  • Gopal S. Ramachandran, Ph.D
  • Summer Research Program in Genomics
  • Shawna Young
  • Lucia Vielma
  • Maura L. Silverstein
  • Bruce Birren, Ph.D
  • Collaborators
  • - Jordi Barretina, Ph.D
  • - Damian W. Young, Ph.D
  • Broad Institute Screening
  • Nicola Tolliday, Ph.D
  • Josh Bittker, Ph.D
  • Melanie de Silva
  • Kate Hartland

15
References
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    gefitinib. The New England Journal of Medicine.
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  8. Paez, et al. EGFR Mutations in Lung Cancer
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    Renewing the conspiracy theory debate does Raf
    function alone to mediate Ras oncogenesis? Trends
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  10. Schubbert et al. Hyperactive Ras in developmental
    disorders and cancer. Nature, Vol. 7 295-307.
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  11. Swanson et al. Raymond, J. Hohl. Anti-Cancer
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