1 / 13

ROUND TABLE ON PRECLINICAL THERAPETUICS

ROUND TABLE ON PRECLINICAL THERAPETUICS. PANEL : Jon Kurie (M.D. Anderson) Eric Holland (MSKCC) Pier Paolo Pandolfi (MSKCC) Charles Sawyers (UCLA) Kevin Shannon (UCSF). ROUNDTABLE FORMAT. (1) Introduction (Shannon)

fawzi
Download Presentation

ROUND TABLE ON PRECLINICAL THERAPETUICS

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. ROUND TABLE ON PRECLINICAL THERAPETUICS PANEL: Jon Kurie (M.D. Anderson) Eric Holland (MSKCC) Pier Paolo Pandolfi (MSKCC) Charles Sawyers (UCLA) Kevin Shannon (UCSF)

  2. ROUNDTABLE FORMAT (1) Introduction (Shannon) (2) Summary of Discussions Related to Model Validation at Preclinical Therapeutics Meeting (Holland/Richon) (3) Overview of Models and Criteria for Preclinical Validation (Shannon, Kurie, Sawyers, Pandolfi) (4) Group Discussion

  3. MOUSE NF1 LEUKEMIA MODEL • NF1 encodes a GTPase activating protein for Ras • Children with NF1 and heterozygous Nf1 mutant mice are predisposed to myeloproliferative disorders (MPD) and leukemias • Murine and human leukemias show loss of normal Nf1/NF1 allele, and hyperactive Ras signaling • Although homozygous Nf1 mutant mice die in utero from cardiac defects, Nf1-deficient fetal hematopoietic cells consistently induce MPD in irradiated hosts

  4. FEATURES OF Nf1 MURINE LEUKEMIA MODEL • human and myeloid disorders similar at genetic, biochemical, and cell biologic levels • molecular pathogenesis well-characterized • recipient mice are immunocompetent • predictable subacute couse in recipients • assays exist to measure biochemical effects of therapeutics on Ras signaling

  5. Processing Ras GDP Growth Factor Ras GDP P i GTP Neurofibromin p120 GAP SOS, GRF, GRP GDP Ras GTP NF1 or RAS Mutation ? Raf PI3’-Kinase Ral GDS MEK ? Cell Survival ERK

  6. PRECLINICAL/CLINICAL TRAILS OF TARGETED THERAPEUTICS Mouse: Farnesyltransferase inhibitor (Merck) MEK1 inhibitor (Pfizer) PI3 kinase inhibitor (Clapp lab with Lilly) anti-GM-CSF conjugate (with J. Perentesis UMN) Human: Recombinant erythorpoietin (Ortho/Amgen) CMA-676 (anti-CD33 conjugate) (Wyeth)

  7. MODEL VALIDATION

  8. Kras LUNG CANCER MODEL (Jacks) • Latent mutant G12D allele of Kras activated somatically by homologous recombination • Mice consistently develop multiple foci of lung adenocarcinoma by age 2-3 weeks, and die by age 8-10 months from pulmonary insufficiency • Downstream effectors of Ras•GTP activated in lung lesions (e.g. ERK, P13K/Akt, MKK4) • Thymic lumphomas also seen, but not colon or pancreatic cancers

  9. PRECLINICAL TRIALS IN Kras MICE • Aerosolized administration of chemotherapeutic and preventive agents by jut nebulizer (e.g. liposimal retinoic acid, recombinant adenoviral vectors, small molecules such MEK and PI3 kinase inhibitors) • Systemic administration of Cox-2 inhibitor

  10. HUMAN CLINICAL TRIALS Lung Cancer Chemoprevention Trials (1) retinoids in current and former smokers (2) EGFR inhibitor (SUGEN) (3) farnesyltransferase inhibitor (Schering)

  11. PRECLINICAL VALIDATION • creation of Cre/lox Kras allele will facilitate performing prevention trials (no paradigm for human lung cancer) • hope to model human metastatic phenotype by generating Kras/p53 double mutants (Dr. Gigi Lazano) • test agents known to be efficacious in human lung cancer (taxol, CDDP, navelbine) to validate mouse model

  12. DISUCUSSION QUESTION How do you validate a mouse cancer model from the standpoint of preclinical therapeutics? What are the elements of a “validated” model?

  13. DISUCUSSION QUESTION How have you been able to develop collaborations with pharmaceutical companies to test compounds in mice? What elements of a mouse model or preclinical project appeal to pharmaceutical companies and what are companies skeptical about?

More Related