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Met Inhibitors and Solid Malignancies

I have no financial disclosures. . Introduction . What is Met?How does Met function as an OncogeneStatus of Clinical TrialsHow does Met expression help subclasify breast cancerThe interplay of Met and EGFR in breast and lung cancer. What is Met. Met is an a heterodimer receptor TKExtracellula

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Met Inhibitors and Solid Malignancies

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    1. Met Inhibitors and Solid Malignancies Ryan Roop M.D. 3/25/2011

    2. I have no financial disclosures

    3. Introduction What is Met? How does Met function as an Oncogene Status of Clinical Trials How does Met expression help subclasify breast cancer The interplay of Met and EGFR in breast and lung cancer

    4. What is Met Met is an aß heterodimer receptor TK Extracellular a subunit Trans-membrane ß subunit (several key tyrosine residues) Phosphorylated ß subunit acts as docking site for key adaptors Activates downstream pathways (e.g. MAPK, PI3 kinase) Met ligand is hepatocyte growth factor (HGF) aka scatter factor

    7. Physiologic Function of Met Embryonic Life Expressed by epithelial cells and myoblast progenitors HGF secreted by mesenchymal cells HGF essential for placenta and liver development Adult life May have a role in tissue repair HGF increased expression after organ damage

    8. Initial Discovery First isolated from human osteosarcoma cell line TPR locus fused with MET sequence Chromosome 7 Similar gene rearrangement found in gastric CA Full length MET proto-oncogene later sequenced TPR (promotor on chromosome 1)TPR (promotor on chromosome 1)

    9. Oncogenic Met Pathway Normal regulation via: Paracrine ligand delivery Ligand activation at the cell surface Receptor internalization and degradation Pathway dysregulation Increased transcription Constituitive kinase activation Point mutations or gene amplification Aberrant ligand production

    10. Oncogenic Met Pathway Met pathway is dysregulated in multiple cancer subtypes (solid and hematological) Dysregulation promotes: Survival Invasion Angiogenesis metastasis

    13. European Journal of Cancer ReviewEuropean Journal of Cancer Review

    14. Clinical Trials Thus Far

    15. ARQ 197 51 patients with solid tumors for which no known effective treatment available Given ARQ 197 single agent (TKI) DCE-MRI at baseline and every 56 days 14 patients had RECIST stable disease (4 months) CTC’s measured on 35 patients 15 pts had = 3 CTC 8/15 (53%) experienced = 30% decline

    16. Ongoing Investigation Many other trials ongoing Will have to await results Met inhibition may be important as a combination therapy Met useful in other ways Prognostication Defining tumor subtypes

    17. Breast Cancer In normal mammary tissue HGF is expressed by stromal cells HGF can be produced de novo by breast carcinoma cells HGF content in breast tissue correlates with aggressive phenotype Associated with with decreased survival in axillary lymph node negative patients

    18. 115 archival node negative breast cancers. Tumors were stained for met staining.115 archival node negative breast cancers. Tumors were stained for met staining.

    20. Met and Basal Breast CA Molecular profiling of breast cancer has been utilized to define 5 subtypes Two main clusters: luminal and basal group Basal-like has worse prognosis Typically triple negative cancer More aggressive phenotype

    22. Met and Basal Breast Cancer Met is one of the most differentially regulated genes between basal and luminal subtypes Confirmed using tissue from 930 pts High Met staining associated with highly invasive malignancies Associated with known basal markers EGFR and c-Kit are also differentially regulated between subtypes Met defined in context of basal subtype later by Charafe, oncogene 2006 Garcia, Human Pathol 2007 (930 pt study confirmatory)Met defined in context of basal subtype later by Charafe, oncogene 2006 Garcia, Human Pathol 2007 (930 pt study confirmatory)

    23. EGFR inhibitor Resistance A few small clinical trials have looked at EGFR inhibition in breast CA Results have been less promising than other tumor subtypes (e.g. colon/lung) Possibly due to concomitantly active tyrosine kinase receptor pathways Intimate relationship between EGFR and Met signaling Previous trials: Carboplatin + cituximab or cituximab alone Irinotecan + carboplatin +/- cituximabPrevious trials: Carboplatin + cituximab or cituximab alone Irinotecan + carboplatin +/- cituximab

    25. Met and C-src cooperate for EGFR resistnace paperMet and C-src cooperate for EGFR resistnace paper

    26. SUM 149 is EGFR sensitiveSUM 149 is EGFR sensitive

    27. EGFR inhibitor Resistance ? Potential therapeutic benefit to combining met/EGFR inhibition? No combination trials in humans yet Better studied in lung cancer Ongoing clinical trials in lung cancer ? Clinical trials needed in breast CA

    28. NSCLC and EGFR NSCLC sensitive to EGFR inhibitor in patients with: Driver mutation Increased gene copy number Mechanisms of resistance Second mutation (del L747–S752 + T790) KRAS mutation 30% adenoCA and usually not in EGFR mutant tumors Met another culprit

    29. Met and EGFR in NSCLC EGFR inhibitor resistant cell lines ErbB3 was over-expressed ShRNA inhibition of Met decreased ErbB3 phosphorylation Paper published in SciencePaper published in Science

    30. Science paper 2007Science paper 2007

    31. Science paper 2007Science paper 2007

    32. Patient Samples NSCLC samples from EGFR inhibitor resistant patients 4/18 (22%) had over-expression of Met 1/4 (25%) had concomitant T790 mutation Pre-treatment amplification not noted Paired specimens (pre/post tx) for 8 patients Only post tx was amplified Science paper 2007Science paper 2007

    33. Science paper 2007Science paper 2007

    34. Met and Primary Resistance One study looked at primary EGFR resistance and Met amplification Two cohorts of patients (Oncobell n=24 and Humantis n=182) Humantis not likely EGFR mutation, Oncobell patients likely to have mutation No patients with amplification in Oncobell Humantis cohort had 7.2% with amplified Met No difference in outcome for Met amplified + trend though in EGFR mutated or FISH + Annals of oncology Annals of oncology

    36. Response Rate to EGFR Inhibitor Based on High or low Met Copy Number Mutated or FISH positive only Oncobell

    37. Met Activation and Primary EGFR Resistance 23 patients with diagnosis of adenoCA Tissue collected prior to treatment with anti-EGFR Looked at Met expression, phosphorylation, and gene copy gain Met expression and phosphorylation associated with poor response Met copy gain/amplification was not associated with poor response The american journal of pathologyThe american journal of pathology

    39. Used immunoblotting to detect protein expressionUsed immunoblotting to detect protein expression

    40. What Can We Conclude? Met amplification/copy gain Tied to secondary EGFR TKI resistance Not as important in primary resistance Met activation/expression Associated with primary EGFR TKI resistance At least 4 ongoing trials combining met and EGFR inhibitors

    41. Summary Met pathway is a potential therapeutic target in many cancers Met may have prognostic value in many cancers Met expression is associated with the basal-like subtype in breast cancer Met expression, amplification, and activation is correlated with EGFR TKI resistance

    42. THaNK YOU

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