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Exelixis, Inc. Message Board

  • snodgruss snodgruss Apr 4, 2012 10:09 AM Flag

    Worth reading.

    It doesn't get any better:

    Cabozantinib is a multikinase inhibitor that targets
    VEGFR2 and MET; however, it also inhibits RET, KIT, AXL,
    ephrins, and others. In a phase II randomized discontinuation
    trial, 103 patients who completed the 12-week lead-in period for
    evaluation had bone metastatic CRPC.4 Only 3 patients (3%)
    had new lesions on bone scan, 23 (21%) were stable, 61 (56%)
    had partial resolution, and 21 (19%) had complete resolution of
    all lesions. The dramatic effects on bone scans correlated with
    improvement in bone pain and bone turnover markers (i.e.,
    alkaline phosphatase and C-telopeptide) but not prostate- specific
    antigen (PSA). Of 151 evaluable patients by response
    evaluation criteria in solid tumors (RECIST), 79% had stable
    disease at week 12, while 4% had a confirmed partial response;
    however, 74% showed some evidence of tumor regression in
    soft tissue. As a result of fatigue, anorexia, weight loss, and
    gastrointestinal (GI) side effects, efforts are underway to discover
    efficacious yet more tolerable doses of cabozantinib.
    Lower doses are likely to be brought into upcoming phase III
    trials evaluating pain palliation and OS.
    There is strong preclinical rationale that supports MET as a
    major target of cabozantinib. MET expression is negatively
    regulated by the androgen receptor (AR), and androgen deprivation
    (AD) increases MET expression in tumor cells.5 AD also
    increases tumor and stromal expression of hepatocyte growth
    factor (HGF), the ligand for MET.METis also more frequently
    expressed in bone metastases and poorly differentiated prostate
    cancers.6 MET and HGF may contribute directly to cellular
    proliferation, invasion, metastasis, and androgenindependent
    growth.7 Higher levels of plasma HGF are
    associated with shorter survival in men with CRPC.8 MET is
    also expressed on osteoblasts and osteoclasts, although the
    exact role is currently unknown.9 VEGF binding to
    neuropilin-1 may result in HGF-independent activation of
    MET and may tie angiogenesis and MET pathways together.10

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