Therapeutic potential of hepatocyte growth factor/scatter factor neutralizing antibodies: Inhibition of tumor growth in both autocrine and paracrine hepatocyte growth factor/scatter factor:c-Met-driven models of leiomyosarcoma

Abstract

Hepatocyte growth factor/scatter factor

MET Kinase Inhibitor SGX523 Synergizes with Epidermal Growth Factor Receptor Inhibitor Erlotinib in a Hepatocyte Growth Factor–Dependent Fashion to Suppress Carcinoma Growth

“…The hHGF tg -SCID mouse, a genetically engineered strain that produces human HGF/SF (13), overcomes this limitation. The hHGF tg -SCID mice strongly enhance the xenograft growth of MET-expressing tumors such as the SK-LMS-1 leiomyosarcoma model (13), which is a valuable system for evaluating MET drugs such as AMG102 (20).…”

α‐Ketobenzothiazole Serine Protease Inhibitors of Aberrant HGF/c‐MET and MSP/RON Kinase Pathway Signaling in Cancer

“…Preventingb oth the growth factor and kinase activationp redicts ad ramatic improvementi nc linicalo utcome versus either ak inase inhibitor [27] or antibodies to an individual protease, [28] growth factor [29] or the extracellular domain of either receptor. [30] Furthermore, the dual blockade of HGF and MSP production will have effects on both the tumor and its surrounding microenvironment, whichise ssential in the development of invasive tumors and metastasis.…”

“…The resulting precipitate, which is the crude product, was collected by centrifugation, then by decanting out carefully ether solvent. The crude product was purified by HPLC (C 18 ,1 5150 mm column;e luent:a cetonitrile/water (0.05 %T FA)) to give the title compound (0.01 g) in 29 Ac-SKLR-ketobenzothiazole-6-CONH-Trp-amide (23 f):T he title compound was synthesized using the same procedure as 23 g using l-tryptophan amide hydrochloride. Yield:2 4%.…”

Emerging antibody combinations in oncology

“…Originally, complete blockade of HGF-driven cMet activation was identified using multiple mAbs that recognized different epitopes of HGF, 123 although intensive screening has yielded new HGF mAbs with potentially similar inhibitory activity compared with these original mAb combinations. [124][125][126] Met has been more difficult to target due to antibody-mediated agonism induced by bivalent crosslinking, but the ability of two anti-Met mAbs to synergistically inhibit tumor cell growth compared with the activity of the individual mAbs was reported in 2009. 127 Tvorogov and coworkers reported in 2010 that two mAbs directed at VEGFR3, one that blocks ligand blocking and one that blocks receptor dimerization (like the cetuximab/ ch806 mAbs directed against EGFR), can synergistically inhibit VEGF-C-mediated cell survival and vascular sprouting.…”