Enhanced growth of human met-expressing xenografts in a new strain of immunocompromised mice transgenic for human hepatocyte growth factor/scatter factor

Self Cite

108

Because oncogene MET and EGF receptor (EGFR) inhibitors are in clinical development against several types of cancer, including glioblastoma, it is important to identify predictive markers that indicate patient subgroups suitable for such therapies. We investigated in vivo glioblastoma models characterized by hepatocyte growth factor (HGF) autocrine or paracrine activation, or by MET or EGFR amplification, for their susceptibility to MET inhibitors. HGF autocrine expression correlated with high phospho-MET levels in HGF autocrine cell lines, and these lines showed high sensitivity to MET inhibition in vivo. An HGF paracrine environment may enhance glioblastoma growth in vivo but did not indicate sensitivity to MET inhibition. EGFRvIII amplification predicted sensitivity to EGFR inhibition, but in the same tumor, increased copies of MET from gains of chromosome 7 did not result in increased MET activity and did not predict sensitivity to MET inhibitors. Thus, HGF autocrine glioblastoma bears an activated MET signaling pathway that may predict sensitivity to MET inhibitors. Moreover, serum HGF levels may serve as a biomarker for the presence of autocrine tumors and their responsiveness to MET therapeutics.hepatocyte growth factor-autocrine loop | molecular marker | oncogene addiction | targeted therapy T he intrinsic ability of glioblastoma multiforme (GBM) tumor cells to invade normal brain tissue impedes complete surgical eradication and predictably results in early local recurrence and mortality. Understanding the molecular mechanisms of GBM invasiveness will lead to novel therapeutic strategies. The major signaling pathways driving GBM tumorigenesis and invasion are Ras-MAPK and AKT. Hepatocyte growth factor (HGF) binding to its receptor MET triggers this series of intracellular signaling, leading to tumor cell proliferation, invasion, survival, and angiogenesis (1-6). Aberrant MET activation can occur through numerous mechanisms, such as autocrine or paracrine stimulation, transcriptional regulation (7), ligand-independent or mutational activation (1, 8); MET amplification can be a major driver after acquired resistance to EGF receptor (EGFR) inhibitors (9), because of cross-talk with other receptor tyrosine kinase (RTK) family members.Most glioblastomas show MET overexpression, and some display HGF autocrine activation of the MET signaling pathway (10). Approximately 88% of GBM patients have an aberrant RTK/Ras-PI3K pathway activity. MET is located on chromosome 7q, and gains of chromosome 7 occur frequently in GBM. Also, though MET mutations are rare (11, 12), a high level of MET amplification is found in ∼4% of GBM tumors. Amplification of EGFR occurs in 45% of GBM tumors and could be associated with aberrant MET expression (11).HGF can also transcriptionally activate EGFR signaling in GBM cell lines (13), and EGFR variant III (EGFRvIII) can activate MET signaling (14), suggesting the importance of using a combination of MET and EGFR inhibitors in targeting GBM. EGFRvIII and MET inhibitors synergize against...

Section: Discussionmentioning

confidence: 58%

Hepatocyte growth factor (HGF) autocrine activation predicts sensitivity to MET inhibition in glioblastoma

Xie

Bradley

Kang

et al. 2011

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108

“…3F). At doses ≥30 mg/kg, tumor volumes were static or reduced in size ( Because murine HGF does not activate huMET (38,39), onartuzumab was evaluated in paracrine-driven human xenograft models grown in hHGF tg -C3H-SCID mice (40). The NCI-H596 (MET exon14del ) NSCLC cell line harbors a deletion in exon 14 of the MET gene.…”

Section: Resultsmentioning

confidence: 99%

“…356231; BD Biosciences) inoculated s.c. in the rear right flank of nude (nu/nu) mice. The NCI-H596 tumor model was performed as described previously (40,54). Briefly, 2 × 10 6 NCI-H596 tumor cells were inoculated s.c. in the shaved right rear flank or hHGF Tg -C3H-SCID or littermate C3H-SCID mice.…”

Section: Discussionmentioning

confidence: 99%

Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent

Merchant¹,

Ma²,

Maun

et al. 2013

Self Cite

210

221

Binding of hepatocyte growth factor (HGF) to the receptor tyrosine kinase MET is implicated in the malignant process of multiple cancers, making disruption of this interaction a promising therapeutic strategy. However, targeting MET with bivalent antibodies can mimic HGF agonism via receptor dimerization. To address this limitation, we have developed onartuzumab, an Escherichia coliderived, humanized, and affinity-matured monovalent monoclonal antibody against MET, generated using the knob-into-hole technology that enables the antibody to engage the receptor in a one-to-one fashion. Onartuzumab potently inhibits HGF binding and receptor phosphorylation and signaling and has antibody-like pharmacokinetics and antitumor activity. Biochemical data and a crystal structure of a ternary complex of onartuzumab antigen-binding fragment bound to a MET extracellular domain fragment, consisting of the MET Sema domain fused to the adjacent Plexins, Semaphorins, Integrins domain (MET Sema-PSI), and the HGF β-chain demonstrate that onartuzumab acts specifically by blocking HGF α-chain (but not β-chain) binding to MET. These data suggest a likely binding site of the HGF α-chain on MET, which when dimerized leads to MET signaling. Onartuzumab, therefore, represents the founding member of a class of therapeutic monovalent antibodies that overcomes limitations of antibody bivalency for targets impacted by antibody crosslinking.scatter factor | HGFR | MetMAb | OA5D5

“…(iii) Factors important for supporting NCC proliferation and migration may be species-specific, causing the mouse environment to be suboptimal for hNCCs. The use of humanized host embryos that express human growth factors may enhance chimera formation from the human donor cells (25).…”

Section: Discussionmentioning

confidence: 99%

Human neural crest cells contribute to coat pigmentation in interspecies chimeras after in utero injection into mouse embryos

Cohen

Wert

Goldmann

et al. 2016

The neural crest (NC) represents multipotent cells that arise at the interphase between ectoderm and prospective epidermis of the neurulating embryo. The NC has major clinical relevance because it is involved in both inherited and acquired developmental abnormalities. The aim of this study was to establish an experimental platform that would allow for the integration of human NC cells (hNCCs) into the gastrulating mouse embryo. NCCs were derived from pluripotent mouse, rat, and human cells and microinjected into embryonic-day-8.5 embryos. To facilitate integration of the NCCs, we used recipient embryos that carried a c-Kit mutation (W sh /W sh ), which leads to a loss of melanoblasts and thus eliminates competition from the endogenous host cells. The donor NCCs migrated along the dorsolateral migration routes in the recipient embryos. Postnatal mice derived from injected embryos displayed pigmented hair, demonstrating differentiation of the NCCs into functional melanocytes. Although the contribution of human cells to pigmentation in the host was lower than that of mouse or rat donor cells, our results indicate that hNCCs, injected in utero, can integrate into the embryo and form mature functional cells in the animal. This mouse-human chimeric platform allows for a new approach to study NC development and diseases.human neural crest cells | chimera | embryonic stem cells | melanocytes