The Novel Anti-cMet Antibody seeMet 12 Potentiates Sorafenib Therapy and Radiotherapy in a Colorectal Cancer Model

Abstract

Rational: cMet is abnormally regulated in gastrointestinal cancer, and is associated with increased invasiveness of the disease and poor overall survival. There are indications that targeted therapy against cMet, alone or in combination with additional cancer therapies, can help improve treatment outcome. Thus, in the present study we investigated the therapeutic efficacy of a novel cMet-targeting antibody therapy in gastrointestinal cancer models, and assessed potential augmenting effects in combination with tyrosine kinase inhibitor (TKI) targeted therapy or radiotherapy. Methods: Three different cMet-targeting antibodies were first characterized with respect to antigen binding and effects on cell viability in vitro. The best performing candidate seeMet 12 was then further assessed for effects on colorectal cancer cell growth, proliferation and migration. Combinations with the TKI-inhibitor sorafenib or external beam radiotherapy were then evaluated for potential additive or synergistic effects in vitro using monolayer-and multicellular tumor spheroid assays. Finally, the combination of seeMet 12 and radiotherapy was evaluated in vivo in a proof-of-concept colorectal cancer xenograft study. Results: Dose-dependent therapeutic effects were demonstrated for all three cMettargeting antibodies. Monotherapy using seeMet 12 resulted in impaired cellular migration/proliferation and reduced tumor spheroid growth. Moreover, seeMet 12 was able to potentiate therapeutic effects in vitro for both sorafenib and radiotherapy treatments. Finally, the in vivo therapy study demonstrated promising results, where a combination of seeMet 12 and fractionated radiotherapy increased median survival by 79% compared to radiotherapy alone, and tripled maximum survival. Conclusion: The novel anti-cMet antibody seeMet 12 demonstrated therapeutic effects in cMet positive gastrointestinal cancer cells in vitro. Moreover, the addition of seeMet

Novel radiation and targeted therapy combinations for improving rectal cancer outcomes

“…Data from clonogenic assays from this study showed that HT29 cells treated with a combination of 2 Gy and seeMet 12 compound (c-MET inhibitor) had significantly reduced colony formation than 2 Gy monotherapy ( P < 0.001) (Ref. 53). This was potentiated when the radiation dose was escalated to 4 Gy ( P < 0.001) (Ref.…”

“…Similarly, novel antibodies targeting c-MET acted synergistically with RT in CRC cell lines and in murine xenograft models (Ref. 53). Data from clonogenic assays from this study showed that HT29 cells treated with a combination of 2 Gy and seeMet 12 compound (c-MET inhibitor) had significantly reduced colony formation than 2 Gy monotherapy ( P < 0.001) (Ref.…”

“…This was potentiated when the radiation dose was escalated to 4 Gy ( P < 0.001) (Ref. 53). These data are corroborated by findings from a study which found c-MET inhibitor crizotinib radio-sensitised a panel of KRAS mutant CRC cell lines (Ref.…”

PrPC Regulates the Cancer Stem Cell Properties via Interaction With c-Met in Colorectal Cancer Cells

“…Also, abnormal expression of c-Met has been reported in a variety of cancers, such as CRC, non-small lung cancer, gastric cancer, and breast cancer (7)(8)(9)(10). In addition, c-Met over-expression is related to the proliferation, invasion, and angiogenesis of tumors (11,12). Crizotinib is a small molecule targeting inhibitor of diverse receptor tyrosine kinases (RTKs), such as c-Met, anaplastic lymphoma kinase (ALK), and ROS1 receptor (13).…”