ARQ 197

Definition from NCI Drug Dictionary: c-Met inhibitor ARQ 197 An orally bioavailable small molecule inhibitor of c-Met with potential antineoplastic activity. c-Met inhibitor ARQ 197 binds to the c-Met protein and disrupts c-Met signal transduction pathways, which may induce cell death in tumor cells overexpressing c-Met protein or expressing consitutively activated c-Met protein. c-Met protein, the product of the proto-oncogene c-Met, is a receptor tyrosine kinase also known as hepatocyte growth factor receptor (HGFR); this protein is overexpressed or mutated in many tumor cell types and plays key roles in tumor cell proliferation, survival, invasion, and metastasis, and tumor angiogenesis.

Manufacturer: Arqule (in collaboration with Daiichi Sankyo)

relevant information at Arqule website: http://www.arqule.com/res/onc/

According to a news story, "ARQ 197 is a selective inhibitor of c-Met, a receptor tyrosine kinase. When abnormally activated, c-Met plays multiple roles in aspects of human cancer, including cancer cell growth, survival, angiogenesis, invasion and metastasis. Pre-clinical data have demonstrated that ARQ 197 inhibits c-Met activation in a range of human tumor cell lines and shows anti-tumor activity against several human tumor xenografts. In clinical studies to date, treatment with ARQ 197 has been well tolerated and has resulted in tumor responses and prolonged stable disease across broad ranges of tumors and doses."

Quote from Arqule website about posters presented at AACR in April 2009:

1. Combination studies of tyrosine kinase inhibitors (TKIs): Assessment of potential cytotoxic synergy of ARQ 197 with sorafenib or sunitinib (Abstract Number 820, Poster Section 35, Poster Board Number 6, Hall B-F, April 19, 2009, 8:00 AM — 12:00 PM)

ArQule researchers examined the potential synergy in vitro of ARQ 197 with two marketed tyrosine kinase inhibitors (TKIs), sorafenib and sunitinib. The combination of ARQ 197 and sorafenib showed synergistic cytotoxicity in non-small cell lung cancer, breast cancer, melanoma, small cell lung cancer and cervical cancer cell lines. Additive cytotoxicity with this combination was shown in breast cancer, colon cancer, renal cell carcinoma, squamous cell carcinoma, non-small cell lung cancer and hepatocellular carcinoma cell lines. In vivo confirmation of some of these findings in a human tumor xenograft model was also presented. The combination of ARQ 197 and sunitinib showed synergistic cytotoxicity in gastric carcinoma cell lines and additive cytotoxicity in a number of cancer cell lines. ARQ 197 and sorafenib showed synergy and additive effects in a larger number of cell lines than did ARQ 197 and sunitinib. These data suggest the potential clinical utility of combining ARQ 197 with other TKIs in cancer therapies.

2. Inhibition of the HGF/c-Met pathway by ARQ 197: Characterization of pharmacodynamic markers in vitro and in vivo (Abstract Number 1748, Poster Section 35, Poster Board Number 10, Hall B-F, April 19, 2009, 1:00 PM — 5:00 PM)

C-Met inhibition by ARQ 197 in human tumor cells was demonstrated through the analysis of two c-Met phosphorylation sites and downstream signals. Immunofluorescent staining of human gastric cancer (MKN45), colon cancer (HT29), and breast cancer (MDA-MB-231) cells in vitro showed clear reduction of c-Met phosphorylation after exposure to ARQ 197 in a concentration-dependent manner. Maximum inhibition was observed after 24 hours of ARQ 197 treatment and was sustained for at least eight hours following the removal of the compound. These findings were further supported by pharmacodynamic analysis of human tumor xenograft tissue data. The pharmacodynamic effect of ARQ 197 on c-Met and downstream markers, which has been confirmed in human tumor biopsies, provides a rationale for biomarker strategies in the clinical development of ARQ 197.

Clinical trials potentially applicable to GIST patients:

A combination trial using ARQ 197 plus sorafenib seems most relevant to GIST patients:

NCT00827177 Dose Escalation Study of ARQ 197 in Combination With Sorafenib in Adult Patients With Advanced Solid Tumors

The following are Phase I trials using ARQ 197 as a single agent:

NCT00302172 ARQ 197 in Subjects With Metastatic Solid Tumors

NCT00612209 A Phase 1 Study of ARQ 197 in Adult Patients With Advanced Solid Tumors

NCT00612703 A Phase 1 Study of ARQ 197 in Adult Patients With Advanced Solid Tumors