Vascular endothelial growth factor receptor that has shown preclinical Dipeptidyl peptidase-4 activity in lung adenocarcinoma cell lines. Another SFK inhibitor, KX2 391, targets the peptide substratebinding site rather than the ATP binding site. Based on the promising results from phase I study, a phase II study has been initiated with Castration Resistant Prostate Cancer Bone Metastatic patients, All these therapeutic agents appear to be well tolerated and we eagerly await their detailed clinical results. 10. Conclusions Our understanding of Src structure and function, regulation, and localization has increased dramatically since its discovery. One hundred years after the original description of Src, this protein continues to attract keen interest because of its multiplicity of actions in the molecular signaling pathways underlying developmental as well as oncogenic events.
Many studies have NVP-AUY922 addressed the molecular mechanisms of Src regulation in cells and tumor tissues. In order to clarify and fully elucidate the normal physiologic function of Src and other SFKs and to fully comprehend Src signaling networks in various cancers, Src interactions with specific targets or binding partners in different subcellular localization studies should be characterized in as much detail as possible. Special focus should be placed on the role of Src in bone metastasis because of the protein,s role in osteoclast and osteoblast function. Moreover, preclinical reports of combination treatments involving chemotherapy, radiation therapy, and targeted therapies with a Src inhibitor warrant further investigation.
Abstract BACKGROUND INNO 406, an oral dual Abl/Lyn tyrosine kinase inhibitor, demonstrates specific Lyn kinase activity with no or limited activity against other Src family member kinases. Several Bcr Abl kinase domain mutations are sensitive to INNO 406 in vitro, including the F317L and F317V mutations. In this study, we evaluated INNO 406 in Philadelphia chromosome positive chronic myelogenous leukemia or acute lymphocytic leukemia post imatinib resistance or intolerance. METHODS A dose escalation study was conducted with a starting dose of 30mg administered orally once daily. Cohorts of at least 3 patients were treated at each dose level until the maximum tolerated dose was reached. Twice daily dosing was also evaluated. Therapy was allowed for a maximum of 24 months.
RESULTS INNO 406 was administered to 56 patients with imatinib resistance or intolerance. Other previous treatments included nilotinib, dasatinib, and dasatinib/nilotinib. Common mutations upon study entry included Y253H, G250E, T315I and F317L. Among 31 patients with CML in chronic phase treated with INNO 406, the major cytogenetic response rate was 19%. In this study, no responses were seen in patients with CML AP, CML BP, or Ph positive ALL. Dose limiting toxicities at INNO 406 480mg BID were liver function abnormalities and thrombocytopenia. CONCLUSIONS INNO 406 showed anti CML efficacy in this heavily pretreated study population. Based on the classical determinations of both DLT and MTD, the recommended phase 2 dose of INNO 406 is 240mg orally BID. Lower doses of INNO 406 may be equally effective and should be exploredINTRODUCTION Chronic myeloid leukemia is a hematopoietic stem cell disorder in which