12017 Background: Ixabepilone belongs to a class of structurally novel, microtubule-stabilizing agents that exert their antimitotic action by binding to tubulin with a binding mode that is distinct from the taxanes. Preclinical findings that ixabepilone has antitumor activity in a broad spectrum of tumor types, including taxane-resistant tumors, is borne out by Phase II clinical trials where ixabepilone has demonstrated activities in multiple tumor types including breast, renal, pancreatic, prostate and lymphoma. The aim of this series of studies was to further characterize the therapeutic potential of ixabepilone in combination with currently approved chemotherapy agents. Methods: Antitumor activity was evaluated in the GEO human colon and L2987 human lung carcinoma xenografts. Therapeutic synergism of the combination was defined as the attainment of efficacy that was significantly better than the best response of the individual single agents administered at their maximum-tolerated dose (MTD) or optimal dose (OD). Results: In the GEO tumors, single-agent ixabepilone produced 1.1 log cell kill (LCK) at its MTD. Cetuximab at its OD yielded 0.8 LCK. The combination of ixabepilone and cetuximab produced 1.7 LCK which was significantly superior to ixabepilone alone (P=0.0173) and cetuximab alone (P=0.0002). Similar synergistic efficacy was observed in the L2987 tumors. The combined efficacy of capecitabine plus ixabepilone was evaluated in the GEO tumors. In this tumor, single-agent ixabepilone was modestly active (LCK = 0.8) at its MTD. Single-agent capecitabine was not effective (LCK = 0.4) at its MTD. However, the combination of the two agents produced therapeutic synergism, yielding antitumor efficacy (1.9 LCK) that was superior to either of the agents alone at their MTDs (P=0.035 and 0.0004, respectively). Conclusions: Ixabepilone demonstrates robust synergistic antitumor efficacy when used in combination with cetuximab or capecitabine in human xenografts providing a biologic rationale for these combinations in the treatment of cancer. [Table: see text]
2326 Human folate receptor alpha (FR) is selectively overexpressed in certain tumor types, including ovarian, endometrial, renal, lung and breast carcinomas. Folic acid (FA) is a high affinity ligand which upon binding is internalized by endocytosis; therefore conjugation of a therapeutic to FA is a promising strategy for targeting agents to tumors while limiting exposure to normal tissues. The epothilones (e.g. ixabepilone) are a new class of microtubule agents with broad-spectrum antineoplastic activity and proven efficacy against taxane-resistant diseases. The epothilone-folate conjugate BMS-753493 was developed as a therapeutic strategy to specifically target a highly potent epothilone to human tumors. METHODS: Clonogenic assays were used to assess the cytotoxicity of BMS-753493 in vitro. Antitumor activity was evaluated in the KB nasopharyngeal, IGROV ovarian, HeLa cervical, and murine 98M109 lung models. The combinability of BMS-753493 with bevacizumab, cisplatin, or ixabepilone was evaluated in tumor xenografts in vivo. Proof of concept in vitro and in vivo was assessed by testing the activity of BMS-753493 in the presence of excess folate-analog against FR positive cancer cell lines and in FR negative tumors. Enteropathy was assessed by histopathology and neuropathy by the plantar test and the rotorod motor function test. RESULTS: Theepothilone-folate conjugate BMS-753493 induced potent cytotoxicity in a panel of FR positive human tumor cells, including human KB and IGROV models in vitro. The cell-killing effect of BMS-753493 was abolished when excess folic acid was present; moreover BMS-753493 was inactive against FR negative cells. In several different FR positive tumor models, BMS-753493 demonstrated antitumor activity in vivo and showed excellent combinability with other chemotherapeutic agents. Similar to the in vitro experiments, antitumor activity of BMS-753493 was significantly reduced by the co-administration of 20-fold excess folate analog (EC-20) and the growth of FR negative tumors was unaffected by BMS-753493 at all doses tested. BMS-753493 combined synergistically with bevacizumab, cisplatin and ixabepilone in vivo against FR positive human tumor xenografts. Finally, rodents treated with BMS-753493 at the maximum tolerated dose did not demonstrate clinical signs of neuropathy and displayed minimal enteropathy, side-effects that are frequently associated with anti-microtubule cytotoxic agents. CONCLUSION: These data provide strong proof of concept that the antitumor activity of BMS-753493 is mediated mainly through the FR. Furthermore, these data support the notion that BMS-753493 would be cytotoxic against FR positive tumors but would have reduced adverse effects on normal tissues that do not express the FR. BMS-753493 thus represents a promising novel targeted-cytotoxic agent for the treatment of FR positive malignancies.
BMS-754807 is a potent and reversible inhibitor of the insulin-like growth factor 1 receptor/insulin receptor family kinases (Ki, <2 nmol/L). It is currently in phase I development for the treatment of a variety of human cancers. BMS-754807 effectively inhibits the growth of a broad range of human tumor types in vitro, including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines (IC50, 5-365 nmol/L); the compound caused apoptosis in a human rhabdomyosarcoma cell line, Rh41, as shown by an accumulation of the sub-G1 fraction, as well as by an increase in poly ADP ribose polymerase and Caspase 3 cleavage. BMS-754807 is active in vivo in multiple (epithelial, mesenchymal, and hematopoietic) xenograft tumor models with tumor growth inhibition ranging from 53% to 115% and at a minimum effective dose of as low as 6.25 mg/kg dosed orally daily. Combination studies with BMS-754807 have been done on multiple human tumor cell types and showed in vitro synergies (combination index, <1.0) when combined with cytotoxic, hormonal, and targeted agents. The combination of cetuximab and BMS-754807 in vivo, at multiple dose levels, resulted in improved clinical outcome over single agent treatment. These data show that BMS-754807 is an efficacious, orally active growth factor 1 receptor/insulin receptor family-targeted kinase inhibitor that may act in combination with a wide array of established anticancer agents.
<div>Abstract<p>BMS-754807 is a potent and reversible inhibitor of the insulin-like growth factor 1 receptor/insulin receptor family kinases (Ki, <2 nmol/L). It is currently in phase I development for the treatment of a variety of human cancers. BMS-754807 effectively inhibits the growth of a broad range of human tumor types <i>in vitro</i>, including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines (IC<sub>50</sub>, 5–365 nmol/L); the compound caused apoptosis in a human rhabdomyosarcoma cell line, Rh41, as shown by an accumulation of the sub-G<sub>1</sub> fraction, as well as by an increase in poly ADP ribose polymerase and Caspase 3 cleavage. BMS-754807 is active <i>in vivo</i> in multiple (epithelial, mesenchymal, and hematopoietic) xenograft tumor models with tumor growth inhibition ranging from 53% to 115% and at a minimum effective dose of as low as 6.25 mg/kg dosed orally daily. Combination studies with BMS-754807 have been done on multiple human tumor cell types and showed <i>in vitro</i> synergies (combination index, <1.0) when combined with cytotoxic, hormonal, and targeted agents. The combination of cetuximab and BMS-754807 <i>in vivo</i>, at multiple dose levels, resulted in improved clinical outcome over single agent treatment. These data show that BMS-754807 is an efficacious, orally active growth factor 1 receptor/insulin receptor family–targeted kinase inhibitor that may act in combination with a wide array of established anticancer agents. [Mol Cancer Ther 2009;8(12):3341–9]</p></div>
Structure-activity relationships in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides identified highly potent inhibitors of γ-secretase mediated signaling of Notch1/2/3/4 receptors. On the basis of its robust in vivo efficacy at tolerated doses in Notch driven leukemia and solid tumor xenograft models, 12 (BMS-906024) was selected as a candidate for clinical evaluation.
