litronesib and Neoplasms

Eg5, a mitotic motor kinesin protein, plays an essential role in bipolar spindle formation in the M phase of the cell cycle. LY2523355 (litronesib) is an allosteric inhibitor of Eg5. This phase 1 and dose-finding study aimed to assess the safety, pharmacokinetics (PK), recommended dose for further studies, and preliminary efficacy in Japanese patients with advanced solid tumors.. LY2523355 was given on days 1, 2, and 3 every 3 weeks at one of three dose levels: 2, 4, and 5 mg/m²/day. Toxicity was assessed according to NCI-CTCAE version 4.0, and tumor response according to RECIST version 1.1. granulocyte colony-stimulating factor (G-CSF) was used only for grade 4 neutropenia or grade 3 febrile neutropenia.. Twelve patients were treated at doses of 2 (n = 3), 4 (n = 3), and 5 (n = 6) mg/m²/day. Most frequent treatment-related adverse events were neutropenia and leukopenia (100 %). Grade 4 neutropenia was observed in 83 %, but all recovered to above 500 neutrophils/μl within 7 days. All patients at 4 and 5 mg/m²/day required G-CSF support. No dose-limiting toxicities were reported up to 5 mg/m²/day. In PK analysis, LY2523355 exposure increased in a dose-dependent manner. The PK parameters for LY2523355 were similar to those observed in Western populations. No objective tumor responses were observed.. The recommended dose of LY2523355 with therapeutic G-CSF use for further studies was determined to be 5 mg/m²/day in Japanese patients with advanced solid tumors.

Topics: Adult; Aged; Allosteric Regulation; Antineoplastic Agents; Cancer Care Facilities; Chemotherapy-Induced Febrile Neutropenia; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drugs, Investigational; Enzyme Inhibitors; Female; Half-Life; Humans; Japan; Kinesins; Leukopenia; Male; Middle Aged; Neoplasm Proteins; Neoplasms; Severity of Illness Index; Sulfonamides; Thiadiazoles

Intervention of cancer cell mitosis by antitubulin drugs is among the most effective cancer chemotherapies. However, antitubulin drugs have dose-limiting side effects due to important functions of microtubules in resting normal cells and are often rendered ineffective by rapid emergence of resistance. Antimitotic agents with different mechanisms of action and improved safety profiles are needed as new treatment options. Mitosis-specific kinesin Eg5 represents an attractive anticancer target for discovering such new antimitotic agents, because Eg5 is essential only in mitotic progression and has no roles in resting, nondividing cells. Here, we show that a novel selective Eg5 inhibitor, LY2523355, has broad target-mediated anticancer activity in vitro and in vivo. LY2523355 arrests cancer cells at mitosis and causes rapid cell death that requires sustained spindle-assembly checkpoint (SAC) activation with a required threshold concentration. In vivo efficacy of LY2523355 is highly dose/schedule-dependent, achieving complete remission in a number of xenograft tumor models, including patient-derived xenograft (PDX) tumor models. We further establish that histone-H3 phosphorylation of tumor and proliferating skin cells is a promising pharmacodynamic biomarker for in vivo anticancer activity of LY2523355.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Cell Cycle Checkpoints; Cell Line, Tumor; Dose-Response Relationship, Drug; HCT116 Cells; HeLa Cells; HT29 Cells; Humans; Immunoblotting; Kinesins; Mice, Nude; Mitosis; Neoplasms; Sulfonamides; Thiadiazoles; Time Factors; Treatment Outcome; Tumor Burden; Xenograft Model Antitumor Assays