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AACR Roundup
(BioWorld Today Via Thomson Dialog NewsEdge) The following items were presented at the American Association for Cancer Research meeting in San Diego. The conference ended Wednesday. (Also see, p. 8.)
? Ardea Biosciences Inc., of San Diego, reported data demonstrating the activity and favorable pharmacokinetic profile of its mitogen-activated ERK kinase (MEK) inhibitor family of compounds in cancerous tumors. Data showed that RDEA119 and RDEA436 were potent inhibitors of MEK1/2 and that both compounds suppressed tumor cell growth in vitro and in vivo and have significant anti-inflammatory activity with limited potential for central nervous system toxicity.
? Celator Pharmaceuticals, of Princeton, N.J., reported results on a novel approach designed to deliver drugs that are incapable of dissolving in water in nanoparticles to enhance and control drug circulation. The company said the findings allow it to combine hydrophobic drugs such as paclitaxel with other anti-cancer drugs, based on its CombiPlex technology. According to the research findings, the ability to optimize paclitaxel conjugates could make it possible for higher drug levels to be maintained in plasma for extended periods, which is associated with superior preclinical antitumor efficacy when compared to drug delivery involving paclitaxel at its maximum tolerated dose.
? Cyclacel Pharmaceuticals Inc., of Berkeley Heights, N.J., presented eight posters with preclinical data demonstrating the ability of Cyclacel's cell cycle inhibitors to induce cancer cell death by inhibiting key enzymes. Five of the preclinical studies evaluated Cyclacel's CYC116 cell cycle inhibitor. The company said the studies provided additional evidence that CYC116 inhibits aurora kinases and vascular endothelial growth factor receptor-2 tyrosine kinase, or VEGFR-2 kinase. Aurora kinases are target proteins that are essential for mitosis, the process by which a cell divides. VEGFR-2 kinase is a validated target promoting angiogenesis or new vessel formation in the vicinity of cancer cells. CYC116 is currently being studied in a Phase I trial in patients with solid tumors. The study is designed to identify the maximum tolerated dose of CYC116 and evaluate its pharmacokinetic, pharmacodynamic and antitumor effects.
? Cytokinetics Inc., of South San Francisco, reported interim data from the first clinical trial of GSK-923295, a centromere-associated protein E inhibitor, showing that six of eight patients experienced adverse events, though only 3 percent of those were reported to be Grade 3 and there were no Grade 4 events. The pharmacokinetics of the drug generally were dose-proportional over the dose range of 10 mg/m2 to 80 mg/m2, and researchers found that intrapatient pharmacokinetics on days 1 and 15 were similar. A separate poster on GSK923295 concluded that CENP-E is a rational target for neuroblastoma as increased expression is associated with both tumor progression in a transgenic mouse model driven the gene MYCN and with high-risk disease in humans, and said the drug is effective in vitro and in vivo against neuroblastoma.
? EntreMed Inc., of Rockville, Md., said results for MKC-1 administered in combination with paclitaxel in a preclinical, orthotopic breast tumor model demonstrated synergistic tumor inhibition. The combination of MKC-1 and paclitaxel, but neither agent alone, demonstrated tumor regression of the bulky breast cell line tumors grown in that model. The combination also decreased angiogenesis and proliferation and increased apoptosis as early as four days post-treatment and decreased the oncogenic proteins HIF-1alpha, pAKT and pS6 ribosomal proteins. Separately, data showed that treatment of the 1A9 human ovarian carcinoma cell line with ENMD-1198 induced cell cycle arrest and decreased levels of the oncogenic transcription factor proteins HIF-1alpha, pSTAT3 and pNFkappaB. ENMD-1198 treatment also down-regulated expression of several tubulin isotypes in 1A9 cells, but not in ENMD-1198-resistant (1A9-1198R) cells.
? Geron Corp., of Menlo Park, Calif., said data showed that GRN163L effectively inhibited telomerase in HER2-positive breast cancer cells, including breast cancer cells that had become resistant to trastuzumab and, that GRN163L acts synergistically on these cells in combination with trastuzumab. The data also showed that exposure of trastuzumab-resistant cells to GRN163L restored the cells' sensitivity to trastuzumab. Separate data showed that GRN163L effectively inhibited telomerase in three different non-small-cell lung cancer lines and caused shortening of their telomeres. Additionally, the data showed that treatment of NSCLC cells with GRN163L increased their sensitivity to paclitaxel and carboplatin.
? Halozyme Therapeutics Inc., of Munich, Germany, announced new preclinical findings on the local tolerability and pharmacokinetics of bisphosphonates combined with rHuPH20. In rodent intradermal models, injection of bisphosphonates without rHuPH20 created injection-site reactions characterized by erythema, induration and ulceration in a concentration dependent manner. Also in rodent intradermal models, the maximal concentration of bisphosphonates that could be administered without producing ISRs was increased three- to fivefold when co-administered in combination with rHuPH20. In porcine pharmacokinetic models, absolute bioavailability by subcutaneous injection with rHuPH20 was comparable to I.V. infusion.
? Lorus Therapeutics Inc., of Toronto, presented preclinical data showing that LOR-253 had a favorable pharmacokinetic profile in animal studies following intravenous dosing, and the study indicated the drug's significant potential in treating non-small-cell lung and colon cancers. A second presentation showed that the company's LOR-2040 (formerly GTI-2040) significantly improved the anticancer efficacy of a group of cytokine immunotherapeutic agents, including interferon alpha and interleukin-2, which have been used in the treatment of solid tumors.
? MethylGene Inc., of Montreal, said preclinical data of MGCD265, an oral, multitargeted (c-Met) kinase inhibitor for cancer that targets the c-Met, Tie-2, Ron and VEGF receptor tyrosine kinases demonstrated significant inhibition of tumor growth in a broad range of cancer types. In c-Met driven gastric cancer and glioblastoma tumor models, MGCD265 decreased tumor volume by more than 95 percent compared with untreated tumors. In addition, the compound showed antitumor activity in breast, colorectal and non-small-cell lung cancer tumor models that were not c-Met driven, with an average reduction in tumor volume of 76 percent. MGCD265 potently inhibited c-Met and VEGFR2 cellular phenotypes, including cell motility and angiogenesis.
? Oncothyreon Inc., of Bellevue, Wash., said data from pharmacokinetic studies of PX-12, an irreversible inhibitor of thioredoxin (Trx)-1, a protein that is overexpressed in many tumor types and is associated with aggressive tumor growth and poor prognoses, reduced plasma Trx-1 levels in all patients with initial levels greater than 18 ng/mL, the upper limit of the normal range. Patients with normal Trx-1 levels remained in the normal range following PX-12 treatment. About 33 percent of patients with elevated Trx-1 levels achieved stable disease with PX-12 treatment. No patients achieved stable disease if their starting Trx-1 levels were within the normal range. Separately, data showed that treatment with PX-866, a small-molecule inhibitor of phosphotidylinositol-3 kinase (PI-3K), a key point of control of cellular responses including signaling of cell survival and growth, migration and metabolism, resulted in metabolic changes that are consistent with a partial normalization of cellular metabolism and that those changes can be detected by MRS. Tumor volume decreased about 75 percent in tumors treated with PX-866 compared with controls.
? Pharmacyclics Inc., of of Sunnyvale, Calif, presented preclinical results demonstrating the antitumor activity of PCI-27483, its small-molecule Factor VIIa inhibitor. Researchers reported that in animal models of human pancreatic tumors, treatment with PCI-27483 led to inhibition of tumor growth. PCI-27483 was administered twice daily at either 60 mg/kg or 90 mg/kg, resulting in 42 percent and 85 percent inhibition of tumor growth, respectively, after 15 days of treatment. Additional mechanistic studies showed that PCI-27483 blocked key tumor growth signals.
? SGX Pharmaceuticals Inc., of San Diego, said data demonstrated potent antitumor activity when SGX523 was dosed orally in various mouse models of human cancer including glioblastoma, gastric cancer and lung cancer. In addition, the firm said, its second development candidate, SGX126, is structurally distinct and may possess several advantages over SGX523, including the potential for a lower human dose.
? SuperGen Inc., of Dublin, Calif., reported that it identified a lead PIM kinase inhibitor, SGI-1776, which causes tumor regression in acute myelogenous leukemia xenograft models. The compound was shown to selectively inhibit PIM kinases to induce apoptosis and cell cycle arrest, thereby causing a reduction in phosphor-BAD levels and enhancing mTOR inhibition in vitro. SGI-1776 induced significant tumor regression in AML xenograft models.
? Ziopharm Oncology Inc., of of Bethesda, Md., presented positive data from a Phase II study of darinaparsin, the company's novel organic arsenic compound, in advanced hematological malignancies. A total of 40 patients with a variety of hematological malignancies have been enrolled, with 40 patients evaluable for safety and 21 evaluable for efficacy. In three of seven lymphoma patients evaluable for efficacy, one patient (peripheral T-cell lymphoma) achieved a complete response, one patient (nodular sclerosis) is ongoing in cycle three with a PET scan interval response, and one patient (B-cell lymphoma) is ongoing with stable disease after five cycles of therapy. Of 14 leukemia patients evaluable for efficacy, six achieved stable disease (three MDS and three CML) and one patient withdrew consent prior to efficacy evaluation. The study is ongoing. Darinaparsin was well tolerated with the most common serious adverse events being constitutional (pyrexia), pulmonary (dyspnea), cardiovascular (hypotension) and infection (sepsis) related.
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