pd-184352 and Colonic-Neoplasms

This multicenter, open-label, phase II study was undertaken to assess the antitumor activity and safety of the oral mitogen-activated extracellular signal regulated kinase kinase (MEK) inhibitor, CI-1040, in breast cancer, colon cancer, non-small-cell lung cancer (NSCLC), and pancreatic cancer.. Patients with advanced colorectal, NSCLC, breast, or pancreatic cancer received oral CI-1040 continuously at 800 mg bid. All patients had measurable disease at baseline, a performance status of 2 or less, and adequate bone marrow, liver, and renal function. Expression of pERK, pAkt, and Ki-67 was assessed in archived tumor specimens by quantitative immunohistochemistry.. Sixty-seven patients with breast (n = 14), colon (n = 20), NSCLC (n = 18), and pancreatic (n = 15) cancer received a total of 194 courses of treatment (median, 2.0 courses; range, one to 14 courses). No complete or partial responses were observed. Stable disease (SD) lasting a median of 4.4 months (range, 4 to 18 months) was confirmed in eight patients (one breast, two colon, two pancreas, and three NSCLC patients). Treatment was well tolerated, with 81% of patients experiencing toxicities of grade 2 or less severity. Most common toxicities included diarrhea, nausea, asthenia, and rash. A mild association (P < .055) between baseline pERK expression in archived tumor specimens and SD was observed.. CI-1040 was generally well tolerated but demonstrated insufficient antitumor activity to warrant further development in the four tumors tested. PD 0325901, a second generation MEK inhibitor, has recently entered clinical development and, with significantly improved pharmacologic and pharmaceutical properties compared with CI-1040, it may better test the therapeutic potential of MEK inhibition in cancer.

Topics: Administration, Oral; Aged; Benzamides; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Colonic Neoplasms; Female; Humans; Lung Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Treatment Outcome

Inhibition of centromere-associated protein-E (CENP-E) has demonstrated preclinical anti-tumor activity in a number of tumor types including neuroblastoma. A potent small molecule inhibitor of the kinesin motor activity of CENP-E has recently been developed (GSK923295). To identify an effective drug combination strategy for GSK923295 in neuroblastoma, we performed a screen of siRNAs targeting a prioritized set of genes that function in therapeutically tractable signaling pathways. We found that siRNAs targeted to extracellular signal-related kinase 1 (ERK1) significantly sensitized neuroblastoma cells to GSK923295-induced growth inhibition (p = 0.01). Inhibition of ERK1 activity using pharmacologic inhibitors of mitogen-activated ERK kinase (MEK1/2) showed significant synergistic growth inhibitory activity when combined with GSK923295 in neuroblastoma, lung, pancreatic and colon carcinoma cell lines. Synergistic growth inhibitory activity of combined MEK/ERK and CENP-E inhibition was a result of increased mitotic arrest and apoptosis. There was a significant correlation between ERK1/2 phosphorylation status in neuroblastoma cell lines and GSK923295 growth inhibitory activity (r = 0.823, p = 0.0006). Consistent with this result we found that lung cancer cell lines harboring RAS mutations, which leads to oncogenic activation of MEK/ERK signaling, were significantly more resistant than cell lines with wild-type RAS to GSK923295-induced growth inhibition (p = 0.047). Here we have identified (MEK/ERK) activity as a potential biomarker of relative GSK923295 sensitivity and have shown the synergistic effect of combinatorial MEK/ERK pathway and CENP-E inhibition across different cancer cell types including neuroblastoma.

Topics: Antineoplastic Agents; Apoptosis; Benzamides; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Camptothecin; Cell Line, Tumor; Cell Proliferation; Chromosomal Proteins, Non-Histone; Colonic Neoplasms; Dacarbazine; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Irinotecan; Lung Neoplasms; M Phase Cell Cycle Checkpoints; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 3; Neuroblastoma; Pancreatic Neoplasms; RNA Interference; RNA, Small Interfering; Sarcosine; Temozolomide

This paper reports a second generation MEK inhibitor. The previously reported potent and efficacious MEK inhibitor, PD-184352 (CI-1040), contains an integral hydroxamate moiety. This compound suffered from less than ideal solubility and metabolic stability. An oxadiazole moiety behaves as a bioisostere for the hydroxamate group, leading to a more metabolically stable and efficacious MEK inhibitor.

Topics: Antineoplastic Agents; Benzamides; Colonic Neoplasms; Combinatorial Chemistry Techniques; Drug Screening Assays, Antitumor; Esters; Humans; Hydroxamic Acids; Microsomes, Liver; Mitogen-Activated Protein Kinase Kinases; Molecular Structure; Oxadiazoles; Structure-Activity Relationship

We have investigated the contribution of CDK4 and CDK2 inhibition to G1 arrest in colon cancers following inhibition of the MEK/MAP kinase pathway. CDK4 inhibition is sufficient to cause arrest, but inhibition of CDK2 by p27 Kip1 redistribution or ectopic expression has no effect on proliferation. Likewise, inhibition of CDK2 through expression of dominant-negative (DN) CDK2 or antisense oligonucleotides did not prevent cell proliferation in these cells. We therefore tested whether CDK2 activity is dispensable in other cells. Surprisingly, osteosarcomas and Rb-negative cervical cancers continued to proliferate after depletion of CDK2 through antisense oligonucleotides or small interfering (si) RNA. Here we report of sustained cell proliferation in the absence of CDK2, and we suggest that CDK2 is not a suitable target for cancer therapy.

Topics: Benzamides; Butadienes; CDC2-CDC28 Kinases; Cell Division; Colonic Neoplasms; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases; Cyclins; Ecdysterone; Enzyme Inhibitors; Female; G1 Phase; HeLa Cells; Humans; MAP Kinase Kinase Kinases; Models, Biological; Mutagenesis, Site-Directed; Mutation; Nitriles; Oligonucleotides, Antisense; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Retinoblastoma Protein; Tumor Cells, Cultured

The mitogen-activated protein kinase pathway is thought to be essential in cellular growth and differentiation. Here we report the discovery of a highly potent and selective inhibitor of the upstream kinase MEK that is orally active. Tumor growth was inhibited as much as 80% in mice with colon carcinomas of both mouse and human origin after treatment with this inhibitor. Efficacy was achieved with a wide range of doses with no signs of toxicity, and correlated with a reduction in the levels of activated mitogen-activated protein kinase in excised tumors. These data indicate that MEK inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer.

Topics: Animals; Benzamides; Cadherins; Calcium-Calmodulin-Dependent Protein Kinases; Cell Cycle; Cell Division; Colonic Neoplasms; Enzyme Activation; Enzyme Inhibitors; Female; Hepatocyte Growth Factor; Humans; Male; Mice; Mice, Inbred Strains; Mice, Nude; Neoplasm Invasiveness; Signal Transduction; Transplantation, Heterologous; Tumor Cells, Cultured