pd-184352 and Neoplasms

Targeting of oncogenic driver mutations with small-molecule inhibitors resulted in powerful treatment options for cancer patients in recent years. The RAS (rat sarcoma) pathway is among the most frequently mutated pathways in human cancer. Whereas targeting mutant Kirsten RAS (KRAS) remains difficult, mutant B rapidly accelerated fibrosarcoma (BRAF) kinase is an established drug target in cancer. Now data show that neuroblastoma RAS (NRAS) and even Harvey RAS (HRAS) mutations could be predictive markers for treatment with mitogen-activated protein kinase (MEK) inhibitors. This review discusses recent preclinical and clinical studies of MEK inhibitors in BRAF and RAS mutant cancer.

Topics: Animals; Azetidines; Benzamides; Benzimidazoles; Diphenylamine; Genes, ras; GTP Phosphohydrolases; Humans; Membrane Proteins; Mice; Mitogen-Activated Protein Kinases; Mutation; Neoplasms; Niacinamide; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Signal Transduction; Sulfonamides

Identification of the key roles of protein kinases in signaling pathways leading to development of cancer has caused pharmacological interest to concentrate extensively on targeted therapies as a more specific and effective way for blockade of cancer progression. This review will mainly focus on inhibitors targeting these key components of cellular signaling by employing a technology-based point of view with respect to ATP- and non-ATP-competitive small molecule inhibitors and monoclonal antibodies of selected protein kinases, particularly, mammalian target of rapamycin (mTOR), BCR-ABL, MEK, p38 MAPK, EGFR PDGFR, VEGFR, HER2 and Raf. Inhibitors of the heat shock protein Hsp90 are also included in a separate section, as this protein plays an essential role for the maturation/proper activation of cancer-related protein kinases. In the following review, the molecular details of the mode of action of these inhibitors as well as the emergence of drug resistance encountered in several cases are discussed in light of the structural, molecular and clinical studies conducted so far.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzamides; Benzenesulfonates; Gefitinib; HSP90 Heat-Shock Proteins; Humans; Imatinib Mesylate; Neoplasms; Niacinamide; p38 Mitogen-Activated Protein Kinases; Phenylurea Compounds; Piperazines; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Quinazolines; Signal Transduction; Sirolimus; Sorafenib; Trastuzumab

Significant advances in the field of molecular biology over the past decade have led to a new era in cancer therapeutics, with an explosion of rationally designed therapeutic strategies directed against selective molecular targets. The complex array of aberrant signal transduction proteins involved in carcinogenesis has been the focus of target-based anticancer agents. Inhibitors of intracellular signal transduction represent a unique approach in that they inhibit critical downstream regulatory proteins, which are vital to the process of cellular communication. Although these agents are in early-phase evaluations, the preliminary data suggest that they are well tolerated and capable of target inhibition in surrogate and tumor tissue. Although the primary therapeutic benefit of these agents is expected to be decreased tumor growth, evidence suggests that objective tumor responses may also be achieved. There are many unresolved questions pertaining to the development of this class of compounds, including selection of optimal dose and schedule, determination of relevant endpoints, methods for target validation, and strategies for combination with cytotoxic agents. However, despite the numerous unresolved issues, the emergence of this class of compounds has resulted in an undeniable impact on the present and future of cancer therapeutics.

Topics: Adult; Animals; Antineoplastic Agents; Benzamides; Benzenesulfonates; Child; Clinical Trials as Topic; Drug Delivery Systems; Drug Resistance, Neoplasm; Female; Humans; Mice; Mitogen-Activated Protein Kinase Kinases; Molecular Structure; Neoplasm Proteins; Neoplasms; Niacinamide; Oligodeoxyribonucleotides, Antisense; Phenylurea Compounds; Proto-Oncogene Proteins c-raf; Pyridines; Signal Transduction; Sorafenib; Thionucleotides; Xenograft Model Antitumor Assays

This phase I study was undertaken to define the toxicity, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD), and clinical activity of CI-1040, a small-molecule inhibitor of the dual-specificity kinases MEK(mitogen-activated protein kinase kinase) -1 and MEK2 , in patients with advanced malignancy.. CI-1040 was tested in multiple daily dosing frequencies administered for 21 days repeated every 28 days leading ultimately to continuous administration, and effect of food on absorption was tested. Single dose and steady-state pharmacokinetics were assessed during cycle 1 and phosphorylated extracellular receptor kinase (pERK) levels were assessed in WBCs and also in tumor tissue from selected patients.. Seventy-seven patients received CI-1040 at dose levels ranging from 100 mg QD to 800 mg tid. Grade 3 asthenia was dose limiting at the highest dose level tested, 800 mg tid administered with food. Ninety-eight percent of all drug-related adverse events were grade 1 or 2 in severity; most common toxicities included diarrhea, asthenia, rash, nausea, and vomiting. Plasma concentrations of CI-1040 and its active metabolite, PD 0184264, increased in a less than dose proportional manner from 100 to 800 mg QD. Administration with a high-fat meal resulted in an increase in drug exposure. The MTD and recommended phase II dose was 800 mg BID administered with food. Sixty-six patients were assessable for response. One partial response was achieved in a patient with pancreatic cancer and 19 patients (28%) achieved stable disease lasting a median of 5.5 months (range, 4 to 17 months). Inhibition of tumor pERK (median, 73%; range, 46% to 100%) was demonstrated in 10 patients.. CI-1040 was well tolerated at 800 mg BID administered with food. Both target suppression and antitumor activity were demonstrated in this phase I study.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Benzamides; Calcium-Calmodulin-Dependent Protein Kinases; Enzyme Inhibitors; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasms; Treatment Outcome

Topics: Animals; Benzamides; Calcium-Calmodulin-Dependent Protein Kinases; Enzyme Inhibitors; Humans; MAP Kinase Signaling System; Neoplasms