semaxinib and Carcinoma--Non-Small-Cell-Lung

The institution of combined modality therapy for unresected solid tumors has resulted in significant improvements in tumor control and survival benefit compared with radiotherapy (RT) alone. A number of chemotherapy agents that can enhance the effectiveness of RT, such as cisplatin and 5-fluorouracil, are now considered standard treatment for patients with a number of cancer types. There is growing interest in a number of additional agents that have also been found to have radiosensitizing ability. These include paclitaxel, docetaxel, irinotecan, gemcitabine, and vinorelbine, as well as biologic agents. Other agents may be of value because they act to counter dose-limiting toxicities associated with RT. This article provides an update of some important, recently completed and ongoing clinical trials evaluating novel chemoradiation protocols, with examples taken primarily from studies conducted by the Radiation Therapy Oncology Group (RTOG). Theoretical approaches to the development of new agents and combined modality regimens are also discussed.

Topics: Alkyl and Aryl Transferases; Angiogenesis Inhibitors; Angiostatins; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dose Fractionation, Radiation; Drugs, Investigational; Endothelial Growth Factors; Enzyme Inhibitors; Esophageal Neoplasms; Farnesyltranstransferase; Female; Head and Neck Neoplasms; Humans; Indoles; Intercellular Signaling Peptides and Proteins; Isoenzymes; Laryngeal Neoplasms; Lung Neoplasms; Lymphokines; Male; Membrane Proteins; Neoplasms; Peptide Fragments; Plasminogen; Prostaglandin-Endoperoxide Synthases; Prostatic Neoplasms; Pyrroles; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Treatment Outcome; Uterine Cervical Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Anaplastic lymphoma kinase (ALK) has been in the spotlight in recent years as a promising new target for therapy of non-small-cell lung cancer (NSCLC). Since the identification of the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene in some NSCLC patients was reported in 2007, various research groups have been seeking ALK inhibitors. Above all, crizotinib (PF-02341066) has been under clinical trial, and its therapeutic efficacy of inhibiting ALK in NSCLC has been reported. Among anticancer drugs, drug resistance appears frequently necessitating various kinds of inhibitors. We identified novel ALK inhibitors by virtual screening from the public chemical library collected by the Chemical Biology Research Initiative (CBRI) at the University of Tokyo, and inhibitors that are more potent were developed.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Drug Design; Humans; Lung Neoplasms; Models, Molecular; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Increased expression of cyclooxygenase (COX) 2 and the production of PGs appear to provide a survival advantage to transformed cells through the inhibition of apoptosis, increased attachment to extracellular matrix, increased invasiveness and the stimulation of angiogenesis. The purpose of this study was to determine whether an angiogenic antagonist, SU5416, could inhibit endogenous and phorbol 12-myristate 13-acetate (PMA)-mediated induction of COX-2 expression. SU5416 (5 micro M) inhibited endogenous as well as PMA-mediated induction of COX-2 expression when analyzed by immunoblot and Northern blot analysis. However, COX-1 expression remained unchanged under similar conditions. PMA is a potent inducer of reactive oxygen species that can play an important role during the induction of COX-2 expression. Our results demonstrated that PMA-mediated induction of COX-2 expression was found to be dependent on NADPH oxidase activity. An inhibitor of NADPH oxidase (diphenyleneiodonium chloride) blocked the PMA-mediated induction of COX-2 expression. The oxidase complex exhibited a temporal pattern of activation after exposure to PMA in which maximum activation was observed at 30 min after the addition of PMA. Activation of NADPH oxidase was also inhibited by SU5416, whereas an inhibitor of epidermal growth factor receptor signaling was unable to prevent the PMA-mediated induction of NADPH oxidase activity. When we blocked the PMA-mediated production of reactive oxygen species by blocking NADPH oxidase with SU5416, COX-2 expression and PGE(2) synthesis were also inhibited. Our results suggest that inhibition of NADPH oxidase activity, blocking of COX-2 expression, and PGE(2) synthesis may represent novel targets for SU5416.

Topics: Angiogenesis Inhibitors; Carcinoma, Non-Small-Cell Lung; Cyclooxygenase 2; Down-Regulation; Drug Interactions; Enzyme Induction; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Indoles; Isoenzymes; Lung Neoplasms; Membrane Proteins; NADPH Oxidases; Prostaglandin-Endoperoxide Synthases; Pyrroles; Superoxides; Tetradecanoylphorbol Acetate

The multifaceted nature of the angiogenic process in malignant neoplasms suggests that protocols that combine antiangiogenic agents may be more effective than single-agent therapies. However it is unclear which combination of agents would be most efficacious and will have the highest degree of synergistic activity while maintaining low overall toxicity. Here we investigate the concept of combining a "direct" angiogenesis inhibitor (endostatin) with an "indirect" antiangiogenic compound [SU5416, a vascular endothelial growth factor receptor 2 (VEGFR2) receptor tyrosine kinase (RTK) inhibitor]. These angiogenic agents were more effective in combination than when used alone in vitro (endothelial cell proliferation, survival, migration/invasion, and tube formation tests) and in vivo. The combination of SU5416 and low-dose endostatin further reduced tumor growth versus monotherapy in human prostate (PC3), lung (A459), and glioma (U87) xenograft models, and reduced functional microvessel density, tumor microcirculation, and blood perfusion as detected by intravital microscopy and contrast-enhanced Doppler ultrasound. One plausible explanation for the efficacious combination could be that, whereas SU5416 specifically inhibits vascular endothelial growth factor signaling, low-dose endostatin is able to inhibit a broader spectrum of diverse angiogenic pathways directly in the endothelium. The direct antiangiogenic agent might be able to suppress alternative angiogenic pathways up-regulated by the tumor in response to the indirect, specific pathway inhibition. For future clinical evaluation of the concept, a variety of agents with similar mechanistic properties could be tested.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Division; Cell Movement; Cell Survival; Drug Synergism; Endostatins; Endothelium, Vascular; Female; Glioblastoma; Humans; Indoles; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Mice, SCID; Neoplasms; Neovascularization, Pathologic; Prostatic Neoplasms; Pyrroles; Ultrasonography; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Angiogenesis inhibitors differ from conventional cytotoxic chemotherapy agents by targeting normal cells rather than tumor cells, which may contain multiple mutations. Because of this, the traditional strategy used in clinical development of cytotoxic agents may not be appropriate for these novel agents. Many clinical studies are now evaluating these agents with a new approach, referred to as the cytostatic paradigm. The cornerstone of the cytostatic paradigm is the use of time to progression (TTP) of disease as the decision-making criterion for "go/no go" in the early phases of clinical development. However, the use of TTP as the main criterion for clinical trials is complicated for a variety of reasons, including: A) the lack of standardized criteria accepted by regulatory authorities; B) the heterogeneity of the historical database, and C) the larger number of patients needed for the "go/no go" decision-making process. In addition, clinical trials of cytotoxic agents have traditionally used objective response (despite the controversy regarding objective response as a surrogate for clinical activity) as the main criterion for determining whether the results of phase II studies justify the pivotal phase III studies. Another aspect of the clinical development strategy is combining angiogenesis inhibitors with cytotoxic chemotherapy. The rationale for combination of angiogenesis inhibitors with cytotoxic agents is based on: A) different targets for these agents; B) lack of cross-resistance patterns; C) lack of myelosuppression with angiogenesis inhibitors allows administration of full doses of all agents, and D) the assumption that combining these agents will result in additive antitumor activity. Combination therapy with angiogenesis inhibitors may be attractive to both clinicians and their patients because it allows cytostatic agents to be used upfront in treatment while contributing to drug registration strategy (cytostatic/cytotoxic combination therapy versus cytotoxic therapy). The clinical development of the angiogenesis inhibitor SU5416, a small molecule inhibitor of vascular endothelial growth factor, is currently ongoing. In phase I trials, SU5416 demonstrated activity in both colorectal and non-small-cell lung cancer patients. Based on these encouraging results, phase III studies to evaluate combination of SU5416 with established cytotoxic therapy are planned. These studies will include an interim analysis, the equivalent of a phase II evaluation

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Decision Making; Disease Progression; Drug Evaluation; Drug Resistance, Neoplasm; Drugs, Investigational; Endothelial Growth Factors; Enzyme Inhibitors; Humans; Indoles; Lung Neoplasms; Lymphokines; Protein Isoforms; Protein-Tyrosine Kinases; Pyrroles; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors