semaxinib and Lung-Neoplasms

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Cetuximab; ErbB Receptors; Erlotinib Hydrochloride; Gene Targeting; Genetic Therapy; Humans; Imatinib Mesylate; Indoles; Lung Neoplasms; Piperazines; Pyrimidines; Pyrroles; Quinazolines; Receptor Protein-Tyrosine Kinases; Signal Transduction; Trastuzumab

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

Through both gain- and loss-of-TTF-1 expression strategies, we show that TTF-1 positively regulates vascular endothelial growth factor (VEGF) and that the VEGF promoter element contains multiple TTF-1-responsive sequences. The major signaling receptor for VEGF, i.e VEGFR2, also appears to be under a direct and positive regulation of TTF-1. The TTF-1-dependent upregulation of VEGF was moderately sensitive to rapamycin, implicating a partial involvement of mammalian target of rapamycin (mTOR). However, hypoxia did not further increase the secreted VEGF level of the TTF-1(+) lung cancer cells. The TTF-1-induced VEGF upregulation occurs in both compartments (exosomes and exosome-depleted media (EDM)) of the conditioned media. Surprisingly, the EDM of TTF-1(+) lung cancer cells (designated EDM-TTF-1(+)) displayed an anti-angiogenic activity in the endothelial cell tube formation assay. Mechanistic studies suggest that the increased granulocyte-macrophage colony-stimulating factor (GM-CSF) level in the EDM-TTF-1(+) conferred the antiangiogenic activities. In human lung cancer, the expression of TTF-1 and GM-CSF exhibits a statistically significant and positive correlation. In summary, this study provides evidence that TTF-1 may reprogram lung cancer secreted proteome into an antiangiogenic state, offering a novel basis to account for the long-standing observation of favorable prognosis associated with TTF-1(+) lung adenocarcinomas.

Topics: A549 Cells; Angiogenic Proteins; Antibodies; Blotting, Western; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Culture Media, Conditioned; Cytokines; Enzyme-Linked Immunosorbent Assay; Exosomes; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Indoles; Lung Neoplasms; Neovascularization, Physiologic; Nuclear Proteins; Promoter Regions, Genetic; Pyrroles; Real-Time Polymerase Chain Reaction; RNA Interference; RNA, Small Interfering; Thyroid Nuclear Factor 1; TOR Serine-Threonine Kinases; Transcription Factors; Up-Regulation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2

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

The majority of patients with a diagnosis of cancer die from metastatic disease. Targeting specific steps in the metastatic process has the potential to improve patient outcomes. In this study, a novel lung metastasis model was developed by injecting DiI (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbo-cyanine perchlorate)-labeled Lewis lung carcinoma cells into the tail vein of mice. The temporal development of tumor metastases was studied in the lung, liver and spleen. Additionally, the effects of vascular endothelial growth factor receptor inhibitor SU5416 and platelet activation inhibitor prostacyclin were tested in this metastasis model. Systemically injected Lewis lung carcinoma cells present in the lung at 15 min slowly accumulated in the liver and spleen reaching a peak at 4 days. After 8 days, tumor development was only evident in the lung. Use of SU5416 or prostacyclin lowered the initial density of Lewis lung carcinoma-labeled cells in the lung by a factor 1.8 and 2.3, respectively (P<0.05). Furthermore, treatment with prostacyclin or SU5416 decreased lung weight by over 50% and the number of visible metastatic nodes by over 90% (P<0.05). Combined treatment resulted in grossly normal lung tissue. Additionally, systemic treatment with prostacyclin reduced harvested metastatic cell adherence to endothelial cells by a factor of 10 and treatment with SU5416 attenuated vascular formation (P<0.001). In conclusion, SU5416 and prostacyclin effectively attenuated metastasis formation in this model. DiI labeling is an effective technique to monitor the temporal and spatial distribution of metastatic cells.

Topics: Animals; Carcinoma, Lewis Lung; Cell Adhesion; Cells, Cultured; Disease Progression; Epoprostenol; Indoles; Liver Neoplasms; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Transplantation; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Splenic Neoplasms

SU5416 is a multi-targeted kinase inhibitor that potentially has the ability to directly block tumor growth by inhibiting Kit signaling, as well as blocking angiogenesis by inhibiting vascular endothelial growth factor receptor (VEGFR) signaling. Previous work has demonstrated that SU5416 efficiently blocks Kit-mediated growth of small cell lung cancer (SCLC) in vitro. To determine the drug's effect on in vivo growth of SCLC, we studied its activity, alone and in combination with carboplatin, in chemotherapy-resistant H526, and chemotherapy-sensitive H209 murine xenograft models. SU5416 efficiently inhibited Kit activity in vivo when administered on a twice-weekly schedule. When administered over a 3-week period to animals bearing established tumors, it inhibited growth by at least 70%. It was at least as effective as carboplatin in suppressing growth of H526 xenografts. However, the combination with carboplatin was not superior to the most active single agent in either xenograft model at the doses and schedule utilized. SU5416 clearly inhibited growth in part by inhibiting angiogenesis, with microvessel density dropping by approximately 50% in treated xenografts. In addition to the recognized mechanism of inhibition of VEGFR, we uncovered a novel mechanism of angiogenesis suppression by demonstrating reduced VEGF expression in SU5416-treated xenografts. In vitro, stem cell factor treatment of the H526 cell line enhanced expression of VEGF, which was efficiently blocked with SU5416. Thus, we have demonstrated that SU5416 can inhibit SCLC growth by directly inhibiting tumor cell proliferation and by inhibiting angiogenesis, in part by inhibiting Kit-mediated VEGF expression. These data suggest that kinase inhibitors that target both Kit and VEGFR could play an important role in the treatment of SCLC, as well as other malignancies that express Kit.

Topics: Animals; Carcinoma, Small Cell; Drug Resistance, Neoplasm; Female; Humans; Indoles; Lung Neoplasms; Mice; Mice, Nude; Neovascularization, Pathologic; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyrroles; Transplantation, Heterologous; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

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

Vascular endothelial growth factor (VEGF) is an angiogenic factor that acts by binding to specific high-affinity tyrosine kinase receptors. SU5416 is an antiangiogenic agent that acts as a potent and selective inhibitor of the VEGF Flk-1/KDR receptor tyrosine kinase. SU5416 has been shown to inhibit VEGF-dependent mitogenesis of human endothelial cells and to decrease the growth of xenografts of melanoma, lung carcinoma, ovarian carcinoma, and gliomas. The effect of pre- or perioperative use of this drug on angiogenesis and wound healing in the postoperative setting has not been shown. We sought to analyze the efficacy and safety with respect to functional dosing of SU5416 in the setting of wound healing. This represents an important step forward in the use of this and similar drugs in the perioperative setting of treatment for multiple types of cancers. The use of an inhibitor of VEGF receptors such as SU5416 is distinct and it is likely complementary to other agents in the treatment of such cancers.. We injected 8-week-old male Sprague-Dawley rats with SU5416 (8 or 12 mg/kg) or dimethyl sulfoxide intraperitoneally, daily for 14 days. We then performed a right pulmonary lobectomy and 6-mm full-thickness punch biopsies of the back. Tissue perfusion measured via laser Doppler on Postoperative Day 2 was 1.65, 1.22, and 1.14 perfusion units (P < 0.0004) for control, 8 mg/kg, and 12 mg/kg groups, respectively.. We successfully treated a murine model with functional doses of the anti-VEGF drug SU5416 so as to achieve decreased vascularity and blood flow in postoperative wounds. There was no effect on gross wound healing or infection in either control or treatment groups. Also, no drug-related impairment of histologic healing or decrease in wound tensile strength was demonstrated at either 6 or 14 days.. Preoperative therapy with functional dosing of SU5416 does not appear to have any major effect on postoperative morbidity or mortality in rats. We additionally conclude that preoperative therapy with SU5416 should be investigated further with careful attention to wound integrity.

Topics: Angiogenesis Inhibitors; Animals; Endothelial Growth Factors; Endothelium; Indoles; Lung Neoplasms; Lymphokines; Male; Models, Animal; Neovascularization, Physiologic; Pneumonectomy; Pyrroles; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Wound Healing

Six indolinone tyrosine kinase inhibitors were characterized for their ability to inhibit Kit kinase and for their effects on the growth of small cell lung cancer (SCLC) cell lines. All of the six compounds were potent inhibitors of Kit kinase in a biochemical assay. A homology model of compound binding to the ATP binding site could account for the increased potency observed with the addition of a propionate moiety to the indolinone core but not the increase observed with addition of a chloride moiety. Although all of the compounds tested were potent in the biochemical assay, several exhibited significantly less potency in cellular kinase assays. Their effects on stem cell factor (SCF)-dependent Kit autophosphorylation and SCLC cell growth were also examined. Inhibition of SCF-stimulated Kit activation and cell growth in the H526 cell line was dose-dependent. At concentrations that inhibited SCF-stimulated H526 cell growth, there was little effect on insulin-like growth factor-1-stimulated growth, suggesting that these compounds exhibit reasonable selectivity for inhibition of Kit-mediated proliferation. Higher doses of the compounds were needed to inhibit serum-stimulated growth. Of the six compounds examined, SU5416 and SU6597 demonstrated the best cellular potency and, therefore, their effect on the growth of multiple SCLC cell lines in serum-containing media was examined. In addition to inhibiting proliferation, these compounds also induced significant cell death of several SCLC cell lines, but not of normal human diploid fibroblasts, in complete media. These observations suggest that Kit kinase inhibitors such as these may offer a new approach for inhibiting Kit-mediated proliferation of tumors such as SCLC, gastrointestinal stromal tumors, seminomas, and leukemias.

Topics: Animals; Carcinoma, Small Cell; Cell Division; CHO Cells; Cricetinae; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Growth Inhibitors; Humans; Indoles; Lung Neoplasms; Models, Molecular; Oxindoles; Phosphorylation; Propionates; Proto-Oncogene Proteins c-kit; Pyrroles; Receptor Protein-Tyrosine Kinases; Receptors, Platelet-Derived Growth Factor; Stem Cell Factor; Structure-Activity Relationship; Tumor Cells, Cultured

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