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144 records · Page 8Linked to original sources
PubMed2003

SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer.

The purpose of this study was to evaluate the activity of the indolinone kinase inhibitor SU11248 against the receptor tyrosine kinase KIT in vitro and in vivo, examine the role of KIT in small cell lung cancer (SCLC), and anticipate clinical utility of SU11248 in SCLC. SU11248 is an oral, multitargeted tyrosine kinase inhibitor with direct antitumor and antiangiogenic activity through targeting platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor, KIT, and FLT3 receptors. Treatment of the KIT-expressing SCLC-derived NCI-H526 cell line in vitro with SU11248 resulted in dose-dependent inhibition of stem cell factor-stimulated KIT phosphotyrosine levels and proliferation. The biological significance of KIT inhibition was evaluated in vivo by treating mice bearing s.c. NCI-H526 tumors with SU11248 or another structurally unrelated KIT inhibitor, STI571 (Gleevec), which is also known to inhibit Bcr-Abl and PDGFRbeta. SU11248 treatment resulted in significant tumor growth inhibition, whereas inhibition from STI571 treatment was less dramatic. Both compounds reduced phospho-KIT levels in NCI-H526 tumors, with a greater reduction by SU11248, correlating with efficacy. Likewise, phospho-PDGFRbeta levels contributed by tumor stroma and with known involvement in angiogenesis were strongly inhibited by SU11248 and less so by STI571. Because platinum-based chemotherapy is part of the standard of care for SCLC, SU11248 was combined with cisplatin, and significant tumor growth delay was measured compared with either agent alone. These results expand the profile of SU11248 as a KIT signaling inhibitor and suggest that SU11248 may have clinical potential in the treatment of SCLC via direct antitumor activity mediated via KIT as well as tumor angiogenesis via vascular endothelial growth factor receptor FLK1/KDR and PDGFRbeta.

Animals↗
PubMed2003

SU11248 maintenance therapy prevents tumor regrowth after fractionated irradiation of murine tumor models.

Receptor tyrosine kinase activation contributes to cell viability during cytotoxic therapy. The novel broad spectrum receptor tyrosine kinase inhibitor, SU11248, inhibits vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor, c-kit, and fetal liver tyrosine kinase 3. In this study, we maintained SU11248 plasma levels beyond the completion of radiotherapy to determine whether tumor regrowth can be delayed. The antiangiogenic effects of SU11248 were demonstrated using human umbilical vein endothelial cells in vitro. Apoptosis increased and clonogenic survival decreased when SU11248 was used in combination with radiation from 0 to 6 Gy on endothelial cells. In vivo tumor growth delay was increased in C57B6J mice with Lewis lung carcinoma or glioblastoma multiform (GL261) hind limb tumors. Mice were treated with daily i.p. injections (40 mg/kg) of SU11248 during 7 days of radiation treatment (21 Gy). Combined treatment with SU11248 and radiation significantly reduced tumor volume as compared with either treatment alone. Concomitant reduction in vasculature was confirmed using the dorsal vascular window model. The vascular length established using images taken from a consistent quadrant in the window show the combination therapy was more effective in destroying tumor vasculature than either treatment alone. SU11248 maintenance administration beyond the completion of radiotherapy results in prolongation of tumor control. In summary, SU11248 enhances radiation-induced endothelial cytotoxicity, resulting in tumor vascular destruction and tumor control when combined with fractionated radiotherapy in murine tumor models. Moreover, inhibition of angiogenesis well beyond radiation therapy may be a promising treatment paradigm for refractory human neoplasms.

Angiogenesis Inhibitors↗
PubMed2003

Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with "standard of care" therapeutic agents for the treatment of breast cancer.

SU11248 is an oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities through targeting platelet-derived growth factor receptor, vascular endothelial growth factor receptor, KIT, and FLT3, the first three of which are expressed in human breast cancer and/or its supporting tissues. The purpose of the present studies was to demonstrate the potent anticancer activity of SU11248 alone or in combination with conventional cytotoxic agents against several distinct preclinical models of breast cancer. SU11248 was administered as a monotherapy to (1) mouse mammary tumor virus-v-Ha-ras mice and 7,12-dimethylbenz(a)anthracene-treated rats bearing mammary tumors and (2) mice bearing human breast cancer xenografts of s.c. MX-1 tumors and osseous metastasis of a MDA-MB-435-derived cell line (435/HAL-Luc). SU11248 was also administered in combination with docetaxel both in xenograft models and in combination with 5-fluorouracil and doxorubicin in the MX-1 model. SU11248 treatment potently regressed growth of mammary cancers in mouse mammary tumor virus-v-Ha-ras transgenic mice (82% regression) and 7,12-dimethylbenz(a)anthracene-induced mammary tumors in rats (99% regression at the highest dose; P < 0.05 for both). This agent also inhibited MX-1 tumor growth by 52%, with markedly enhanced anticancer effects when administered in combination with docetaxel, 5-fluorouracil, or doxorubicin compared with either agent alone (P < 0.05). SU11248 treatment in combination with docetaxel effectively prolonged survival of mice, with 435/HAL-Luc cancer xenografts established in bone compared with either agent alone (P < 0.05). These results demonstrate that SU11248 is effective in preclinical breast cancer models and suggest that it may be useful in the treatment of breast cancer in the clinic.

Animals↗
PubMed2003

[Current screening for molecular target therapy of cancer].

Recent progress in molecular biology and cancer biology has revealed that many molecules, which are heavily involved in the un-limited growth, anti-apoptotic effects and invasion of tumors, would be targets of cancer therapy. Part of the drugs which inhibit these molecules have shown clinical response as well as clinical benefits. In this review article, the summary of mechanism based drug screening for cancer as well as recent status of new molecular target drugs for cancer, are described.

Angiogenesis Inhibitors↗
PubMed2003

An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients.

PURPOSE: Obtaining direct and rapid proof of molecular activity in early clinical trials is critical for optimal clinical development of novel targeted therapies. SU11248 is an oral multitargeted kinase inhibitor with selectivity for fms-related tyrosine kinase 3/Flk2 (FLT3), platelet-derived growth factor receptor alpha/beta, vascular endothelial growth factor receptor 1/2, and KIT receptor tyrosine kinases. FLT3 is a promising candidate for targeted therapy in acute myeloid leukemia (AML), because activating mutations occur in up to 30% of patients. We conducted an innovative single-dose clinical study with a primary objective to demonstrate inhibition of FLT3 phosphorylation by SU11248 in AML. EXPERIMENTAL DESIGN: Twenty-nine AML patients each received a single dose of SU11248, escalated from 50 to 350 mg, in increments of 50 mg and cohorts of three to six patients. FLT3 phosphorylation and plasma pharmacokinetics were evaluated at seven time points over 48 h after SU11248 administration, and FLT3 genotype was determined. Study drug-related adverse events occurred in 31% of patients, mainly grade 1 or 2 diarrhea and nausea, at higher dose levels. RESULTS: Inhibition of FLT3 phosphorylation was apparent in 50% of FLT3-wild-type (WT) patients and in 100% of FLT3-mutant patients. FLT3 internal tandem duplication (ITD) mutants showed increased sensitivity relative to FLT3-WT, consistent with preclinical predictions. The primary end point, strong inhibition of FLT3 phosphorylation in >50% patients, was reached in 200 mg and higher dose cohorts. Downstream signaling pathways were also inhibited; signal transducer and activator of transcription 5 (STAT5) was reduced primarily in internal tandem duplication patients and at late time points in FLT3-WT patients, whereas extracellular signal-regulated kinase (ERK) activity was reduced in the majority of patients, independent of FLT3 inhibition. CONCLUSIONS: This novel translational study bridges preclinical models to the patient setting and provides the first evidence of anti-FLT3 activity in patients. Proof of target inhibition accomplishes a crucial milestone in the development of novel oncology therapeutics.

Administration, Oral↗
PubMed2004

Su-11248 Sugen.

SUGEN is developing SU-11248, an orally active inhibitor of platelet-derived growth factor tyrosine kinase (TK) and other TK signaling pathways, as a potential anticancer agent. By October 2003, phase III trials for gastrointestinal stromal tumors and renal cell carcinoma were underway.

Animals↗
PubMed2005

Sonographic depiction of changes of tumor vascularity in response to various therapies.

PURPOSE: To evaluate the diagnostic accuracy of power Doppler sonography for the depiction of changes in tumor vascularity with various therapeutic regimens. MATERIALS AND METHODS: Tumor cells were implanted subcutaneously in thirty-two mice and assigned to four treatment groups: control, radiation therapy, antiangiogenesis therapy (VEGF [vascular endothelial growth factor] receptor antagonist, SU11248), or combined antiangiogenesis and radiation therapy. Twenty of these mice were scanned with power Doppler sonography at two time points over the course of treatment, and power-weighted pixel densities were assessed. The other twelve mice each underwent subcutaneous placement of a dorsal skin-fold window over the tumor site, allowing for daily angiogenesis assessment of vascular length density. All tumor specimens had correlative histologic analyses performed, including immunohistochemical stains for microvasculature. RESULTS: Sonographic measurements revealed significant longitudinal differences in tumor vascularity among the four treatment groups: control mice receiving no treatment demonstrated a doubling in intra-tumor color pixel density (P < 0.02); those receiving radiation alone increased by 68% (P < 0.04); those receiving oral therapy alone increased by 44% (P = 0.016); and those receiving combination therapy decreased by 38% (P < 0.02). Tumor vascularity independently measured in the twelve mice with the skin-fold windows revealed a similar response to each type of treatment. Post-mortem tumor histology was consistent with both sonographic and skin-fold window measurements. CONCLUSION: Power Doppler sonography was accurate and reliable in measuring tumor vascularity changes in this model. These results were independently confirmed by a quantitative method relying on direct visualization of the microvasculature. Because it is rapid and non-invasive, sonographic quantification is beneficial in assessing the anti-angiogenic effects of various treatment strategies for cancer.

Angiogenesis Inhibitors↗
PubMed2004

Novel agents for the treatment of advanced kidney cancer.

Advanced kidney cancer accounts for over 12,000 deaths in the United States each year. Immunotherapy, typically interleukin-2 or interferon-alpha, have been the mainstay of treatment. Response rates are low for these immune-based treatments, and most patients with advanced kidney cancer succumb to their disease. There are several novel agents currently in clinical trials that show promise in this refractory disease. These compounds include antiangiogenic agents, raf kinase pathway inhibitors, and novel antimicrotubule agents. This review discusses some of the agents currently being explored for the treatment of advanced kidney cancer.

Angiogenesis Inhibitors↗
PubMed2006

[Progress in therapeutic strategy for renal cell carcinoma].

The standard treatment for renal cell carcinoma (RCC) is surgery. Partial nephrectomy is often performed for treatment of small RCC. Radiofrequency ablation (RFA) offers another nephron-sparing minimally invasive approach. It is most successful for tumors not larger than 3 cm in diameter. The rate of severe complications of RFA is low. Further studies are necessary to determine the long-term efficacy of RFA in RCC. Metastatic RCC is currently mainly treated with cytokine-based therapy. Transient responses and moderate survival advantages have been achieved in a subset of patients. New therapies such as targeted molecular therapies are being developed to improve efficacy and treat those patients who are resistant to systemic immunotherapy. Targeted molecular therapies include inhibition of the Raf kinase pathway, inhibition of its receptor kinases, anti-vascular endothelial growth factor monoclonal antibody or the mammalian target of rapamycin pathway. Further clinical research will be required to develop a more effective therapy and the application of combined treatment modalities.

Antibodies, Monoclonal↗
PubMed2006

[Molecular-targeted agents in breast cancer].

Recently, molecular-biological analyses of the mechanisms of cancer development have created new anticancer agents, molecular-targeted agents. Among them, the humanized anti-HER 2 monoclonal antibody, trastuzumab (Herceptin), has been available for clinical use in metastatic breast cancer in Japan since June, 2001. Now, it has become one of the key drugs for metastatic breast cancer. Recently, large-scale randomized trials revealed its usefulness in the adjuvant setting of postoperative breast cancer. Furthermore, a new anti-angiogenic agent, bevacizumab, showed significant survival benefits with paclitaxel in metastatic breast cancer. This paper reviews the details of these molecular-targeted agents are reviewed in clinical studies.

Adult↗