A Phase I Trial of Sunitinib and Rapamycin in Patients with Advanced Non-Small Cell Lung Cancer

Waqar, Saiama N.; Gopalan, Priya; Williams, Kristina; Devarakonda, Siddhartha; Govindan, Ramaswamy

doi:10.1159/000348584

Cited by 17 publications

(8 citation statements)

References 20 publications

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“…Rapamycin selectively targets mTOR to stimulate autophagy, while CQ is known to disrupt autophagosome-lysosome fusion, leading to the accumulation of autophagic vacuoles, as demonstrated by a marked accumulation of LC3II [43, 44]. Importantly, CQ has been used to overcome resistance of lung carcinoma cells to different chemotheraputics such as the dual PI3K/mTOR inhibitor PI103 and crizotinib [45, 46], while rapamycin has been administrated in a phase I trial of patients with advanced non-small cell lung cancer [47]. The two compounds had no effect on cell viability at the concentrations used in our preliminary trial.…”

Section: Resultsmentioning

confidence: 99%

Pharmacological modulation of autophagy enhances Newcastle disease virus-mediated oncolysis in drug-resistant lung cancer cells

Jiang

Zhu

et al. 2014

BMC Cancer

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BackgroundOncolytic viruses represent a promising therapy against cancers with acquired drug resistance. However, low efficacy limits its clinical application. The objective of this study is to investigate whether pharmacologically modulating autophagy could enhance oncolytic Newcastle disease virus (NDV) strain NDV/FMW virotherapy of drug-resistant lung cancer cells.MethodsThe effect of NDV/FMW infection on autophagy machinery in A549 lung cancer cell lines resistant to cisplatin (A549/DDP) or paclitaxel (A549/PTX) was investigated by detection of GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3) puncta, formation of double-membrane vesicles and conversion of the nonlipidated form of LC3 (LC3-I) to the phosphatidylethanolamine-conjugated form (LC3-II). The effects of autophagy inhibitor chloroquine (CQ) and autophagy inducer rapamycin on NDV/FMW-mediated antitumor activity were evaluated both in culture cells and in mice bearing drug-resistant lung cancer cells.ResultsWe show that NDV/FMW triggers autophagy in A549/PTX cells via dampening the class I PI3K/Akt/mTOR/p70S6K pathway, which inhibits autophagy. On the contrary, NDV/FMW infection attenuates the autophagic process in A549/DDP cells through the activation of the negative regulatory pathway. Furthermore, combination with CQ or knockdown of ATG5 significantly enhances NDV/FMW-mediated antitumor effects on A549/DDP cells, while the oncolytic efficacy of NDV/FMW in A549/PTX cells is significantly improved by rapamycin. Interestingly, autophagy modulation does not increase virus progeny in these drug resistant cells. Importantly, CQ or rapamycin significantly potentiates NDV/FMW oncolytic activity in mice bearing A549/DDP or A549/PTX cells respectively.ConclusionsThese results demonstrate that combination treatment with autophagy modulators is an effective strategy to augment the therapeutic activity of NDV/FMW against drug-resistant lung cancers.

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Section: Resultsmentioning

confidence: 99%

Pharmacological modulation of autophagy enhances Newcastle disease virus-mediated oncolysis in drug-resistant lung cancer cells

Jiang

Zhu

et al. 2014

BMC Cancer

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“…Endostar has also shown antitumor activity in vitro in a murine tumor model of broad-spectrum cancers (such as S180 sarcoma and H22 hepatocellular carcinoma cells). is also used to treat numerous other types of solid tumors, including breast, lung, prostatic and colorectal cancer (10)(11)(12)(13). For example, the efficacy of the TKIs imatinib (Gleevec) and sunitinib (Sutent) in patients with advanced gastrointestinal stromal tumors (GISTs) has been demonstrated by observations in the clinic, a disease for which there were previously no highly effective treatment options for metastatic disease.…”

Section: Discussionmentioning

confidence: 99%

Pleural synovial sarcoma patient treated with combined chemotherapy and Endostar, plus sunitinib maintenance therapy: A case report and review of the literature

Teng

Shen

et al. 2015

Oncology Letters

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Synovial sarcoma is a rare, highly malignant soft-tissue tumor that occurs primarily in the extremities. At present, there is no effective clinical treatment for this condition. The present study reports the case of a 49-year-old male who was diagnosed with pleural synovial sarcoma and treated with recombinant human endostatin (Endostar) combined with chemotherapy for a total of six cycles, followed by sunitinib maintenance therapy. To the best of our knowledge, this is the first reported use of sunitinib for maintenance therapy in pleural synovial sarcoma. The patient survived for 25 months after the recurrence of the disease following surgery. The results indicate that this combination therapy was effective in the treatment of pleural synovial sarcoma. The present study also briefly reviews the literature on pleural synovial sarcoma, and the features and treatments for this rare case are discussed.

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“…Its activity against other tumor types such as hepatocellular carcinoma or non-small cell lung cancer is currently investigated in numerous clinical trials [5,6]. Although SUN has improved survival rates in patients with RCC and GIST, several adverse effects have been reported, such as gastrointestinal disturbances, skin abnormalities, arthralgia, mucositis, aesthesia and altered sense of taste [7].…”

Section: Introductionmentioning

confidence: 99%

Mitogen-Activated Protein Kinases Pathways Mediate the Sunitinib-Induced Hypertrophy in Rat Cardiomyocyte H9c2 Cells

et al. 2014

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Sunitinib (SUN) is a multi-targeted tyrosine kinase inhibitor used for the treatment of gastrointestinal stromal tumors and renal cell carcinoma. Cardiotoxicity has been reported as a significant side effect associated with the SUN treatment, yet the mechanism is poorly understood. The main purpose of this study was to investigate the potential effects of SUN on cardiac hypertrophic genes and the role of mitogen-activated protein kinases (MAPKs) signaling pathway in rat cardiomyocyte H9c2 cell line. In the present study, real-time quantitative polymerase chain reaction showed that the treatment of H9c2 cells with increasing concentrations of SUN (0, 1, 2.5, and 5 µM) significantly induced hypertrophic gene markers, such as brain natriuretic peptides (BNP) and myosin heavy chain (β-MHC and α-MHC) in concentration- and time-dependent manners. The onset of mRNA induction was observed as early as 9 h and remained elevated for at least 18 h after treatment with SUN 5 µM. At the protein level, Western blot analysis showed that SUN increased BNP and β-MHC, while it inhibited α-MHC protein levels in a concentration-dependent manner. These SUN-mediated effects were associated with increase in cell size and hypertrophy by approximately 70 % at the highest concentration, 5 µM. Importantly, inhibition of the MAPK signaling pathway using SB203580 (p38 MAPK inhibitor), U0126 (extracellular signal-regulated kinase inhibitor), and SP600125 (c-Jun NH2-terminal kinase inhibitor) significantly potentiated the SUN-induced BNP and β-MHC mRNA levels, but did alter the α-MHC level. Whereas at the protein level, MAPK inhibitors generally decreased the SUN-induced BNP, whereas only SB and U0 increased β-MHC protein levels with no effect on α-MHC, which were associated with a significant decrease in cell size. Together, these results indicate that SUN induced hypertrophic gene expression through MAPK-dependent mechanisms.

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A Phase I Trial of Sunitinib and Rapamycin in Patients with Advanced Non-Small Cell Lung Cancer

Cited by 17 publications

References 20 publications

Pharmacological modulation of autophagy enhances Newcastle disease virus-mediated oncolysis in drug-resistant lung cancer cells

Pharmacological modulation of autophagy enhances Newcastle disease virus-mediated oncolysis in drug-resistant lung cancer cells

Pleural synovial sarcoma patient treated with combined chemotherapy and Endostar, plus sunitinib maintenance therapy: A case report and review of the literature

Mitogen-Activated Protein Kinases Pathways Mediate the Sunitinib-Induced Hypertrophy in Rat Cardiomyocyte H9c2 Cells

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