Phase I study of safety and tolerability of sunitinib in combination with sirolimus in patients with refractory solid malignancies and determination of VEGF (VEGF-A) and soluble VEGF-R2 (sVEGFR2) in plasma

Li, Jia; Kluger, Harriet M.; Devine, Lesley; Lee, James J.; Kelly, William Kevin; Rink, Linda; Saif, Muhammad Wasif

doi:10.1007/s00280-016-3033-7

Cited by 8 publications

(4 citation statements)

References 25 publications

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“…As mTOR inhibitors, temsirolimus and everolimus had been approved by FDA for the treatment of patients with metastatic renal cell carcinoma 32 , 33 . Although rapamycin (sirolimus) was usually used as immunosuppressant for organ transplantation 34 , the role of rapamycin in inhibiting the protein kinase activity of mTOR and anitproliferative ability makes it a potential anticancer agent 30 , 31 . Preclinical studies have suggested that the combination of rapamycin with a VEGF antibody or trastuzumab exhibited a synergistic antitumor effect in a pancreatic or breast cancer model, respectively 35 , 36 .…”

Section: Discussionmentioning

confidence: 99%

“…However, many clinical trials did not show the desired pharmacological properties 37 . A phase I study indicated that a combination of sunitinib and rapamycin is unacceptable due to irresistible toxicities in patients with refractory solid malignancies including CRC 34 . Therefore, it is a long way to go before it could be used in the clinic.…”

Section: Discussionmentioning

confidence: 99%

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CENPH Inhibits Rapamycin Sensitivity by Regulating GOLPH3-dependent mTOR Signaling Pathway in Colorectal Cancer

Wang

et al. 2017

J. Cancer

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Background: Centromere protein H (CENPH) is known as a fundamental component of the active centromere complex, and its overexpression is correlated with poor prognosis in various solid tumors. mTOR inhibitor rapamycin has been shown to possess antitumor activity, as well as prevent intestinal tumorigenesis. However, the prognostic value of CENPH in colorectal cancer (CRC) and the role of CENPH in rapamycin sensitivity remain unknown.Materials and methods: The effect of CENPH on the cell proliferation, clonogenicity, and cell response to rapamycin in CRC were evaluated by MTT and/or colony formation assays. For the underlying mechanisms, the interaction between CENPH and GOLPH3 were detected by co-immunoprecipitation, GST pull-down, and His-tag pull-down assays, as well as the laser scanning confocal microscopy. The status of kinases in mTOR signaling was determined by Western blot. Finally, the clinical significance of CENPH was analyzed using public CRC datasets with CENPH transcripts and clinical information.Results: CENPH inhibited CRC malignant phenotypes, conferred reduced sensitivity to rapamycin, and attenuated both mTORC1 and mTORC2 in mTOR signaling pathway through the interaction with golgi phosphoprotein 3 (GOLPH3), which has been identified as a potential oncogene and modulates the response to rapamycin. Moreover, elevated levels of CENPH were detected in CRC tissues, compared with normal colorectal tissues. High levels of CENPH expression gradually decreased according to CRC tumor stages. Patients with high CENPH expression had favorable survival.Conclusions: Our results suggest that CENPH inhibits rapamycin sensitivity by regulating GOLPH3 dependent mTOR pathway. High CENPH expression is associated with better prognosis in CRC patients. Taken together, CENPH may serve as a potential predictor for rapamycin sensitivity and therapeutic target for CRC patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CENPH Inhibits Rapamycin Sensitivity by Regulating GOLPH3-dependent mTOR Signaling Pathway in Colorectal Cancer

Wang

et al. 2017

J. Cancer

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“… 6 , 7 Combination therapies of TKI/m-TOR inhibitors have not proven superior to single agents. 10 , 11 …”

Section: Introductionmentioning

confidence: 99%

Combining Sunitinib and Bevacizumab for the Management of Advanced Renal Cell Carcinoma: A Phase I/II Trial

et al. 2023

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Background Tyrosine kinase inhibitors remain a cornerstone in managing metastatic clear cell renal cell carcinoma (RCC). The 4 weeks on/2 weeks off intermittent sunitinib schedule could result in rebound angiogenesis and tumor progression in the 2-week rest period. We propose using bevacizumab during this period for continuous antiangiogenic effects. Method This was a phase I/II study of patients with advanced clear cell RCC. Sunitinib was given 50 mg daily on a 4-week on/2-week off schedule. Bevacizumab was given on day 29 of each sunitinib cycle. The bevacizumab starting dose was 5 mg/kg, and the dose was escalated to 10 mg if there was no dose-limiting toxicity. The primary endpoints were response rate and progression-free survival (PFS). Results Twenty-five patients were recruited. The study was closed prematurely because of poor accrual. No dose-limiting toxicity was observed with 5 mg bevacizumab. One patient achieved a complete response, and 12 achieved a partial response (52% response rate). At a median follow-up of 42.2 months (95%, confidence interval (CI) 32.9 to 51.4), the median PFS duration was 16.5 months (95% CI 4.1-28.8), and the median overall survival time was 33.3 months (95% CI 19.4-47.3). Twenty-two patients (88%) had at least one grade 3 or 4 toxicity; the most common were thrombocytopenia (32%), lymphopenia (32%), hypertension (28%), and fatigue (24%). Conclusion Continuous angiogenesis blockade by adding bevacizumab to the sunitinib on/off regimen for advanced RCC yields significant antitumor activity with manageable increased toxicity.

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“…Furthermore, doxorubicin has been used for the therapy of leukemia and soft tissue and bone sarcomas for several years 21 . Rapamycin (sirolimus), another macrolide antibiotic isolated from Streptomyces sp., originally approved by FDA for use as an immunosuppressive agent, is being currently evaluated the safety and tolerability when used in combination with sunitinib for the treatment of solid tumors during Phase I study 22,23 . In our study of secondary metabolites from Streptomyces sp., one of the constituents, JBIR‐100, 24 a macrolide that displays a spectrum of activities, including anti‐microbial 25 and anti‐cancer 24 .…”

Section: Introductionmentioning

confidence: 99%

A macrolide from Streptomyces sp. modulates apoptosis and autophagy through Mcl‐1 downregulation in human breast cancer cells

Chiu

et al. 2021

Environmental Toxicology

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Secondary metabolites in marine organisms exhibit various pharmacological activities against diseases, such as cancer. In this study, the anti‐proliferative effect of JBIR‐100, a macrolide isolated from Streptomyces sp., was investigated in breast cancer cells. Cell growth was inhibited in response to JBIR‐100 treatment concentration‐ and time‐dependently in both MCF‐7 and MDA‐MB‐231 breast cancer cells. JBIR‐100 caused apoptosis, as verified by caspase activation and the cleavage of PARP. Western blotting revealed that JBIR‐100 modulated the expression of Akt/NF‐κB signaling components and Bcl‐2 family members. Overexpression of Mcl‐1 partially rescued MCF‐7 cells from JBIR‐100‐induced cytotoxicity. In addition, transmission electron microscopy analyses, confocal analysis, and western blot assay indicated that JBIR‐100 inhibited autophagy in MCF‐7 cells. Exposure to the autophagy inhibitor did not synergize JBIR‐100‐induced apoptosis. In summary, our results suggested that JBIR‐100 may be potentially used for breast cancer therapy.

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Phase I study of safety and tolerability of sunitinib in combination with sirolimus in patients with refractory solid malignancies and determination of VEGF (VEGF-A) and soluble VEGF-R2 (sVEGFR2) in plasma

Abstract: Toxicity precluded dose escalation of weekly sirolimus in combination with a standard sunitinib dose/schedule. These results suggest caution when combining targeted agents lacking specificity for tumor signaling or vasculature.

Cited by 8 publications

References 25 publications

CENPH Inhibits Rapamycin Sensitivity by Regulating GOLPH3-dependent mTOR Signaling Pathway in Colorectal Cancer

CENPH Inhibits Rapamycin Sensitivity by Regulating GOLPH3-dependent mTOR Signaling Pathway in Colorectal Cancer

Combining Sunitinib and Bevacizumab for the Management of Advanced Renal Cell Carcinoma: A Phase I/II Trial

A macrolide from Streptomyces sp. modulates apoptosis and autophagy through Mcl‐1 downregulation in human breast cancer cells

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