Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572

Schiff, David; Jaeckle, Kurt A.; Anderson, S. Keith; Galanis, Evanthia; Giannini, Caterina; Buckner, Jan C.; Stella, Phillip J.; Flynn, Patrick J.; Erickson, Bradley J.; Schwerkoske, John F.; Kaluza, Vesna; Twohy, Erin; Dancey, Janet; Wright, John J.; Sarkaria, Jann N.

doi:10.1002/cncr.31219

Cited by 48 publications

(28 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite the promising pre-clinical evidence, clinical trials using combined mTOR and Ras/MAPK pathway inhibition of different cancer types have had varied results. In a phase I/II study of patients with recurrent glioblastoma, combination treatment with temsirolimus and sorafenib (Raf kinase and VEGFR-2 inhibitor) led to significant toxicity and lacked efficacy [254]. In phase I studies of everolimus and sorafenib for advanced renal cell cancer, there was enhanced antitumor activity and reasonable tolerability [255,256].…”

Section: Combining Mtor Inhibition With Other Protein Kinase Inhibitorsmentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

172

128

View full text Add to dashboard Cite

Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

show abstract

Section: Combining Mtor Inhibition With Other Protein Kinase Inhibitorsmentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

172

128

View full text Add to dashboard Cite

show abstract

“…Schiff et al also assayed the combined administration of sorafenib plus temsirolimus in patients with recurrent glioblastoma, but at higher doses: 200 mg twice a day for sorafenib and 20 mg/week for temsirolimus. Those authors found a significantly lower prevalence of adverse effects; however, the disease-free survival at 6 months (DFS-6) failed to improve; in fact, a slightly better result was observed in patients who did not received VEGF inhibitors [362]. Hottinger et al assayed the security and efficacy of sorafenib in a phase-I study, establishing as safe a dose of 200 mg twice a day combined with the daily administration of 75 mg/m 2 of TMZ.…”

Section: Sorafenibmentioning

confidence: 96%

“…Temsirolimus was not superior to TMZ in patients with an unmethylated MGMT promoter in glioblastoma [407]. Phase-II studies with recurrent glioblastoma have reported no efficacy of temsirolimus, neither alone nor combined with TMZ, sorafenib, bevacizumab, nor erlotinib [362,408]. Recurrent GBM patients showed no radiological response after a temsirolimus-bevacizumab combined treatment (median PFS was 8 weeks, and OS was 15 weeks) [409].…”

Section: Temsirolimusmentioning

confidence: 99%

See 1 more Smart Citation

Autophagy as a Potential Therapy for Malignant Glioma

et al. 2020

View full text Add to dashboard Cite

Glioma is the most frequent and aggressive type of brain neoplasm, being anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), its most malignant forms. The survival rate in patients with these neoplasms is 15 months after diagnosis, despite a diversity of treatments, including surgery, radiation, chemotherapy, and immunotherapy. The resistance of GBM to various therapies is due to a highly mutated genome; these genetic changes induce a de-regulation of several signaling pathways and result in higher cell proliferation rates, angiogenesis, invasion, and a marked resistance to apoptosis; this latter trait is a hallmark of highly invasive tumor cells, such as glioma cells. Due to a defective apoptosis in gliomas, induced autophagic death can be an alternative to remove tumor cells. Paradoxically, however, autophagy in cancer can promote either a cell death or survival. Modulating the autophagic pathway as a death mechanism for cancer cells has prompted the use of both inhibitors and autophagy inducers. The autophagic process, either as a cancer suppressing or inducing mechanism in high-grade gliomas is discussed in this review, along with therapeutic approaches to inhibit or induce autophagy in pre-clinical and clinical studies, aiming to increase the efficiency of conventional treatments to remove glioma neoplastic cells.

show abstract

“…GBM, the most aggressive and malignant form of gliomas, is distinguished by highly invasive behaviors with tentacle-like projections, making complete surgical removal difficult. Median overall survival of GBM patients is less than 18 months despite the adoption of optimized therapeutic scheme in combination of neurosurgery, chemotherapy, and radiotherapy [ 3 ]. In consideration of the significant toxicity and chemotherapy resistance in treatment, it is necessary to develop other effective strategies, for example, the exploration of potential benefits from traditional herbal formulas for glioblastoma treatment.…”

Section: Introductionmentioning

confidence: 99%

Xihuang Pill Induces Apoptosis of Human Glioblastoma U‐87 MG Cells via Targeting ROS‐Mediated Akt/mTOR/FOXO1 Pathway

Shao

Yin

et al. 2018

Evidence-Based Complementary and Alternative Medicine

View full text Add to dashboard Cite

Xihuang pill (XHP), a traditional Chinese herbal formula, has long been used as an effective agent against multiple tumors. The aim of this study is to evaluate the effects of XHP on the growth inhibition and apoptosis in glioblastoma U-87 MG cells. Gas chromatography-mass spectrometry (GC-MS) was performed for constituent analysis of XHP. Cell viability, cell cycle arrest, generation of reactive oxygen species (ROS), and apoptosis were measured by CCK-8 assay, PI/RNase staining, DCFH-DA assay, TUNEL assay, Annexin V-FITC/PI double staining, and JC-1 assay, respectively. The role of XHP in the regulation of Akt/mTOR/FOXO1 interaction was clarified by using Western Blotting (WB), immunofluorescence (IF), pharmacological inhibitor or antioxidant, and siRNA silencing. The results suggested that XHP could inhibit U-87 MG cells growth and arrest cells in S-phase cell cycle significantly and that the generation of ROS, collapse of mitochondrial membrane potential, enhancement of Bax/Bcl-xL ratio, and reduction of the precursor forms of caspase-9 and caspase-3 caused by XHP prompted that a ROS-mediated mitochondria-dependent apoptosis was possibly involved. Furthermore, XHP affected the Akt/mTOR/FOXO1 pathway via inhibiting the phosphorylation of Akt, mTOR, and FOXO1 and increasing both prototype and nuclear translocation of FOXO1. Inhibition of Akt, mTOR, and FOXO1 by specific inhibitors or siRNA could interpose the apoptotic induction. In conclusion, we demonstrate for the first time that XHP may regulate glioblastoma U-87 MG cell apoptosis via ROS-mediated Akt/mTOR/FOXO1 pathway.

show abstract

Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572

Cited by 48 publications

References 37 publications

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Autophagy as a Potential Therapy for Malignant Glioma

Xihuang Pill Induces Apoptosis of Human Glioblastoma U‐87 MG Cells via Targeting ROS‐Mediated Akt/mTOR/FOXO1 Pathway

Contact Info

Product

Resources

About