Phase I Trial of Everolimus and Capecitabine in Metastatic HER2 − Breast Cancer

Vidal, Gregory A.; Chen, Mary; Sheth, Shreya; Svahn, Tiffany; Guardino, Ellie

doi:10.1016/j.clbc.2017.03.003

Cited by 5 publications

(2 citation statements)

References 26 publications

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“…In a phase Ib study of everolimus plus mFOLFOX-6, a combination chemotherapy regimen of 5-FU, folinic acid, and oxaliplatin, 83% of patients with metastatic gastroesophageal adenocarcinoma experienced a partial response [276]. In phase I trials of everolimus combined with capecitabine, which is a pro-drug of 5-FU, the treatment was found to be well tolerated and safe with promising clinical benefit in metastatic triple negative breast cancer and in advanced solid malignancies [302,303]. Gemcitabine is a nucleoside analogue used to treat several types of cancers.…”

Section: Co-targeting Mtor and Metabolismmentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

165

128

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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.

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Section: Co-targeting Mtor and Metabolismmentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

165

128

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“…However, its poor solubility and low bioavailability renders it inefficient for the treatment of cancer and leads to the development of numerous rapamycin derivatives known as rapalogs, two of which have already been approved by the FDA for the use in cancer therapy (temsirolimus and everolinus since 2007 and 2009, respectively)(Dufour et al 2011;Hudes et al 2007; Motzer et al 2008;Waldner et al 2016). For example, everolimus was approved for patients with progressive neuroendocrine tumors of pancreatic origin(Feldmann et al 2012; Thompson et al 2012;Vidal et al 2017;Yao et al 2013; Yao et al 2011). This rapalog has also shown potential in treating patients with advanced gastric cancer(Cejka et al 2008; Doi et al et al 2013;Taguchi et al 2011) and advanced non-small cell lung cancer(Besse et al 2014;Dong et al 2012;Singhal et al 2015).…”

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confidence: 99%

mTOR signalling: jack-of-all-trades

Hiani

Egom

Dong

2019

Biochem. Cell Biol.

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The mechanistic target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that senses and integrates environmental information into cellular regulation and homeostasis. Accumulating evidence has suggested a master role of mTOR signalling in many fundamental aspects of cell biology and organismal development. mTOR deregulation is implicated in a broad range of pathological conditions, including diabetes, cancer, neurodegenerative diseases, myopathies, inflammatory, infectious, and autoimmune conditions. Here, we review recent advances in our knowledge of mTOR signalling in mammalian physiology. We also discuss the impact of mTOR alteration in human diseases and how targeting mTOR function can treat human diseases.

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