Everolimus with paclitaxel and carboplatin as first-line treatment for metastatic large-cell neuroendocrine lung carcinoma: a multicenter phase II trial

Christopoulos, Petros; Engel-Riedel, Walburga; Grohé, Christian; Kropf-Sanchen, Cornelia; Pawel, Joachim von; Gütz, S; Kollmeier, Jens; Eberhardt, Wilfried; Ukena, D.; Baum, Volker; Nimmrich, Inko; Sieder, Christian; Schnabel, Philipp A.; Serke, Monika; Thomas, Michael

doi:10.1093/annonc/mdx268

Cited by 56 publications

(56 citation statements)

References 31 publications

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“…The results from a phase II clinical trial combining carboplatinpaclitaxel chemotherapy with daily everolimus maintenance treatment (mTOR [first generation]) showed encouraging results. 78 However, the survival results were only slightly better than those reported for an European chemotherapy phase II trial 67 and a retrospective study with taxane chemotherapy. 72 Evaluation of RB1 status and mTOR pathway genes might be interesting to select patients with LCNEC with improved treatment response.…”

Section: Lcnecmentioning

confidence: 71%

New Insights into the Molecular Characteristics of Pulmonary Carcinoids and Large Cell Neuroendocrine Carcinomas, and the Impact on Their Clinical Management

Derks

Leblay

Lantuéjoul

et al. 2018

Journal of Thoracic Oncology

115

103

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Carcinoids and large cell neuroendocrine carcinomas (LCNECs) are rare neuroendocrine lung tumors. Here we provide an overview of the most updated data on the molecular characteristics of these diseases. Recent genomic studies showed that carcinoids generally contain a low mutational burden and few recurrently mutated genes. Most of the reported mutations occur in chromatin-remodeling genes (e.g., menin 1 gene [MEN1]), and few affect genes of the phosphoinositide 3-kinase (PI3K)-AKT-mechanistic target of rapamycin gene pathway. Aggressive disease has been related to chromothripsis, DNA-repair gene mutations, loss of orthopedia homeobox/CD44, and upregulation of ret proto-oncogene gene (RET) gene expression. In the case of LCNECs, which present with a high mutation burden, two major molecular subtypes have been identified: one with biallelic inactivation of tumor protein p53 gene (TP53) and retinoblastoma gene (RB1), a hallmark of SCLC; and the other one with biallelic inactivation of TP53 and serine/threonine kinase 11 gene (STK11)/kelch like ECH associated protein 1 gene (KEAP1), genes that are frequently mutated in NSCLC. These data, together with the identification of common mutations in the different components of combined LCNEC tumors, provide further evidence of the close molecular relation of LCNEC with other lung tumor types. In terms of therapeutic options, future studies should explore the association between mechanistic target of rapamycin pathway mutations and response to mechanistic target of rapamycin inhibitors in carcinoids. For LCNEC, preliminary data suggest that the two molecular subtypes might have a predictive value for chemotherapy response, but this observation needs to be validated in randomized prospective clinical trials. Finally, delta like Notch canonical ligand 3 inhibitors and immunotherapy may provide alternative options for patient-tailored therapy in LCNEC.

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Section: Lcnecmentioning

confidence: 71%

New Insights into the Molecular Characteristics of Pulmonary Carcinoids and Large Cell Neuroendocrine Carcinomas, and the Impact on Their Clinical Management

Derks

Leblay

Lantuéjoul

et al. 2018

Journal of Thoracic Oncology

115

103

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“…mTOR inhibitor combination therapy has also shown activity in many types of lung cancer. Christopoulos et al [79] reported that carboplatin and paclitaxel combined with everolimus were effective and well-tolerated in patients with metastatic large-cell neuroendocrine carcinoma (LCNEC). In addition, Hai et al [80] showed that the combined use of mTOR and Wee1 inhibitors could synergically inhibit KRAS mutated NSCLC cell lines.…”

Section: Combination Therapy With Mtor Inhibitorsmentioning

confidence: 99%

“…Chen et al [78] Rapamycin AR inhibitor enzalutamide HCC Rapamycin inhibits the AKT/mTOR signaling pathway activated by enzalutamide, while enzalutamide inhibits the up-regulation of AR expression caused by rapamycin Zhang et al [77] Everolimus Carboplatin and paclitaxel LCNEC They improve the overall response rate and disease control rate Christopoulos et al [79] AZD2014…”

Section: Conclusion and Prospectmentioning

confidence: 99%

mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges

et al. 2020

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Mammalian target of rapamycin (mTOR) regulates cell proliferation, autophagy, and apoptosis by participating in multiple signaling pathways in the body. Studies have shown that the mTOR signaling pathway is also associated with cancer, arthritis, insulin resistance, osteoporosis, and other diseases. The mTOR signaling pathway, which is often activated in tumors, not only regulates gene transcription and protein synthesis to regulate cell proliferation and immune cell differentiation but also plays an important role in tumor metabolism. Therefore, the mTOR signaling pathway is a hot target in anti-tumor therapy research. In recent years, a variety of newly discovered mTOR inhibitors have entered clinical studies, and a variety of drugs have been proven to have high activity in combination with mTOR inhibitors. The purpose of this review is to introduce the role of mTOR signaling pathway on apoptosis, autophagy, growth, and metabolism of tumor cells, and to introduce the research progress of mTOR inhibitors in the tumor field.

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“…However, the addition of everolimus to carboplatin in patients with metastatic prostate cancer had minimal clinical efficacy [265]. In a phase II clinical trial of everolimus combined with paclitaxel, which blocks the cell cycle by stabilizing the microtubules, and carboplatin as first-line treatment for metastatic large-cell neuroendocrine lung carcinoma, the treatment was well tolerated and displayed efficacy [267]. In a randomized phase II study in patients with triple negative breast cancer, addition of everolimus to the paclitaxel/cisplatin combination was associated with more adverse events without improvement in clinical response compared to paclitaxel/cisplatin treatment [268].…”

Section: Combining Mtor Inhibition With Conventional Chemotherapies Amentioning

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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Everolimus with paclitaxel and carboplatin as first-line treatment for metastatic large-cell neuroendocrine lung carcinoma: a multicenter phase II trial

Abstract: EudraCT number 2010-022273-34, NCT01317615.

Cited by 56 publications

References 31 publications

New Insights into the Molecular Characteristics of Pulmonary Carcinoids and Large Cell Neuroendocrine Carcinomas, and the Impact on Their Clinical Management

New Insights into the Molecular Characteristics of Pulmonary Carcinoids and Large Cell Neuroendocrine Carcinomas, and the Impact on Their Clinical Management

mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

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