Phase I study of temsirolimus in combination with cetuximab in patients with advanced solid tumours

Hollebecque, Antoine; Bahleda, Rastilav; Faivre, Laurence; Adam, Julien; Poinsignon, Vianney; Paci, Angélo; Gomez‐Roca, Carlos; Thery, Jean Christophe; Deley, Marie-Cécile Le; Varga, Andréa; Gazzah, A.; Ileana, Ecaterina; Gharib, Myriam; Angevin, Eric; Malekzadeh, Katty; Massard, Christophe; Soria, Jean‐Charles; Spano, Jean‐Philippe

doi:10.1016/j.ejca.2017.05.021

Cited by 11 publications

(11 citation statements)

References 37 publications

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“…16,36 Moreover, the therapy targeted against MTOR has been considered an important anticancer strategy. 37,38 Taken together, our results further suggest that the MTORC1 variants may be also involved in tumor progression, exerting an impact on cancer patients' survival.…”

Section: Discussionsupporting

confidence: 63%

“…Third, MTORC1 is involved in the regulation of autophagy, a common biological process in cells that is associated with cancer progression . Moreover, the therapy targeted against MTOR has been considered an important anti‐cancer strategy . Taken together, our results further suggest that the MTORC1 variants may be also involved in tumor progression, exerting an impact on cancer patients’ survival.…”

Section: Discussionmentioning

confidence: 51%

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Functional variant of MTOR rs2536 and survival of Chinese gastric cancer patients

Cheng

Qiu

Zhang

et al. 2018

Intl Journal of Cancer

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We previously reported that some single nucleotide polymorphisms (SNPs) of candidate genes involved in the MTOR complex1 (MTORC1) were associated with risk of gastric cancer (GCa). In the present study, we further evaluated associations of eight potentially functional SNPs of MTOR, MLST8 and RPTOR with survival of 1002 GCa patients and also investigated molecular mechanisms underlying such associations. Specifically, we found that the MTOR rs2536 C allele at the microRNA binding site was independently associated with a 26% reduction of death risk (HR = 0.74, 95% CI = 0.57-0.96, p = 0.022). The results remained noteworthy with a prior false positive probability of 0.1. Genotype-phenotype correlation analysis in 144 patients' adjacent normal gastric tissue samples revealed that the MTOR expression levels were lower in rs2536 TC/CC carriers than that in wild-type TT carriers (p = 0.043). Dual luciferase assays revealed that the rs2536 C allele had a higher binding affinity to microRNA-150, leading to a decreased transcriptional activity of MTOR, compared to the rs2536 T allele. Further functional analysis revealed that MTOR knockdown by small interference RNA impaired proliferation, migration, and invasion ability in GCa cell lines. In conclusion, The MTOR rs2536 T > C change may be a biomarker for survival of Chinese GCa patients, likely by modulating microRNA-induced gene expression silencing. Additional studies are needed to validate our findings.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 51%

Functional variant of MTOR rs2536 and survival of Chinese gastric cancer patients

Cheng

Qiu

Zhang

et al. 2018

Intl Journal of Cancer

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“…Although temsirolimus is well tolerated as a single agent, phase I combination studies including temsirolimus have frequently been found to have significant toxicities . Oral mucositis was the predominant toxicity in a pediatric phase I combination of temsirolimus with cixutumumab, resulting in two grade 3 mucositis DLTs and required two dose deescalations to achieve a RP2D (temsirolimus 8 mg/m 2 ) .…”

Section: Discussionmentioning

confidence: 99%

“…12 Although temsirolimus is well tolerated as a single agent, phase I combination studies including temsirolimus have frequently been found to have significant toxicities. [16][17][18][19][20][21][22] Oral mucositis was the predominant toxicity in a pediatric phase I combination of temsirolimus with cixutumumab, resulting in two grade 3 mucositis DLTs and required two dose deescalations to achieve a RP2D (temsirolimus 8 mg/m 2 ). 19 Significant oral mucositis and hypertriglyceridemia, accounting for four DLTS, occurred in a pediatric study of temsirolimus (15 mg/m 2 weekly) with vinorelbine and cyclophosphamide for rhabdomyosarcoma.…”

Section: Discussionmentioning

confidence: 99%

Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218

Deyell

Rassekh

et al. 2018

Pediatric Blood & Cancer

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Combining mammalian target of rapamycin (mTOR) inhibitors and vinca alkaloids has shown therapeutic synergy in xenograft models of pediatric cancers. This phase I study assessed safety and toxicity of temsirolimus in combination with vinblastine in children. Procedure Patients ≥ 1 and ≤ 18 years with recurrent/refractory solid or CNS tumors were eligible. Vinblastine (4 mg/m2) and temsirolimus (15 mg/m2) were administered i.v. weekly, with planned dose escalation of vinblastine using a rolling six phase I design. Pharmacokinetic and pharmacodynamic data were collected. Results Seven patients with median age 12 years (range, 8–18 years) were enrolled; all were evaluable for toxicity and six for response. At dose level 1, four of six patients developed grade 3 mucositis, of which one met duration criteria for dose‐limiting toxicity (DLT). Four patients required dose omissions for grade 3 or 4 hematologic toxicity, including one prolonged neutropenia DLT. A subsequent patient was enrolled on dose level −2 (temsirolimus 10 mg/m2, vinblastine 4 mg/m2) with no protocol‐related toxicity > grade 1, except grade 2 neutropenia. Two serious adverse events (SAE) occurred—an allergic reaction to temsirolimus (grade 2) and an intracranial hemorrhage in a CNS tumor patient (grade 3)—unlikely related to study therapy. Soluble VEGFR2 was reduced at cycle 1, day 36 in keeping with inhibition of angiogenesis. Four patients achieved prolonged stable disease for a median of 5.0 months (range, 3.1–8.3 months). Conclusion The combination of weekly temsirolimus (15 mg/m2) and vinblastine (4 mg/m2) exceeds the maximum tolerated dose in children, with frequent oral mucositis and hematologic toxicity.

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“…In a phase I study of temsirolimus with the c-Met inhibitor tivantinib for the treatment of various advanced solid tumors, the combination treatment was well tolerated and had some clinical activity [247]. In a phase I study of combination temsirolimus with cetuximab (anti-EGFR monoclonal antibody) for treatment of advanced solid tumors, clinical activity was modest and thus not further pursued [248]. A combination of temsirolimus with the VEGF inhibitor bevacizumab and cetuximab had partial responses in head and neck squamous cell carcinoma with numerous toxicities [249].…”

Section: Co-targeting Mtorc1 and Growth Factor Signalingmentioning

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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Phase I study of temsirolimus in combination with cetuximab in patients with advanced solid tumours

Cited by 11 publications

References 37 publications

Functional variant of MTOR rs2536 and survival of Chinese gastric cancer patients

Functional variant of MTOR rs2536 and survival of Chinese gastric cancer patients

Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

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