Gemcitabine Combined with the mTOR Inhibitor Temsirolimus in Patients with Locally Advanced or Metastatic Pancreatic Cancer. A Hellenic Cooperative Oncology Group Phase I/II Study

Karavasilis, Vasilios; Samantas, Epaminontas; Koliou, Georgia-Angeliki; Kalogera‐Fountzila, Anna; Pentheroudakis, George; Varthalitis, Ioannis; Linardou, Helena; Rallis, Grigorios; Skondra, Maria; Papadopoulos, Georgios; Papatsibas, George; Sgouros, Joseph; Goudopoulou, Athina; Kalogeras, Konstantine T.; Dervenis, Christos; Pectasides, Dimitrios; Fountzilas, George

doi:10.1007/s11523-018-0605-y

Cited by 19 publications

(10 citation statements)

References 40 publications

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“…In a phase II study, 48.5% of patients with osteosarcoma were observed to have stabilized disease when treated with a combination of gemcitabine and sirolimus [304]. However, in advanced pancreatic cancer, combination treatment with temsirolimus and gemcitabine lacked clinical efficacy [305]. In a phase Ib/II study of everolimus in combination with azacitidine, a cytidine analog used in patients with relapsed/refractory acute myeloid leukemia, the treatment was tolerable and has promising clinical activity [306].…”

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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“…The genetic algorithm found six specific drug-targets, with five significant in pancreatic cancer: IGF1R 164 , SRC 165 , PDPK1 166 , AKT1 167 , and MTOR 168 , as opposed to only two for the greedy algorithms, both of significance in pancreatic cancer: GSK3B 181 , CDK4 182 . We found ten drugs specific to the genetic algorithm, out of which six investigated for the treatment of pancreatic cancer (arsenic trioxide 169 , cixutumumab 171 , everolimus 172 , genistein 174 , nintedanib 175 , and temsirolimus 178 ), and four under clinical trials (arsenic trioxide 170 , everolimus 173 , nintedanib 176 , and temsirolimus 179 ). In contrast, we found only one drug specific to the greedy algorithm.…”

Section: Resultsmentioning

confidence: 99%

Network controllability solutions for computational drug repurposing using genetic algorithms

Popescu

Kanhaiya

Nastac

et al. 2022

Sci Rep

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Control theory has seen recently impactful applications in network science, especially in connections with applications in network medicine. A key topic of research is that of finding minimal external interventions that offer control over the dynamics of a given network, a problem known as network controllability. We propose in this article a new solution for this problem based on genetic algorithms. We tailor our solution for applications in computational drug repurposing, seeking to maximize its use of FDA-approved drug targets in a given disease-specific protein-protein interaction network. We demonstrate our algorithm on several cancer networks and on several random networks with their edges distributed according to the Erdős–Rényi, the Scale-Free, and the Small World properties. Overall, we show that our new algorithm is more efficient in identifying relevant drug targets in a disease network, advancing the computational solutions needed for new therapeutic and drug repurposing approaches.

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“…Currently, more and more mTOR inhibitors have been applied in the clinical treatment of malignancies, such as lung cancer, laryngeal cancer, and pancreatic cancer [ 23 , 24 ]. Some drugs targeting the mTOR signaling pathway have also been used for CSCC patients, which are now in phase I/II clinical trials [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Expression and significance of mammalian target of rapamycin in cutaneous squamous cell carcinoma and precancerous lesions

Fang

et al. 2021

Bioengineered

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The aim of this study is to explore the role of mammalian target of rapamycin (mTOR) in cutaneous squamous cell carcinoma (CSCC), Bowen’s disease (BD), and actinic keratosis (AK) with squamous cell differentiation abnormality and its relationship with the degree of tumor proliferation. Thirty cases of clinical paraffin specimens of CSCC, BD, and AK were each collected from Jinhua Fifth Hospital, while 30 cases of normal skin specimens surgically resected in Department of Plastic Surgery were selected as controls. The expressions of mTOR and Ki-67 in tissues were detected by immunohistochemical staining. The positive expression rate of mTOR in the CSCC group was higher than those in the BD group and AK group ( P < 0.05), while it was higher in the BD group and AK group than in the normal skin group ( P < 0.05). The CSCC group had a higher positive expression rate of Ki-67 than the AK group ( P < 0.01). The results of logistic regression analysis showed that the pathogenic site [odds ratio (OR) = 1.189, 95% confidence interval (95%CI): 1.028–1.381, P = 0.021], course of disease (OR = 2.059, 95%CI: 1.036–4.087, P = 0.043), and differentiation degree (OR = 1.325, 95%CI: 1.169–1.512, P = 0.001) were independent factors for the positive expression of mTOR. OR>1, indicating that the factor is a risk factor. The expression levels of mTOR in CSCC, BD, and AK were positively correlated with the expression level of Ki-67 ( r = 0.827, P < 0.01, r = 0.608, P < 0.01, r = 0.368, P = 0.045). These results suggest that mTOR may be involved in the pathogenesis of CSCC, and related to the proliferation degree of CSCC, as an index reflecting the proliferation status of CSCC.

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Gemcitabine Combined with the mTOR Inhibitor Temsirolimus in Patients with Locally Advanced or Metastatic Pancreatic Cancer. A Hellenic Cooperative Oncology Group Phase I/II Study

Cited by 19 publications

References 40 publications

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Network controllability solutions for computational drug repurposing using genetic algorithms

Expression and significance of mammalian target of rapamycin in cutaneous squamous cell carcinoma and precancerous lesions

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