The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents

A broad spectrum of novel targeted therapies with prime antitumor activity and/or ample control of hormonal symptoms together with an overall acceptable safety profile have emerged for patients with metastatic neuroendocrine neoplasms (NENs). In this systematic review and quantitative meta-analysis, the PubMed, EMBASE, Cochrane Central Register of Controlled Trials and clinicaltrials.gov databases were searched to assess and compare the safety profile of NEN treatments with special focus on the cardiovascular adverse effects of biotherapy and molecular targeted therapies (MTTs). Quality/risk of bias were assessed using GRADE criteria. Placebo-controlled randomized clinical trials (RCTs) in patients with metastatic NENs, including medullary thyroid cancer (MTC) were included. A total of 3695 articles and 122 clinical trials registered in clinicaltrials.gov were screened. We included sixteen relevant RCTs comprising 3408 unique patients assigned to different treatments compared with placebo. All the included studies had a low risk of bias. We identified four drug therapies for NENs with eligible placebo-controlled RCTs: somatostatin analogs (SSAs), tryptophan hydroxylase (TPH) inhibitors, mTOR inhibitors and tyrosine kinase inhibitors (TKI). Grade 3 and 4 adverse effects (AE) were more often encountered in patients treated with mTOR inhibitors and TKI (odds ratio [OR]: 2.42, 95% CI: 1.87–3.12 and OR: 3.41, 95% CI: 1.46–7.96, respectively) as compared to SSAs (OR:0.77, 95% CI: 0.47–1.27) and TPH inhibitors (OR:0.77, 95% CI: 0.35–1.69). MTOR inhibitors had the highest risk for serious cardiac AE (OR:3.28, 95% CI: 1.66–6.48) followed by TKIs (OR:1.51, 95% CI: 0.59–3.83). Serious vascular AE were more often encountered in NEN patients treated with mTOR inhibitors (OR: 1.72, 95% CI: 0.64–4.64) and TKIs (OR:1.64, 95% CI: 0.35–7.78). Finally, patients on TKIs were at higher risk for new-onset or exacerbation of pre-existing hypertension (OR:3.31, 95% CI: 1.87–5.86). In conclusion, SSAs and TPH inhibitors appear to be safer as compared to mTOR inhibitors and TKIs with regards to their overall toxicity profile, and cardiovascular toxicities in particular. Special consideration should be given to a patient-tailored approach with anticipated toxicities of targeted NEN treatments together with assessment of cardiovascular comorbidities, assisting clinicians in treatment selection and early recognition/management of cardiovascular toxicities. This approach could improve patient compliance and preserve cardiovascular health and overall quality of life.

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Revisiting mTOR inhibitors as anticancer agents

Drug Discovery Today ◽

10.1016/j.drudis.2019.05.030 ◽

2019 ◽

Vol 24 (10) ◽

pp. 2086-2095 ◽

Cited By ~ 5

Author(s):

Qiu-Xu Teng ◽

Yunali V. Ashar ◽

Pranav Gupta ◽

Eddie Gadee ◽

Ying-Fang Fan ◽

...

Keyword(s):

Anticancer Agents ◽

Mtor Inhibitors

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A theoretical insight in interactions of some chemical compounds as mTOR inhibitors

Bulletin of the National Research Centre ◽

10.1186/s42269-021-00525-x ◽

2021 ◽

Vol 45 (1) ◽

Author(s):

David Ebuka Arthur ◽

Jibrin Noah Akoji ◽

Riadh Sahnoun ◽

Greatman C. Okafor ◽

Karimatu Lami Abdullahi ◽

...

Keyword(s):

Hydrogen Bond ◽

Binding Affinity ◽

Anticancer Agents ◽

Mtor Inhibitors ◽

Stable Complex ◽

Hydrogen Bond Energy ◽

Atp Binding Site ◽

Binding Pockets ◽

Theoretical Insight ◽

High Binding Affinity

Abstract Background A series of known Food and Drug Administration (FDA) approved anticancer drugs were collected from the literature and docked against mTOR receptor which has been identified in present time as a target for therapeutic anticancer agents. The compounds binding affinity were calculated after minimising the interaction within the binding pockets’ of the mTOR (4JT6) receptor. Results The result shows that PF-04691502 ligand best inhibited mTOR while occupying the Adenosine triphosphate (ATP)-binding site on the receptor. PF-04691502 had the best binding affinity with a reported value of − 39.261 kcal/mol, and a hydrogen bond energy contribution of − 8.326 kcal/mol. Polamid529 is also found to have a good binding affinity of − 36.75 kcal/mol with the receptor, but was less significant than that calculated for the reference or standard inhibitor (X6K) used (− 37.862 kcal/mol). Further analysis revealed that Palomid529 formed a more stable complex with the receptor than torin2 and X6K due to the significant hydrogen bond contributions it adds to its overall binding score. Conclusion PF-04691502 ligand was identified as the best inhibitor due to its high binding affinity for mTOR and should be considered as the best alternative to the reference inhibitor X6K.

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Current development of mTOR inhibitors as anticancer agents

Nature Reviews Drug Discovery ◽

10.1038/nrd2062 ◽

2006 ◽

Vol 5 (8) ◽

pp. 671-688 ◽

Cited By ~ 671

Author(s):

Sandrine Faivre ◽

Guido Kroemer ◽

Eric Raymond

Keyword(s):

Anticancer Agents ◽

Mtor Inhibitors ◽

Current Development

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Review of postmarketing surveillance of molecular targeted anticancer agents in Japan

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.6598 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 6598-6598

Author(s):

Y. Miura ◽

M. Kami ◽

T. Morita ◽

M. Tsubokura ◽

N. Takei ◽

...

Keyword(s):

Interstitial Lung Disease ◽

Adverse Events ◽

Anticancer Agents ◽

Safety Profile ◽

Performance Status ◽

Safety Information ◽

Mortality Rates ◽

Gemtuzumab Ozogamicin ◽

Postmarketing Surveillance ◽

Related Mortality

6598 Background: Since the safety profile of molecular targeted anticancer agents is different from that of conventional anticancer agents, the safety information is limited. Although postmarketing surveillance (PMS) on safety is important, the appropriate methods of PMS have not been established. Methods: We investigated PMS methods, patients’ performance status (PS), and safety of the eight molecular targeted anticancer agents (imatinib, rituximab, trastuzumab, gefitinib, gemtuzumab ozogamicin [GO], bortezomib, bevacizumab, erlotinib) approved in Japan. We excluded sunitinib and sorafenib as the PMS of these agents were ongoing. Results: Besides PMS of gefitinib, seven PMS enrolled all the patients that received the study agents. The inclusive type of PMS was required at approval of the latest four agents, GO, bortezomib, bevacizumab, and erlotinib. The total number of enrolled patients was 8,776. Seven PMS of imatinib, rituximab, trastuzumab, GO, bortezomib, bevacizumab, and erlotinib enrolled 309, 2,575, 1,142, 316, 666, 2,698, and 1,070 patients, respectively. Data on the frequencies of patients with PS 3–4 were available in five of seven PMS, which were 7%, 7%, 20%, 3%, and 0.1% in PMS of rituximab, trastuzumab, GO, bortezomib, bevacizumab, respectively. Frequencies of severe adverse events were described in four of seven PMS, which were 3–6%, 0.3–4%, 0–45, and 0–2% in PMS of imatinib, rituximab, bortezomib, and bevacizumab, respectively. Interstitial lung disease related to Bevacizumab was unknown in premarketing studies and was observed in 0.4% in PMS. Drug related mortality rates were described in four of seven PMS, which were 1%, 8%, 3%, and 2% in PMS of rituximab, GO, bortezomib, and bevacizumab, respectively. Conclusions: Although PS varied among PMS of different molecular targeted anticancer agents, patients with poor PS were not included in most PMS. Disclosure of PMS results was insufficient. Further investigation on appropriate methods of PMS and its disclosure is warranted. No significant financial relationships to disclose.

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