New Frontiers in Mucositis

2012 ◽  
pp. 545-551 ◽  
Author(s):  
Douglas E. Peterson ◽  
Dorothy M. Keefe ◽  
Stephen T. Sonis
Keyword(s):  
Kinase Inhibitors ◽  
Management Strategies ◽  
Mammalian Target Of Rapamycin ◽  
Cancer Therapeutics ◽  
Mtor Inhibitors ◽  
Mucosal Injury ◽  
Mucosal Damage ◽  
Nucleotide Polymorphisms ◽  
Oncology Patient ◽  
Novel Technologies

Overview: Mucositis is among the most debilitating side effects of radiotherapy, chemotherapy, and targeted anticancer therapy. Research continues to escalate regarding key issues such as etiopathology, incidence and severity across different mucosae, relationships between mucosal and nonmucosal toxicities, and risk factors. This approach is being translated into enhanced management strategies. Recent technology advances provide an important foundation for this continuum. For example, evolution of applied genomics is fostering development of new algorithms to rapidly screen genomewide single-nucleotide polymorphisms (SNPs) for patient-associated risk prediction. This modeling will permit individual tailoring of the most effective, least toxic treatment in the future. The evolution of novel cancer therapeutics is changing the mucositis toxicity profile. These agents can be associated with unique mechanisms of mucosal damage. Additional research is needed to optimally manage toxicity caused by agents such as mammalian target of rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors, without reducing antitumor effect. There has similarly been heightened attention across the health professions regarding clinical practice guidelines for mucositis management in the years following the first published guidelines in 2004. New opportunities exist to more effectively interface this collective guideline portfolio by capitalizing upon novel technologies such as an Internet-based Wiki platform. Substantive progress thus continues across many domains associated with mucosal injury in oncology patients. In addition to enhancing oncology patient care, these advances are being integrated into high-impact educational and scientific venues including the National Cancer Institute Physician Data Query (PDQ) portfolio as well as a new Gordon Research Conference on mucosal health and disease scheduled for June 2013.

scholarly journals Marine-Derived Natural Products as ATP-Competitive mTOR Kinase Inhibitors for Cancer Therapeutics

2021 ◽  
Vol 14 (3) ◽  
pp. 282
Author(s):  
Shraddha Parate ◽  
Vikas Kumar ◽  
Gihwan Lee ◽  
Shailima Rampogu ◽  
Jong Chan Hong ◽  
...  
Keyword(s):  
Natural Products ◽  
In Silico ◽  
Cellular Proliferation ◽  
Kinase Inhibitors ◽  
Binding Free Energy ◽  
Mammalian Target Of Rapamycin ◽  
Cancer Therapeutics ◽  
Mtor Inhibitors ◽  
Binding Pocket ◽  
Pharmacophore Modeling

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase portraying a quintessential role in cellular proliferation and survival. Aberrations in the mTOR signaling pathway have been reported in numerous cancers including thyroid, lung, gastric and ovarian cancer, thus making it a therapeutic target. To attain this objective, an in silico investigation was designed, employing a pharmacophore modeling approach. A structure-based pharmacophore (SBP) model exploiting the key features of a selective mTOR inhibitor, Torkinib directed at the ATP-binding pocket was generated. A Marine Natural Products (MNP) library was screened using SBP model as a query. The retrieved compounds after consequent drug-likeness filtration were subjected to molecular docking with mTOR, thus revealing four MNPs with better scores than Torkinib. Successive refinement via molecular dynamics simulations demonstrated that the hits formed crucial interactions with key residues of the pocket. Furthermore, the four identified hits exhibited good binding free energy scores through MM-PBSA calculations and the subsequent in silico toxicity assessments displayed three hits deemed essentially non-carcinogenic and non-mutagenic. The hits presented in this investigation could act as potent ATP-competitive mTOR inhibitors, representing a platform for the future discovery of drugs from marine natural origin.

Pancreatic endocrine disorders and multiple endocrine neoplasia

2020 ◽  
pp. 2449-2463
Author(s):  
B. Khoo ◽  
T.M. Tan ◽  
S.R. Bloom
Keyword(s):  
Kinase Inhibitors ◽  
Neuroendocrine Tumours ◽  
Mammalian Target Of Rapamycin ◽  
Peptide Receptor Radionuclide Therapy ◽  
Mtor Inhibitors ◽  
Somatostatin Analogues ◽  
Endocrine Disorders ◽  
Pancreatic Neuroendocrine Tumours ◽  
Islet Cell Tumours ◽  
Cancer Syndromes

Pancreatic neuroendocrine tumours (islet-cell tumours) are rare and usually sporadic, but they may be associated with complex familial endocrine cancer syndromes. Recognized types of pancreatic neuroendocrine tumours are those that are non-functioning (often advanced at diagnosis and presenting with mass effects due to the absence of symptoms attributable to hormone hypersecretion), insulinoma (the most frequent type), and others including gastrinoma, VIPoma, and glucagonoma. The following should be considered in addition to the symptomatic treatments: surgical resection—the only curative treatment, but not possible in many cases; tyrosine kinase inhibitors which inhibit specific kinases involved in tumour cell proliferation, growth, and angiogenesis; mammalian Target of Rapamycin (mTOR) inhibitors; peptide-receptor radionuclide therapy (radiolabelled somatostatin analogues).

scholarly journals mTOR-targeted cancer therapy: great target but disappointing clinical outcomes, why?

2020 ◽  
Author(s):  
Shi-Yong Sun
Keyword(s):  
Cancer Therapy ◽  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Targeted Cancer Therapy ◽  
Biological Functions ◽  
New Findings ◽  
Survival Signaling ◽  
Mtor Complex 1

Abstract The mammalian target of rapamycin (mTOR) critically regulates several essential biological functions, such as cell growth, metabolism, survival, and immune response by forming two important complexes, namely, mTOR complex 1 (mTORC1) and complex 2 (mTORC2). mTOR signaling is often dysregulated in cancers and has been considered an attractive cancer therapeutic target. Great efforts have been made to develop efficacious mTOR inhibitors, particularly mTOR kinase inhibitors, which suppress mTORC1 and mTORC2; however, major success has not been achieved. With the strong scientific rationale, the intriguing question is why cancers are insensitive or not responsive to mTOR-targeted cancer therapy in clinics. Beyond early findings on induced activation of PI3K/Akt, MEK/ERK, and Mnk/eIF4E survival signaling pathways that compromise the efficacy of rapalog-based cancer therapy, recent findings on the essential role of GSK3 in mediating cancer cell response to mTOR inhibitors and mTORC1 inhibition-induced upregulation of PD-L1 in cancer cells may provide some explanations. These new findings may also offer us the opportunity to rationally utilize mTOR inhibitors in cancer therapy. Further elucidation of the biology of complicated mTOR networks may bring us the hope to develop effective therapeutic strategies with mTOR inhibitors against cancer.

scholarly journals Immunotherapy in Metastatic Renal Cell Carcinoma: A Comprehensive Review

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Rachna Raman ◽  
Daniel Vaena
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Progression Free Survival ◽  
Mtor Inhibitors ◽  
Immune Therapies ◽  
Localized Renal Cell Carcinoma ◽  
Metastatic Rcc

Localized renal cell carcinoma (RCC) is often curable by surgery alone. However, metastatic RCC is generally incurable. In the 1990s, immunotherapy in the form of cytokines was the mainstay of treatment for metastatic RCC. However, responses were seen in only a minority of highly selected patients with substantial treatment-related toxicities. The advent of targeted agents such as vascular endothelial growth factor tyrosine kinase inhibitors VEGF-TKIs and mammalian target of rapamycin (mTOR) inhibitors led to a change in this paradigm due to improved response rates and progression-free survival, a better safety profile, and the convenience of oral administration. However, most patients ultimately progress with about 12% being alive at 5 years. In contrast, durable responses lasting 10 years or more are noted in a minority of those treated with cytokines. More recently, an improved overall survival with newer forms of immunotherapy in other malignancies (such as melanoma and prostate cancer) has led to a resurgence of interest in immune therapies in metastatic RCC. In this review we discuss the rationale for immunotherapy and recent developments in immunotherapeutic strategies for treating metastatic RCC.

Risk of pneumonitis with mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13573-e13573
Author(s):  
Vishal Navnitray Ranpura ◽  
Shenhong Wu
Keyword(s):  
Clinical Trials ◽  
Cancer Patients ◽  
Meta Analysis ◽  
Single Agent ◽  
Mammalian Target Of Rapamycin ◽  
Cancer Therapeutics ◽  
Mtor Inhibitors ◽  
High Grade ◽  
Significant Difference ◽  
American Society

e13573 Background: Pneumonitis is associated with the use of mTOR inhibitors, everolimus and temsirolimus, which have been used widely in cancer therapeutics and clinical trials. Currently, the overall risk of pneumonits in patients treated with mTOR inhibitors has not been defined. We performed a systematic review and meta-analysis of published clinical trials to assess the risk of pneumonitis in cancer patients treated with mTOR inhibitors. Methods: Databases from PUBMED, the Web of Science, and abstracts presented at the American Society of Clinical Oncology conferences until May 2012 were searched to identify relevant studies. Eligible studies included prospective clinical trials in which patients received treatment with everolimus or temsirolimus as a single agent or in combination with other agents. Summary incidence, relative risk (RR), and 95% confidence interval (CI) were calculated employing a fixed- or random-effects model based upon the heterogeneity of the included studies. Results: A total of 2,303 patients with a variety of tumors from 18 studies (everolimus: 12, temsirolimus: 6) were included for the analysis. The overall incidences of all-grade and high-grade pneumonitis with mTOR inhibitors were 6.5% (95% CI: 3.7-11.1%) and 2.5% (95% CI 1.2-5.4%) respectively. The risk of all-grade pneumonitis did not vary significantly with tumor types (P=0.079), but vary significantly with their combination with other agents (P<0.001). There was no significant difference between everolimus and temsirolimus in the incidence of all-grade (P=0.22) and high-grade (P=0.28) pneumonitis. In comparison with controls, mTOR inhibitors significantly increased the risk of all-grade (RR=5.2, 95% CI: 2.09-12.93, P<0.001) but not high-grade pneumonits (RR=2.63, 95% CI: 0.66-10.40, P=0.41). Conclusions: The risk of pneumonitis is increased in cancer patients receiving mTOR inhibitors without significant difference between everolimus and temsirolimus.

scholarly journals Advances in mammalian target of rapamycin kinase inhibitors: application to devices used in the treatment of coronary artery disease

2020 ◽  
Author(s):  
Hiroyuki Jinnouchi ◽  
Liang Guo ◽  
Atsushi Sakamoto ◽  
Yu Sato ◽  
Anne Cornelissen ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Target Of Rapamycin ◽  
Drug Eluting Stents ◽  
Drug Eluting Stent ◽  
Negative Effects ◽  
Pharmacological Agents ◽  
Drug Eluting ◽  
Artery Disease

Mammalian target of rapamycin (mTOR) inhibitors have been applied to vascular coronary devices to avoid neointimal growth and have become the predominant pharmacological agents used to prevent restenosis. mTOR inhibitors can affect not only proliferating vascular smooth muscle cells but also endothelial cells and therefore can result in delayed healing of the vessel including endothelialization. Emerging evidence suggests accelerated atherosclerosis due to the downstream negative effects on endothelial barrier functional recovery. The development of neoatherosclerosis within the neointima of drug-eluting stents can result in late thrombotic events. This type of problematic healing response may open the way for specific mTOR kinase inhibitors, such as ATP-competitive mTOR inhibitors. These inhibitors demonstrate a better healing profile than traditional limus-based drug-eluting stent and their clinical efficacy remains unknown.

scholarly journals Dual mTORC1/mTORC2 inhibition as a Host-Directed Therapeutic Target in Pathologically Distinct Mouse Models of Tuberculosis

2021 ◽  
Author(s):  
Rokeya Tasneen ◽  
Deborah S. Mortensen ◽  
Paul J. Converse ◽  
Michael E. Urbanowski ◽  
Anna Upton ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Kinase Domain ◽  
Lung Damage ◽  
Mtor Inhibition ◽  
Mtor Kinase ◽  
Tb Treatment ◽  
Mtor Complex 1

Efforts to develop more effective and shorter-course therapies for tuberculosis have included a focus on host-directed therapy (HDT). The goal of HDT is to modulate the host response to infection, thereby improving immune defenses to reduce the duration of antibacterial therapy and/or the amount of lung damage. As a mediator of innate and adaptive immune responses involved in eliminating intracellular pathogens, autophagy is a potential target for HDT in tuberculosis. Because Mycobacterium tuberculosis modulates mammalian target of rapamycin (mTOR) signaling to impede autophagy, pharmacologic mTOR inhibition could provide effective HDT. mTOR exists within two distinct multiprotein complexes, mTOR complex-1 (mTORC1) and mTOR complex-2 (mTORC2). Rapamycin and its analogs only partially inhibit mTORC1. We hypothesized that novel mTOR kinase inhibitors blocking both complexes would have expanded therapeutic potential. We compared the effects of two mTOR inhibitors: rapamycin and the orally available mTOR kinase domain inhibitor CC214-2, which blocks both mTORC1 and mTORC2, as adjunctive therapies against murine TB, when added to the first-line regimen (RHZE) or the novel bedaquiline-pretomanid-linezolid (BPaL) regimen. Neither mTOR inhibitor affected lung CFU counts after 4-8 weeks of treatment when combined with BPaL or RHZE. However, addition of CC214-2 to BPaL and RHZE was associated with significantly fewer relapses in C3HeB/FeJ compared to addition of rapamycin and, in RHZE-treated mice, resulted in fewer relapses compared to RHZE alone. Therefore, CC214-2 and related mTOR kinase inhibitors may be more effective candidates for HDT than rapamycin analogs and may have the potential to shorten the duration of TB treatment.

scholarly journals The next 10 years: Challenges for the future and overcoming resistance to targeted therapies for renal cell carcinoma

2016 ◽  
Vol 10 (11-12) ◽  
pp. 256 ◽  
Author(s):  
Daniel Y.C. Heng
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Targeted Therapies ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
Mtor Inhibitors ◽  
Systemic Treatments

The introduction of targeted therapies over the past 10 years revolutionized the treatment of metastatic renal cell carcinoma (mRCC). The next 10 years hold promise for even greater expansion of the therapeutic armamentarium for mRCC. A number of recently completed and ongoing trials have explored the use of antivascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors in the adjuvant setting, the use of predictive biomarkers to guide personalized medicine, as well as new systemic treatments and combination therapies for mRCC.

scholarly journals Dual mTORC1/mTORC2 inhibition as a Host-Directed Therapeutic Target in Pathologically Distinct Mouse Models of Tuberculosis

2021 ◽  
Author(s):  
Rokeya Tasneen ◽  
Deborah S. Mortensen ◽  
Paul J. Converse ◽  
Michael E. Urbanowski ◽  
Anna Upton ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Kinase Domain ◽  
Lung Damage ◽  
Mtor Inhibition ◽  
Mtor Kinase ◽  
Tb Treatment ◽  
Mtor Complex 1

AbstractEfforts to develop more effective and shorter-course therapies for tuberculosis have included a focus on host-directed therapy (HDT). The goal of HDT is to modulate the host response to infection, thereby improving immune defenses to reduce the duration of antibacterial therapy and/or the amount of lung damage. As a mediator of innate and adaptive immune responses involved in eliminating intracellular pathogens, autophagy is a potential target for HDT in tuberculosis. Because Mycobacterium tuberculosis modulates mammalian target of rapamycin (mTOR) signaling to impede autophagy, pharmacologic mTOR inhibition could provide effective HDT. mTOR exists within two distinct multiprotein complexes, mTOR complex-1 (mTORC1) and mTOR complex-2 (mTORC2). Rapamycin and its analogs only partially inhibit mTORC1. We hypothesized that novel mTOR kinase inhibitors blocking both complexes would have expanded therapeutic potential. We compared the effects of two mTOR inhibitors: rapamycin and the orally available mTOR kinase domain inhibitor CC214-2, which blocks both mTORC1 and mTORC2, as adjunctive therapies against murine TB, when added to the first-line regimen (RHZE) or the novel bedaquiline-pretomanid-linezolid (BPaL) regimen. Neither mTOR inhibitor affected lung CFU counts after 4-8 weeks of treatment when combined with BPaL or RHZE. However, addition of CC214-2 to BPaL and RHZE was associated with significantly fewer relapses in C3HeB/FeJ compared to addition of rapamycin and, in RHZE-treated mice, resulted in fewer relapses compared to RHZE alone. Therefore, CC214-2 and related mTOR kinase inhibitors may be more effective candidates for HDT than rapamycin analogs and may have the potential to shorten the duration of TB treatment.

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