Upfront treatment with <scp>mTOR</scp> inhibitor everolimus in pediatric low‐grade gliomas: A single‐center experience

Cacchione, Antonella; Lodi, Mariachiara; Carai, Andrea; Miele, Evelina; Tartaglia, Marco; Megaro, Giacomina; Baldo, Giada Del; Alessi, Iside; Colafati, Giovanna Stefania; Carboni, Alessia; Boccuto, Luigi; Camassei, Francesca Diomedi; Catanzaro, Giuseppina; Pò, Agnese; Ferretti, Elisabetta; Pedace, Lucia; Pizzi, Simone; Folgiero, Valentina; Pezzullo, Marco; Corsetti, Tiziana; Secco, Domitilla Elena; Cefalo, Maria Giuseppina; Locatelli, Franco; Mastronuzzi, Angela

doi:10.1002/ijc.33438

Cited by 19 publications

(17 citation statements)

References 45 publications

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“…This leads us to consider that the penetration through the BBB, the toxicity of everolimus, and the activity of mTORC2 are influential but uncontrollable (158). But the next two early phase studies in pediatric patients demonstrated the manageable toxicity profile of everolimus (160,161). On this basis, we think the prospect of mTOR inhibitors is promising.…”

Section: Aktmentioning

confidence: 99%

Small Molecule Inhibitors in Adult High-Grade Glioma: From the Past to the Future

et al. 2022

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Glioblastoma is the most common primary malignant tumor in the brain and has a dismal prognosis despite patients accepting standard therapies. Alternation of genes and deregulation of proteins, such as receptor tyrosine kinase, PI3K/Akt, PKC, Ras/Raf/MEK, histone deacetylases, poly (ADP-ribose) polymerase (PARP), CDK4/6, branched-chain amino acid transaminase 1 (BCAT1), and Isocitrate dehydrogenase (IDH), play pivotal roles in the pathogenesis and progression of glioma. Simultaneously, the abnormalities change the cellular biological behavior and microenvironment of tumor cells. The differences between tumor cells and normal tissue become the vulnerability of tumor, which can be taken advantage of using targeted therapies. Small molecule inhibitors, as an important part of modern treatment for cancers, have shown significant efficacy in hematologic cancers and some solid tumors. To date, in glioblastoma, there have been more than 200 clinical trials completed or ongoing in which trial designers used small molecules as monotherapy or combination regimens to correct the abnormalities. In this review, we summarize the dysfunctional molecular mechanisms and highlight the outcomes of relevant clinical trials associated with small-molecule targeted therapies. Based on the outcomes, the main findings were that small-molecule inhibitors did not bring more benefit to newly diagnosed glioblastoma, but the clinical studies involving progressive glioblastoma usually claimed “noninferiority” compared with historical results. However, as to the clinical inferiority trial, similar dosing regimens should be avoided in future clinical trials.

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Section: Aktmentioning

confidence: 99%

Small Molecule Inhibitors in Adult High-Grade Glioma: From the Past to the Future

et al. 2022

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“…Vemurafenib, a competitive and selective inhibitor of the BRAFV600E mutant ATP-binding domain, has proved well-tolerated and active as single agent in a case series of pediatric patients with BRAFv600E-positive LGG ( 47 ). Furthermore, as mTOR pathway activation in LGGs is well known, orally administration of everolimus has been studied and demonstrated disease stability also as upfront line ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

Rethinking the Management of Optic Pathway Gliomas: A Single Center Experience

et al. 2022

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BackgroundOptic pathway gliomas (OPGs) are rare neoplasms in children with an unpredictable clinical course. Approximately 15% of OPGs occur in patients affected by neurofibromatosis type 1 (NF1): the clinical course of these cases is more indolently than sporadic ones, and NF1 patients less frequently require treatment including surgery. Instead, over 90% of sporadic OPGs require one or more therapeutic approaches. The management of OPG is controversial. They are also characterized by a high risk of morbidity including hypothalamic damage, endocrine deficits, visual deficit and/or neurological impairment.Materials and MethodsIn this paper, we evaluated visual and endocrinological outcomes of a population of OPG followed at our center from 2013 to 2021, with a particular emphasis on the role of surgery.ResultsTwenty-six patients were included in this study (mean age of 40.7 months). Tumor location on imaging was described by the Dodge classification. Five cases had NF 1. Thirteen cases received biopsy and 13 were partially resected. Histopathology revealed 19 cases of pilocytic astrocytomas, 2 pilomyxoid astrocytoma and 5 ganglioglioma. All the patients required a post-surgical adjuvant treatment according to current indications for low-grade gliomas. Molecular studies (BRAF status and mTOR/pmTOR pathway) have been performed in 24/26 patients, following for the use of target therapy in 11 of these patients. In our study we found that patients underwent biopsy have a better visual and endocrinological outcomes rather than patients with a tumor debulking. The five-year overall survival rate is 98% with a mean follow-up of 60 months.ConclusionsMany children with OPGs survive with a residual tumor. They suffer from chronic diseases such as endocrine dysfunction, visual disturbance, motor deficits and poor quality of life. All patients need comprehensive diagnostic work-up including neuroimaging, clinical evaluations and neuropathology approach; at the same time, they need therapeutic decisions and concepts for the choice of timing and type of neurosurgical intervention, chemotherapy and target therapy as well as surveillance and rehabilitation to maximize survival and overall functional outcomes. Our study showed that minimal invasive surgery with the purpose of molecular characterization of the tumor is desirable to reduce morbidity correlate to surgery.

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“…Remarkably, the lack of mTORC1 activity promotes the dephosphorylation of the GRASP protein, which, in turn, leads to a change in its localization within the cell and can consequently cause the secretion of extracellular matrix proteins via UPS ( Nuchel et al, 2021 ). Interestingly, not only has mTORC1 surfaced as a potential therapeutic target in GBM ( Ronellenfitsch et al, 2018 ), but studies showed that the use of mTORC1 inhibitor everolimus has great therapeutic potential against pediatric low-grade gliomas ( Poore et al, 2019 ; Cacchione et al, 2020 ). GRASPs are closely related to UPS mechanisms such as type III and IV UPS ( Giuliani et al, 2011 ), and GRASP55 is considered an unconventional secretion factor ( van Ziel et al, 2019 ).…”

Section: Unconventional Protein Secretion In Brain Tumorsmentioning

confidence: 99%

Unconventional Protein Secretion in Brain Tumors Biology: Enlightening the Mechanisms for Tumor Survival and Progression

Iglesia

Prado

Alves

et al. 2022

Front. Cell Dev. Biol.

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Non-canonical secretion pathways, collectively known as unconventional protein secretion (UPS), are alternative secretory mechanisms usually associated with stress-inducing conditions. UPS allows proteins that lack a signal peptide to be secreted, avoiding the conventional endoplasmic reticulum-Golgi complex secretory pathway. Molecules that generally rely on the canonical pathway to be secreted may also use the Golgi bypass, one of the unconventional routes, to reach the extracellular space. UPS studies have been increasingly growing in the literature, including its implication in the biology of several diseases. Intercellular communication between brain tumor cells and the tumor microenvironment is orchestrated by various molecules, including canonical and non-canonical secreted proteins that modulate tumor growth, proliferation, and invasion. Adult brain tumors such as gliomas, which are aggressive and fatal cancers with a dismal prognosis, could exploit UPS mechanisms to communicate with their microenvironment. Herein, we provide functional insights into the UPS machinery in the context of tumor biology, with a particular focus on the secreted proteins by alternative routes as key regulators in the maintenance of brain tumors.

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Upfront treatment with mTOR inhibitor everolimus in pediatric low‐grade gliomas: A single‐center experience

Cited by 19 publications

References 45 publications

Small Molecule Inhibitors in Adult High-Grade Glioma: From the Past to the Future

Small Molecule Inhibitors in Adult High-Grade Glioma: From the Past to the Future

Rethinking the Management of Optic Pathway Gliomas: A Single Center Experience

Unconventional Protein Secretion in Brain Tumors Biology: Enlightening the Mechanisms for Tumor Survival and Progression

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