scholarly journals Promises of targeted therapy for low grade gliomas in children

2019 ◽  
Vol 6 (2) ◽  
pp. 28-41
Author(s):  
E. F. Valiakhmetova ◽  
L. A. Yasko ◽  
L. I. Papusha ◽  
A. E. Druy ◽  
A. I. Karachunsky
Keyword(s):  
Targeted Therapy ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Molecular Pathogenesis ◽  
New Drugs ◽  
Mitogen Activated Protein Kinase ◽  
System Control ◽  
Low Grade ◽  
Low Grade Gliomas ◽  
Mitogen Activated Protein

Low grade gliomas are the most common brain tumors in children. Total resection for operable lesion helps to achieve local and system control. Nevertheless, for inaccessible tumors are required more effective treatment both to overcome the refractory course of the disease, and to mi nimize toxicity with conventional adjuvant chemotherapy and various types of radiation therapy. In recent years, there has been an accelerated understanding of the molecular pathogenesis of some tumors in children, including low grade gliomas. Given the fact that the basis of the molecular pathogenesis of the low grade gliomas is the activation of signaling pathways MARK (mitogen activated protein kinase) and mTOR (mammalian target of rapamycin), the most promising targeted agents are BRAF, MEK and mTOR inhibitors. Nevertheless, a number of other agents have been studied to find promising targeted therapy for this tumors type. This article summarizes the latest literature evaluating new drugs in low grade glioma.

Novel RAF Fusions in Pediatric Low-Grade Gliomas Demonstrate MAPK Pathway Activation

2021 ◽  
Author(s):  
Katherine T Lind ◽  
Hannah V Chatwin ◽  
John DeSisto ◽  
Philip Coleman ◽  
Bridget Sanford ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Enrichment Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Immunofluorescent Staining ◽  
Low Grade ◽  
Normal Brain ◽  
Mapk Activation ◽  
Low Grade Gliomas ◽  
Pathway Activation ◽  
Mitogen Activated Protein

Abstract Brain tumors are the most common solid tumor in children, and low-grade gliomas (LGGs) are the most common childhood brain tumor. Here, we report on 3 patients with LGG harboring previously unreported or rarely reported RAF fusions: FYCO1-RAF1, CTTNBP2-BRAF, and SLC44A1-BRAF. We hypothesized that these tumors would show molecular similarity to the canonical KIAA1549-BRAF fusion that is the most widely seen alteration in pilocytic astrocytoma (PA), the most common pediatric LGG variant, and that this similarity would include mitogen-activated protein kinase (MAPK) pathway activation. To test our hypothesis, we utilized immunofluorescent imaging and RNA-sequencing in normal brain, KIAA1549-BRAF-harboring tumors, and our 3 tumors with novel fusions. We performed immunofluorescent staining of ERK and phosphorylated ERK (p-ERK), identifying increased p-ERK expression in KIAA1549-BRAF fused PA and the novel fusion samples, indicative of MAPK pathway activation. Geneset enrichment analysis further confirmed upregulated downstream MAPK activation. These results suggest that MAPK activation is the oncogenic mechanism in noncanonical RAF fusion-driven LGG. Similarity in the oncogenic mechanism suggests that LGGs with noncanonical RAF fusions are likely to respond to MEK inhibitors.

scholarly journals PI3K/AKT/mTOR Inhibitors in Patients With Breast and Gynecologic Malignancies Harboring PIK3CA Mutations

2012 ◽  
Vol 30 (8) ◽  
pp. 777-782 ◽  
Author(s):  
Filip Janku ◽  
Jennifer J. Wheler ◽  
Shannon N. Westin ◽  
Stacy L. Moulder ◽  
Aung Naing ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Mapk Pathway ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Braf Mutations ◽  
Pik3ca Mutations ◽  
Clinical Center ◽  
Mitogen Activated Protein

Purpose Mutations of the PIK3CA gene may predict response to phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitors. Concomitant mutations in the mitogen-activated protein kinase (MAPK) pathway may mediate resistance. Patients and Methods Tumors from patients with breast, cervical, endometrial, and ovarian cancer referred to the Clinical Center for Targeted Therapy (Phase I Program) were analyzed for PIK3CA, KRAS, NRAS, and BRAF mutations. Patients with PIK3CA mutations were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway. Results Of 140 patients analyzed, 25 (18%) had PIK3CA mutations, including five of 14 patients with squamous cell cervical, seven of 29 patients with endometrial, six of 29 patients with breast, and seven of 60 patients with ovarian cancers. Of the 25 patients with PIK3CA mutations, 23 (median of two prior therapies) were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor. Two (9%) of 23 patients had stable disease for more than 6 months, and seven patients (30%) had a partial response. In comparison, only seven (10%) of 70 patients with the same disease types but with wild-type PIK3CA treated on the same protocols responded (P = .04). Seven patients (30%) with PIK3CA mutations had coexisting MAPK pathway (KRAS, NRAS, BRAF) mutations (ovarian cancer, n = 5; endometrial cancer, n = 2), and two of these patients (ovarian cancer) achieved a response. Conclusion PIK3CA mutations were detected in 18% of tested patients. Patients with PIK3CA mutations treated with PI3K/AKT/mTOR inhibitors demonstrated a higher response rate than patients without mutations. A subset of patients with ovarian cancer with simultaneous PIK3CA and MAPK mutations responded to PI3K/AKT/mTOR inhibitors, suggesting that not all patients demonstrate resistance when the MAPK pathway is concomitantly activated.

Molecular Alterations Of Low-Grade Gliomas In Young Patients: Strategies And Platforms For Routine Evaluation

2021 ◽  
Author(s):  
Iman Dandapath ◽  
Rituparna Chakraborty ◽  
Kavneet Kaur ◽  
Swati Mahajan ◽  
Jyotsna Singh ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Young Patients ◽  
Steering Committee ◽  
Mitogen Activated Protein Kinase ◽  
Low Grade ◽  
Low Grade Gliomas ◽  
Molecular Alterations ◽  
Integrated Diagnosis ◽  
Mitogen Activated Protein ◽  
Diffuse Gliomas

Abstract In recent years, it has been established that molecular biology of pediatric low-grade gliomas (PLGGs) is entirely distinct from adults. The majority of the circumscribed pediatric gliomas are driven by mitogen-activated protein kinase (MAPK) pathway, which has yielded important diagnostic, prognostic, and therapeutic biomarkers. Further, the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT) Steering Committee in their fourth meeting, suggested including a panel of molecular markers for integrated diagnosis in "pediatric type" diffuse gliomas. However, a designated set of platforms for the evaluation of these alterations has yet not been mentioned for easier implementation in routine molecular diagnostics. Herein, we have reviewed the relevance of analyzing these markers and discussed the strategies and platforms best apposite for clinical laboratories.

scholarly journals LGG-18. EVEROLIMUS TREATMENT IN PEDIATRIC PATIENTS AFFECTED BY LOW-GRADE GLIOMAS (pLGG) NON-TSC, BRAF v600-WT

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii369-iii369
Author(s):  
Antonella Cacchione ◽  
Evelina Miele ◽  
Maria Chiara Lodi ◽  
Andrea Carai ◽  
Giovanna Stefania Colafati ◽  
...  
Keyword(s):  
Adverse Event ◽  
Disease Progression ◽  
Mapk Pathway ◽  
Brain Mri ◽  
Mammalian Target Of Rapamycin ◽  
Low Grade ◽  
Duration Of Treatment ◽  
Tumor Biopsy ◽  
Low Grade Gliomas ◽  
Personalized Approach

Abstract BACKGROUND MAPK pathway is the hallmark of pediatric low grade gliomas (pLGGs); hyperactivation of mTOR (mammalian target of rapamycin) might be a suitable biomarker for therapeutic response. We investigated the feasibility of Everolimus, mTOR inhibitor, in patients affected by pLGGs. METHODS Patients 1 to 18 years old, diagnosed with pLGG, with a positive tumor biopsy for mTOR/phospho-mTOR and radiological and / or clinical disease progression, treated at Bambino Gesù Children’s Hospital in Rome were evaluated. Tumor DNA methylation analysis was performed in 10 cases. Exclusion criteria included: Tuberous Sclerosis patients, Sub Ependymal Giant Astrocytoma. Everolimus was administered orally at a dose of 2.5 mg or 5 mg daily based on body weight. Patients were evaluated with brain MRI every 4, 8 and 12 months after treatment start and every six months thereafter. RESULTS 16 patients were enrolled from September 2014 and 2019. The median age was 7.5 years old. All patients had at least one adverse event. Events rated as severe (grade 3/4) were reported in 6 patients. Stomatitis was the most frequent adverse event. One patient discontinued treatment due to grade 4 toxicity (ulcerative stomatitis and fatigue). The median duration of treatment was 21 months (4–57 months). Brain MRI evaluations have showed disease stability in 11 patients, partial response in 2 patients and disease progression in 3 patients. CONCLUSIONS Everolimus has proven to be well tolerated and effective treatment in terms of disease stability in patients with pLGGs. It’s also an excellent example of chemo-free personalized approach.

scholarly journals LGG-05. MOLECULAR GUIDED THERAPY FOR A PEDIATRIC LOW GRADE GLIOMA: A CASE REPORT

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii367-iii367
Author(s):  
Jayne VonBergen ◽  
Beth Armstrong ◽  
Morgan Schmitt
Keyword(s):  
Targeted Therapy ◽  
Standard Treatment ◽  
Head Tilt ◽  
Study Patient ◽  
Low Grade ◽  
Temporal Region ◽  
Low Grade Gliomas ◽  
Leptomeningeal Involvement ◽  
The Right ◽  
Guided Therapy

Abstract Low grade gliomas are the most common type of central nervous system tumors among children. Despite the fact that they are not typically life threatening, low grade gliomas remain a significant clinical challenge. Case Study: Patient is a 4-year-old male who presented at 20 months of age with several weeks of ataxia, emesis, and head tilt. Imaging revealed a right temporal lobe lesion; he was subsequently taken to surgery, where a gross total resection was achieved. Imaging 9 months post resection revealed recurrent disease within the right temporal region with leptomeningeal involvement. Four months later imaging revealed progression of multifocal disease and new growth within the sella. At this time the patient started standard treatment, Carboplatin and Vincristine, per CCG 9952A. Persistent slow progression was observed despite receiving standard therapy. The patient developed a grade 3 reaction to carboplatin, worsening with each subsequent dose. At this time, he was referred to our Precision Genomics Neuro Oncology program for tumor molecular characterization. Somatic tumor testing revealed an ETV6-NTRK3 fusion, at which time standard treatment was stopped, and patient began targeted therapy, Larotrectinib. Imaging was preformed 2 months post start of targeted therapy and revealed interval decrease in size of previously enhancing nodular lesions; findings consistent with treatment response. Disease burden continues to decrease with therapy. This case illustrates a clear benefit of using molecular guided therapy in low grade gliomas.

scholarly journals KRASoncogene in lung cancer: focus on molecularly driven clinical trials

2016 ◽  
Vol 25 (139) ◽  
pp. 71-76 ◽  
Author(s):  
Emmanuelle Kempf ◽  
Benoît Rousseau ◽  
Benjamin Besse ◽  
Luis Paz-Ares
Keyword(s):  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Lung Cancers ◽  
Molecular Abnormalities ◽  
Mitogen Activated Protein ◽  
Pathway Inhibition

KRASmutations are the most frequent molecular abnormalities found in one out of four nonsmall cell lung cancers (NSCLC). Their incidence increases in cases of adenocarcinoma, smokers and Caucasian patients. Their negative value in terms of prognosis and responsiveness to both standard chemotherapy and targeted therapies remains under debate. Many drugs have been developed specifically forKRAS-mutated NSCLC patients. Direct inhibition ofRASactivation failed to show any clinical efficacy. Inhibition of downstream targets of the mitogen-activated protein kinase (MEK) pathway is a promising strategy: phase II combinations of MEK 1/2 kinase inhibitors with chemotherapy doubled patients’ clinical outcomes. One phase III trial in such a setting is ongoing. Double inhibition of MEK and epidermal growth factor receptor proteins is currently being assessed in early-phase trials. The association with mammalian target of rapamycin pathway inhibition leads to non-manageable toxicity. Other strategies, such as inhibition of molecular heat-shock proteins 90 or focal adhesion kinase are currently assessed. Abemaciclib, a cyclin-dependent kinase 4/6 inhibitor, showed promising results in a phase I trial, with a 54% disease control rate. Results of an ongoing phase III trial are warranted. Immunotherapy might be the next relevant step inKRAS-mutated NSCLC management due to the high burden of associated mutations and neo-antigens.

Polymorphous Low-Grade Neuroepithelial Tumor of the Young (PLNTY): Molecular Profiling Confirms Frequent MAPK Pathway Activation

2021 ◽  
Author(s):  
Cristiane M Ida ◽  
Derek R Johnson ◽  
Asha A Nair ◽  
Jaime Davila ◽  
Thomas M Kollmeyer ◽  
...  
Keyword(s):  
Copy Number ◽  
Mapk Pathway ◽  
Braf V600e Mutation ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Low Grade ◽  
Pathway Activation ◽  
Mitogen Activated Protein ◽  
Copy Number Changes ◽  
Cd34 Expression

Abstract Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described epileptogenic tumor characterized by oligodendroglioma-like components, aberrant CD34 expression, and frequent mitogen-activated protein kinase (MAPK) pathway activation. We molecularly profiled 13 cases with diagnostic histopathological features of PLNTY (10 female; median age, 16 years; range, 5–52). Patients frequently presented with seizures (9 of 12 with available history) and temporal lobe tumors (9 of 13). MAPK pathway activating alterations were identified in all 13 cases. Fusions were present in the 7 youngest patients: FGFR2-CTNNA3 (n = 2), FGFR2-KIAA1598 (FGFR2-SHTN1) (n = 1), FGFR2-INA (n = 1), FGFR2-MPRIP (n = 1), QKI-NTRK2 (n = 1), and KIAA1549-BRAF (n = 1). BRAF V600E mutation was present in 6 patients (17 years or older). Two fusion-positive cases additionally harbored TP53/RB1 abnormalities suggesting biallelic inactivation. Copy number changes predominantly involving whole chromosomes were observed in all 10 evaluated cases, with losses of chromosome 10q occurring with FGFR2-KIAA1598 (SHTN1)/CTNNA3 fusions. The KIAA1549-BRAF and QKI-NTRK2 fusions were associated respectively with a 7q34 deletion and 9q21 duplication. This study shows that despite its name, PLNTY also occurs in older adults, who frequently show BRAF V600E mutation. It also expands the spectrum of the MAPK pathway activating alterations associated with PLNTY and demonstrates recurrent chromosomal copy number changes consistent with chromosomal instability.

scholarly journals NF2/Merlin Is a Novel Negative Regulator of mTOR Complex 1, and Activation of mTORC1 Is Associated with Meningioma and Schwannoma Growth

2009 ◽  
Vol 29 (15) ◽  
pp. 4250-4261 ◽  
Author(s):  
Marianne F. James ◽  
Sangyeul Han ◽  
Carolyn Polizzano ◽  
Scott R. Plotkin ◽  
Brendan D. Manning ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Suppressor Activity ◽  
Mtorc1 Signaling ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Tumor Suppressive Function ◽  
Mtorc1 Activation

ABSTRACT Inactivating mutations of the neurofibromatosis 2 (NF2) gene, NF2, result predominantly in benign neurological tumors, schwannomas and meningiomas, in humans; however, mutations in murine Nf2 lead to a broad spectrum of cancerous tumors. The tumor-suppressive function of the NF2 protein, merlin, a membrane-cytoskeleton linker, remains unclear. Here, we identify the mammalian target of rapamycin complex 1 (mTORC1) as a novel mediator of merlin's tumor suppressor activity. Merlin-deficient human meningioma cells and merlin knockdown arachnoidal cells, the nonneoplastic cell counterparts of meningiomas, exhibit rapamycin-sensitive constitutive mTORC1 activation and increased growth. NF2 patient tumors and Nf2-deficient mouse embryonic fibroblasts demonstrate elevated mTORC1 signaling. Conversely, the exogenous expression of wild-type merlin isoforms, but not a patient-derived L64P mutant, suppresses mTORC1 signaling. Merlin does not regulate mTORC1 via the established mechanism of phosphoinositide 3-kinase-Akt or mitogen-activated protein kinase/extracellular signal-regulated kinase-mediated TSC2 inactivation and may instead regulate TSC/mTOR signaling in a novel fashion. In conclusion, the deregulation of mTORC1 activation underlies the aberrant growth and proliferation of NF2-associated tumors and may restrain the growth of these lesions through negative feedback mechanisms, suggesting that rapamycin in combination with phosphoinositide 3-kinase inhibitors may be therapeutic for NF2.

scholarly journals Activation of protein synthesis in cardiomyocytes by the hypertrophic agent phenylephrine requires the activation of ERK and involves phosphorylation of tuberous sclerosis complex 2 (TSC2)

2005 ◽  
Vol 388 (3) ◽  
pp. 973-984 ◽  
Author(s):  
Mark ROLFE ◽  
Laura E. McLEOD ◽  
Phillip F. PRATT ◽  
Christopher G. PROUD
Keyword(s):  
Protein Synthesis ◽  
Ribosomal Protein ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Mammalian Target Of Rapamycin ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Erk Activation ◽  
Mitogen Activated Protein

The hypertrophic Gq-protein-coupled receptor agonist PE (phenylephrine) activates protein synthesis. We showed previously that activation of protein synthesis by PE requires MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] and mTOR (mammalian target of rapamycin). However, it remained unclear whether ERK activation was required and which downstream components were involved in activating mTOR and protein synthesis. Using an adenovirus encoding the MKP3 (MAPK phosphatase 3) to inhibit ERK activity, we demonstrate that ERK is essential for the activation of protein synthesis by PE. Activation and phosphorylation of S6K1 (ribosomal protein S6 kinase 1) and phosphorylation of eIF4E (eukaryotic initiation factor 4E)-binding protein (both are mTOR targets) were also inhibited by MKP3, suggesting that ERK is also required for the activation of mTOR signalling. PE stimulation of cardiomyocytes induced the phosphorylation of TSC2 (tuberous sclerosis complex 2), a negative regulator of mTOR activity. TSC2 was phosphorylated only weakly at Thr1462, but phosphorylated at additional sites within the sequence RXRXX(S/T). This differs from the phosphorylation induced by insulin, indicating that MEK/ERK signalling targets distinct sites in TSC2. This phosphorylation may be mediated by p90RSK (90 kDa ribosomal protein S6K), which is activated by ERK, and appears to involve phosphorylation at Ser1798. Activation of protein synthesis by PE is partially insensitive to the mTOR inhibitor rapamycin. Inhibition of the MAPK-interacting kinases by CGP57380 decreases the phosphorylation of eIF4E and PE-induced protein synthesis. Moreover, CGP57380+rapamycin inhibited protein synthesis to the same extent as blocking ERK activation, suggesting that MAPK-interacting kinases and regulation of mTOR each contribute to the activation of protein synthesis by PE in cardiomyocytes.

Sign in / Sign up

Export Citation Format

Share Document