Challenges in Drug Discovery for Neurofibromatosis Type 1-Associated Low-Grade Glioma

Ricker, Cora A.; Pan, Yuan; Gutmann, David H.; Keller, Charles

doi:10.3389/fonc.2016.00259

Cited by 11 publications

(15 citation statements)

References 88 publications

(87 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, human low-grade glioma cells grow poorly in vitro and frequently undergo senescence, 32 and none have been successfully maintained as patient-derived xenografts. 33 For these reasons, 34 much of our current understanding of the pathophysiology of NF1-associated low-grade gliomas derives from analyses of Nf1 genetically-engineered mouse models. Based on the genetics of their human counterparts, mice heterozygous for a targeted germline inactivating mutation in the Nf1 gene ( Nf1+/− mice) have been engineered with a conditional Nf1 allele ( Nf1 flox ) to enable somatic Nf1 loss in neuroglial progenitor cells during embryonic development.…”

Section: Pathophysiologymentioning

confidence: 99%

Optic Pathway Gliomas in Neurofibromatosis Type 1

2017

Self Cite

View full text Add to dashboard Cite

Neurofibromatosis type 1 (NF1) is one of the most common brain tumor predisposition syndromes, in which affected children are prone to the development of low-grade gliomas. While NF1-associated gliomas can be found in several brain regions, the majority arise in the optic nerves, chiasm, tracts, and radiations (optic pathway gliomas; OPGs). Owing to their location, 35-50% of affected children present with reduced visual acuity. Unfortunately, despite tumor stabilization following chemotherapy, vision does not improve in most children. For this reasons, more effective therapies are being sought that reflect a deeper understanding of the NF1 gene and the use of authenticated Nf1 genetically-engineered mouse strains. The implementation of these models for drug discovery and validation has galvanized molecularly-targeted clinical trials in children with NF1-OPG. Future research focused on defining the cellular and molecular factors that underlie optic glioma development and progression also has the potential to provide personalized risk assessment strategies for this pediatric population.

show abstract

Section: Pathophysiologymentioning

confidence: 99%

Optic Pathway Gliomas in Neurofibromatosis Type 1

2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Furthermore, activation and/or inhibition of these protein expressions on cancer cells have shown the potential interest for cancer therapy [ 17 , 21 ]. Given that the PTN protein was overexpressed in the brain glioma patients, its blockade could be a potential target for a treatment strategy of the gliomas as the tumors still remain a therapeutic challenge [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

CREB3L1 and PTN expressions correlate with prognosis of brain glioma patients

et al. 2018

View full text Add to dashboard Cite

The present study was conducted to investigate the clinical significance of cAMP responsive element binding protein 3 like 1 (CREB3L1) and pleiotrophin (PTN) expression in prognosis of patients with brain gliomas. Human brain tissue samples were collected from normal glial tissues (control), low- and high-grade glioma tissues. CREB3L1 and PTN expression levels in cells were assessed by immunohistochemistry (IHC), and population distribution of the CREB3L1- and PTN-presenting patients was examined. The CREB3L1 and PTN mRNA expression levels in three types of the brain cells was determined by RT-PCR. Survival rates for population of the CREB3L1- and PTN-presenting patients were examined. CREB3L1+ cell counts were decreased with increased PTN+ cells in the low-grade and high-grade glioma tissues as compared with the control. Population proportion of the CREB3L1+-presenting patients decreased from the control to the high-grade glioma and the population of the PTN+-presenting patients increased in low- and high-grade gliomas as compared with the control (both P<0.05). The decrease in the CREB3L1 mRNA expression was associated with the increase in the PTN mRNA expression in the low- and high-grade gliomas (P<0.05). Survival time for patients with CREB3L1− and PTN+ gliomas was shorter than patients with CREB3L1+ and PTN− gliomas in the investigated cohorts (both P<0.05). There was a relationship between the expression levels of both proteins and survival time. CREB3L1 and PTN expression levels serve as biomarkers with utility in grading gliomas. Absence of CREB3L1 and presence of PTN in brain glioma cells correlate with survival time of the glioma patients.

show abstract

“…NF1 has the 2 nd highest node count in group A and has links to the MAPK cascade. For example, loss of NF1 gene expression leads to increased RAS activation and hyperactivation of the downstream RAS effectors, including the RAF/MEK/ERK and the PI3K/AKT pathways [38]. Abnormal activation of RAS by defective NF1 is a central driver event in some soft-tissue sarcomas (MPNST).…”

Section: Plos Onementioning

confidence: 99%

Bioinformatic analysis linking genomic defects to chemosensitivity and mechanism of action

Covell

2021

PLoS ONE

View full text Add to dashboard Cite

A joint analysis of the NCI60 small molecule screening data, their genetically defective genes, and mechanisms of action (MOA) of FDA approved cancer drugs screened in the NCI60 is proposed for identifying links between chemosensitivity, genomic defects and MOA. Self-Organizing-Maps (SOMs) are used to organize the chemosensitivity data. Student’s t-tests are used to identify SOM clusters with enhanced chemosensitivity for tumor cell lines with versus without genetically defective genes. Fisher’s exact and chi-square tests are used to reveal instances where defective gene to chemosensitivity associations have enriched MOAs. The results of this analysis find a relatively small set of defective genes, inclusive of ABL1, AXL, BRAF, CDC25A, CDKN2A, IGF1R, KRAS, MECOM, MMP1, MYC, NOTCH1, NRAS, PIK3CG, PTK2, RPTOR, SPTBN1, STAT2, TNKS and ZHX2, as possible candidates for roles in chemosensitivity for compound MOAs that target primarily, but not exclusively, kinases, nucleic acid synthesis, protein synthesis, apoptosis and tubulin. These results find exploitable instances of enhanced chemosensitivity of compound MOA’s for selected defective genes. Collectively these findings will advance the interpretation of pre-clinical screening data as well as contribute towards the goals of cancer drug discovery, development decision making, and explanation of drug mechanisms.

show abstract

Challenges in Drug Discovery for Neurofibromatosis Type 1-Associated Low-Grade Glioma

Cited by 11 publications

References 88 publications

Optic Pathway Gliomas in Neurofibromatosis Type 1

Optic Pathway Gliomas in Neurofibromatosis Type 1

CREB3L1 and PTN expressions correlate with prognosis of brain glioma patients

Bioinformatic analysis linking genomic defects to chemosensitivity and mechanism of action

Contact Info

Product

Resources

About