Neurofibromatosis in the Era of Precision Medicine: Development of MEK Inhibitors and Recent Successes with Selumetinib

Galvin, Robert; Watson, Adrienne L.; Largaespada, David A.; Ratner, Nancy; Osum, Sara H.; Moertel, Christopher L.

doi:10.1007/s11912-021-01032-y

Cited by 23 publications

(17 citation statements)

References 81 publications

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“…In concert with several reports published elsewhere, our data show that MEK inhibitors such as selumetinib or trametinib reliably lead to a significant reduction of PN volume but will not result in the complete disappearance of the tumor. 11 12 13 18 19 20 21 22 23 24 25 For many NF1 patients even this partial response will be a therapeutic success since it might effectively reduce PN-related morbidity or facilitate surgical removal of the remaining tumor. 13 23…”

Section: Discussionmentioning

confidence: 99%

Treatment of Plexiform Neurofibromas with MEK Inhibitors: First Results with a New Therapeutic Option

2021

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Neurofibromatosis type-1 (NF1)-associated plexiform neurofibromas (PN) are peripheral nerve sheath tumors that can significantly affect the quality of life. Until recently, surgery was the only treatment for these tumors. However, in most cases, surgery cannot achieve complete tumor removal and carries a high risk of postoperative deficits. Therefore, the recent approval of the MEK inhibitor selumetinib for the treatment of NF1-associated PN provides a long-awaited novel therapeutic option. Here, we report our experience with MEK inhibitor treatment in 12 pediatric NF1 patients with inoperable symptomatic PN. Eight patients received trametinib (median therapy duration 12.13 months and range 4–29 months), and four patients received selumetinib (median therapy duration 6.25 months and range 4–11 months). Volumetric magnetic resonance imaging (MRI) after 6 months of treatment was available for seven trametinib patients (median tumor volume reduction of 26.5% and range 11.3–55.7%) and two selumetinib patients (21.3% tumor volume reduction in one patient and +3% tumor volume change in the other one). All patients reported clinical benefits such as improved range of motion or reduced disfigurement. Therapy-related adverse events occurred in 58.3% of patients and mainly consisted of skin toxicity, paronychia, and gastrointestinal symptoms. Two patients discontinued trametinib treatment after 14 and 29 months when severe skin toxicity occurred and no further reduction of tumor size was observed. In one patient, discontinuation of therapy resulted in a 27.2% tumor volume increase as demonstrated on volumetric MRI 6 months later. Our data show that MEK inhibition is a novel therapeutic approach for inoperable PN with promising results and a manageable safety profile.

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Section: Discussionmentioning

confidence: 99%

Treatment of Plexiform Neurofibromas with MEK Inhibitors: First Results with a New Therapeutic Option

2021

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“…Unfortunately, and despite extensive efforts, none of the RAF, MEK or ERK kinase inhibitors developed thus far have been approved for the treatment of KRAS mutant tumors. Only the MEK inhibitor selumetinib has been approved for the treatment of pediatric tumors induced by NF1 mutations [ 92 ]. Likewise, another MEK inhibitor widely used in GEM models, trametinib, has been approved for the treatment of metastatic melanoma in combination with the BRAF V600E inhibitor dabrafenib [ 93 ].…”

Section: Inhibitors Of the Mapk Pathwaymentioning

confidence: 99%

Targeting KRAS mutant lung cancer: light at the end of the tunnel

Drosten

Barbacid

2022

Molecular Oncology

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For decades, KRAS mutant lung adenocarcinomas (LUAD) have been refractory to therapeutic strategies based on personalized medicine owing to the complexity of designing inhibitors to selectively target KRAS and downstream targets with acceptable toxicities. The recent development of selective KRAS G12C inhibitors represents a landmark after 40 years of intense research efforts since the identification of KRAS as a human oncogene. Here, we discuss the mechanisms responsible for the rapid development of resistance to these inhibitors, as well as potential strategies to overcome this limitation. Other therapeutic strategies aimed at inhibiting KRAS oncogenic signaling by targeting either upstream activators or downstream effectors are also reviewed. Finally, we discuss the effect of targeting the mitogen-activated protein kinase (MAPK) pathway, both based on the failure of MEK and ERK inhibitors in clinical trials, as well as on the recent identification of RAF1 as a potential target due to its MAPK-independent activity. These new developments, taken together, are likely to open new avenues to effectively treat KRAS mutant LUAD.

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“…However, to leverage this biological information, tissue diagnosis and molecular classification is of utmost importance. Advocacy for standardization of molecular profiling is now being seen throughout the field ( 5 , 10 , 16 , 29 ). Contemporary work has demonstrated the value of standardizing diagnostic processes by supplementing pathological diagnosis with DNA methylation profiles.…”

Section: Genetics Of Optic Pathways Gliomamentioning

confidence: 99%

“…Despite the understanding that a significant portion of these tumors will remain stable, as many as 35% of OPGs in NF1 patients will require treatment at presentation and more than 90% of sporadic OPGs will require treatment ( 2 , 11 ). Long-standing first line treatment is chemotherapy with Carboplatin and Vincristine (CV) ( 4 , 5 , 7 , 8 , 16 ). Alternatives therapies have included TPCV (thioguanine, procarbazine, lomustine, vincristine), vinblastine monotherapy, and more recently targeted therapies.…”

Section: Introductionmentioning

confidence: 99%

Neurosurgery for Optic Pathway Glioma: Optimizing Multidisciplinary Management

2022

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Optic pathway glioma (OPG) comprises 10% of pediatric brain tumors and 40% of all pediatric low-grade gliomas (pLGGs). While generally considered benign pathologically, many require interventions with chemotherapy, radiation, or targeted therapies. Management has historically foregone tissue diagnosis given the classical clinical/radiographic presentation of these tumors, inability to safely remove the lesions surgically, and efficacy and safety of available chemotherapy options. Furthermore, when considering such aspects as their delicate location, the role of surgery continues to be heavily debated. More recently, however, a greater understanding of the genetic drivers of OPGs has made operative tissue sampling a critical step in management planning, specifically for patients without Neurofibromatosis, Type I (NF1). Given the need for long-term, complex management of pediatric OPGs, it is crucial that a multidisciplinary approach is employed, and the rapidly expanding role of molecular characterization be incorporated into their management.

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Neurofibromatosis in the Era of Precision Medicine: Development of MEK Inhibitors and Recent Successes with Selumetinib

Cited by 23 publications

References 81 publications

Treatment of Plexiform Neurofibromas with MEK Inhibitors: First Results with a New Therapeutic Option

Treatment of Plexiform Neurofibromas with MEK Inhibitors: First Results with a New Therapeutic Option

Targeting KRAS mutant lung cancer: light at the end of the tunnel

Neurosurgery for Optic Pathway Glioma: Optimizing Multidisciplinary Management

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