Correction: Co-targeting the MAPK and PI3K/AKT/mTOR pathways in two genetically engineered mouse models of schwann cell tumors reduces tumor grade and multiplicity

Watson, Adrienne L.; Keller, Bryant; Williams, Kyle; Damle, Namrata N.; Finnerty, Samuel; Anderson, Leah K.; Greeley, Andrew D.; Keng, Vincent W.; Rahrmann, Eric P.; Halfond, Amanda L.; Powell, Natasha M.; Collins, Margaret H.; Rizvi, Tilat A.; Moertel, Christopher L.; Ratner, Nancy; Largaespada, David A.

doi:10.18632/oncotarget.27349

Cited by 2 publications

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“…The rationale behind this combination lies in the complementary inhibition of multiple signaling pathways implicated in MPNST progression. The combined inhibition of both the Ras-MAPK and PI3K pathways may lead to a more comprehensive blockade of pro-survival signals, potentially overcoming compensatory mechanisms that limit the effectiveness of single-agent therapies 82 . There is some uncertainty regarding the true cellular target of rigosertib at achievable human doses, with strong evidence suggesting it is a microtubule destabilizing agent 32 .…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenomic synthetic lethal screens reveal hidden vulnerabilities and new therapeutic approaches for treatment of NF1-associated tumors

Williams,

Larsson,

Keller

et al. 2024

Preprint

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Neurofibromatosis Type 1 (NF1) is a common cancer predisposition syndrome, caused by heterozygous loss of function mutations in the tumor suppressor geneNF1. Individuals with NF1 develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage after somatic loss of the wild typeNF1allele, some of which progress further to malignant peripheral nerve sheath tumors (MPNST). There is only one FDA approved targeted therapy for symptomatic plexiform neurofibromas and none approved for MPNST. The genetic basis of NF1 syndrome makes associated tumors ideal for using synthetic drug sensitivity approaches to uncover therapeutic vulnerabilities. We developed a drug discovery pipeline to identify therapeutics for NF1-related tumors using isogeneic pairs ofNF1-proficient and deficient immortalized human Schwann cells. We utilized these in a large-scale high throughput screen (HTS) for drugs that preferentially killNF1-deficient cells, through which we identified 23 compounds capable of killingNF1-deficient Schwann cells with selectivity. Multiple hits from this screen clustered into classes defined by method of action. Four clinically interesting drugs from these classes were testedin vivousing both a genetically engineered mouse model of high-grade peripheral nerve sheath tumors and human MPNST xenografts. All drugs tested showed single agent efficacy in these models as well as significant synergy when used in combination with the MEK inhibitor selumetinib. This HTS platform yielded novel therapeutically relevant compounds for the treatment of NF1-associated tumors and can serve as a tool to rapidly evaluate new compounds and combinations in the future.

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Section: Discussionmentioning

confidence: 99%

Pharmacogenomic synthetic lethal screens reveal hidden vulnerabilities and new therapeutic approaches for treatment of NF1-associated tumors

Williams,

Larsson,

Keller

et al. 2024

Preprint

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“…Active RAS kinase leads to activation of two main effector pathways: the MAPK RAS/RAF/MEK/ERK pathway and the Akt/mTOR pathway, which control cellular functions, including responses to external stimuli like growth factors or chemokines [18,19]. Both these pathways have been described as activated in many types of sarcomas, including MPNST [20]. Furthermore, inhibition of RAS kinase was shown to suppress MPNST cell growth both in vitro and in vivo [21].…”

Section: Mpnst Biology and Geneticsmentioning

confidence: 99%

Malignant peripheral nerve sheath tumor — from genetics to multidisciplinary treatment

Czarnecka,

Chmiel,

Sobczuk

et al. 2024

Oncol Clin Pract

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Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma (STS); it originates from nervous tissue and typically develops in proximity to nerve trunks in the limbs and trunk. These tumors, constituting approximately 5% of soft tissue sarcomas, can either form spontaneously or arise from pre-existing neurofibromas. The majority (90%) of cases occur in individuals between the 2 nd and 5 th decades of life. The main risk factor for MPNST is von Recklinghausen disease (type 1 neurofibromatosis). The cornerstone of MPNST management involves radical surgical measures, specifically tumor excision within healthy tissue boundaries (wide local excision), which is complemented by adjuvant radiotherapy. In case of metastatic disease, palliative chemotherapy employing doxorubicin or a combination of doxorubicin and ifosfamide is utilized. Approximately 25-30% of patients experience clinical improvement after chemotherapy. Looking ahead, advancements in research on molecular biology may lead to the development of inhibitors demonstrating greater efficacy than traditional chemotherapy for MPNST patients. At present, ongoing clinical trials of the therapeutic management of MPNST encompass pembrolizumab, the combination of nivolumab with ipilimumab, pexydartinib (an inhibitor targeting KIT, CSF1R, and FLT3) in conjunction with sirolimus, sapanisertib (a TORC1/2 inhibitor), or LOXO-195 (an inhibitor of neurotrophic tyrosine kinase receptors NTRK type 1, 2, and 3).

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Correction: Co-targeting the MAPK and PI3K/AKT/mTOR pathways in two genetically engineered mouse models of schwann cell tumors reduces tumor grade and multiplicity

Cited by 2 publications

References 0 publications

Pharmacogenomic synthetic lethal screens reveal hidden vulnerabilities and new therapeutic approaches for treatment of NF1-associated tumors

Pharmacogenomic synthetic lethal screens reveal hidden vulnerabilities and new therapeutic approaches for treatment of NF1-associated tumors

Malignant peripheral nerve sheath tumor — from genetics to multidisciplinary treatment

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