Data from A High-Throughput Screening Platform Identifies Novel Combination Treatments for Malignant Peripheral Nerve Sheath Tumors
Juana Fernández‐RodríguezEdgar Creus‐BachillerXiaohu ZhangMaría Martínez‐IniestaSara Ortega‐BertranRajarshi GuhaCraig J. ThomasMargaret R. WallaceCleofé RomagosaLourdes Salazar-HuaynaKarlyne M. ReillyJaishri O. BlakelyJordi Serra-MusachMiguel Ángel PujanaEduard SerraAlberto VillanuevaMarc FerrerConxi Lázaro
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<div>Abstract<p>Malignant peripheral nerve sheath tumors (MPNST) are soft-tissue sarcomas that are the leading cause of mortality in patients with Neurofibromatosis type 1 (NF1). Single chemotherapeutic agents have shown response rates ranging from 18% to 44% in clinical trials, so there is still a high medical need to identify chemotherapeutic combination treatments that improve clinical prognosis and outcome. We screened a collection of compounds from the NCATS Mechanism Interrogation PlatE (MIPE) library in three MPNST cell lines, using cell viability and apoptosis assays. We then tested whether compounds that were active as single agents were synergistic when screened as pairwise combinations. Synergistic combinations <i>in vitro</i> were further evaluated in patient-derived orthotopic xenograft/orthoxenograft (PDOX) athymic models engrafted with primary MPNST matching with their paired primary-derived cell line where synergism was observed. The high-throughput screening identified 21 synergistic combinations, from which four exhibited potent synergies in a broad panel of MPNST cell lines. One of the combinations, MK-1775 with Doxorubicin, significantly reduced tumor growth in a sporadic PDOX model (MPNST-SP-01; sevenfold) and in an NF1-PDOX model (MPNST-NF1–09; fourfold) and presented greater effects in <i>TP53</i> mutated MPNST cell lines. The other three combinations, all involving Panobinostat (combined with NVP-BGT226, Torin 2, or Carfilzomib), did not reduce the tumor volume <i>in vivo</i> at noncytotoxic doses. Our results support the utility of our screening platform of <i>in vitro</i> and <i>in vivo</i> models to explore new therapeutic approaches for MPNSTs and identified that combination MK-1775 with Doxorubicin could be a good pharmacologic option for the treatment of these tumors.</p></div>Keywords:
Panobinostat
Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue malignancy usually found in patients with neurofibromatosis type 1 (NF1) with a poor outcome. Although MPNST can be found in any part of the body including head and neck or extremities, intrathoracic MPNST with or without NF1 is uncommon, especially in children or adolescents. Reported herein is a case of huge intrathoracic MPNST in a 16-year-old girl with NF1, and a brief review of the literature.
Girl
Neurofibromatosis type I
Nerve sheath neoplasm
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Neoplasm
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Abstract Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas that originate in peripheral nerves or neurilemma cells. Here, we report an extremely rare case of an intraosseous MPNST in the mandible of a patient with neurofibromatosis type 1 (NF1). A 57‐year‐old woman with a history of NF1 was referred to our hospital because she had abnormal sensations at her left mandible. She was diagnosed with MPNST and underwent radical resection, although local recurrence and multiple metastases were detected during follow‐up. Despite receiving palliative radiotherapy, the patient died at 13 months after the initial diagnosis.
Mandible (arthropod mouthpart)
Nerve sheath neoplasm
Neurofibromatosis type I
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A malignant peripheral nerve sheath tumor (MPNST) is an aggressive tumor that can arise from the malignant transformation of benign neurofibromas in patients with neurofibromatosis type 1 (NF1). MPNST occurs in 2% of patients with NF1, contributing to significant mortality in these patients. Here, we report the case of a 67-year-old female with a known history of neurofibromatosis type 1 who was referred to general surgery after the discovery of a large left-sided adrenal mass on CT imaging five months earlier. Lab workup revealed elevated urine catecholamines, concerning pheochromocytoma. As pheochromocytoma is also common in those with NF-1, appropriate medical management followed by surgical resection was performed. The final pathology report revealed an MPNST.
Malignant Transformation
Neurofibromatosis type I
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Nerve sheath tumor
Nerve sheath neoplasm
Nerve sheath
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Neurofibromatosis 1 is an autosomal dominant disorder characterized by distinctive clinical problems including scoliosis and malignant peripheral nerve sheath tumors. We present two cases of retroperitoneal malignant peripheral nerve sheath tumor associated with scoliosis in neurofibromatosis. Presence of spinal deformity resulted in delay of the diagnosis of the sarcoma.
Spinal Deformity
Nerve sheath neoplasm
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Malignant peripheral nerve sheath tumor (MPNST) is rare, accounting for 5-10% of all soft tissue sarcomas. MPNST is characteristically aggressive and has a poor prognosis. Fifty percent of patients with MPNST have neurofibromatosis type 1 (NF1). NF-associated MPNST occurs more often at younger ages than sporadic MPNST, but the survival difference is controversial. Superficial MPNST from a recurrent neurofibroma is extremely rare and only a limited number of cases have been reported in the literature. Herein, we report an unusual case of superficial MPNST from a recurrent neurofibroma in a patient without NF1.
Nerve sheath neoplasm
Neurofibromatosis type I
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Malignant peripheral nerve sheath tumor is a very rare soft tissue tumor in the general population but there is an increased incidence in patients with neurofibromatosis type 1. Two cases of malignant peripheral nerve sheath tumor associated with neurofibromatosis type 1 whom we were able to follow-up long term are presented. Although wide excision was performed successfully in these patients, they suffered from local recurrence of the tumors shortly after surgery and died with distant metastases. The literature concerning the natural history and the management of this specific condition was reviewed.
Nerve sheath tumor
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