Treatment Of Malignant Peripheral Nerve Sheath Tumors Research Articles

Abstract 5649: PRRX1-TOP2A interaction is a malignancy-promoting factor in human malignant peripheral nerve sheath tumors

Abstract Background: Paired related-homeobox 1 (PRRX1) is a transcription factor in the regulation of developmental morphogenetic processes. There is growing evidence that PRRX1 is highly expressed in certain cancers and is critically involved in human survival prognosis. However, the molecular mechanism of PRRX1 in cancer malignancy remains to be elucidated. Methods: PRRX1 expression in human Malignant peripheral nerve sheath tumors (MPNSTs) samples was detected immunohistochemically to evaluate survival prognosis. MPNST models with PRRX1 gene knockdown or overexpression were constructed in vitro, and the phenotype of MPNST cells was evaluated. Bioinformatics analysis combined with co-immunoprecipitation, mass spectrometry, RNA seq, and structural prediction were used to identify proteins interacting with PRRX1. Results: High expression of PRRX1 was associated with a poor prognosis for MPNST. PRRX1 knockdown suppressed the tumorigenic potential. PRRX1 overexpressed in MPNSTs directly interacts with topoisomerase 2A (TOP2A) to cooperatively promote epithelial-mesenchymal transition and increase expression of tumor malignancy-related gene sets including mTORC1, KRAS, and SRC signaling pathways. Etoposide, a TOP2A inhibitor used in the treatment of MPNST, may exhibit one of its anticancer effects by inhibiting the PRRX1-TOP2A interaction. Conclusion: Targeting the PRRX1-TOP2A interaction in malignant tumors with high PRRX1 expression might provide a novel tumor-selective therapeutic strategy. Significance: MPNST is a malignant tumor with a poor prognosis and still lacks definitive treatment. Our results could hold promise as an alternative therapeutic strategy to inhibit the interaction between PRRX1 and TOP2A, and may improve the prognosis for malignant tumor patients with high expression of PRRX1 and TOP2A such as MPNSTs. Citation Format: Shota Takihira, Eiji Nakata, Daisuke Yamada, Tatsunori Osone, Tomoka Takao, Takeshi Takarada, Akira Hirasawa, Takuto Itano, Tomohiro Fujiwara, Toshiyuki Kunisada, Toshifumi Ozaki. PRRX1-TOP2A interaction is a malignancy-promoting factor in human malignant peripheral nerve sheath tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5649.

Abstract 7548: Role of bromodomain extra terminal inhibitor (BETi) in combination with radiotherapy for the treatment of NF1-associated malignant peripheral nerve sheath tumor

Abstract Introduction: Neurofibromatosis Type 1 (NF-1) associated malignant peripheral nerve sheath tumors (MPNST) harbor mutations in the polycomb repressive complex 2 (PRC2) in 70% of tumors. PRC2 loss results in epigenetic changes, which increase histone acetylation and make the DNA vulnerable to binding by bromodomain proteins. This interaction could be targeted to uncouple histone acetylation from transcription using bromodomain extra terminal inhibitors (BETi). As radiation therapy (RT) is a cornerstone of MPNST treatment, we analyzed the effects of BETi with and without RT. Methods: Mice were implanted with patient-derived xenografts (PDX) of PRC2-wildtype model developed in the Torres laboratory, MPNST007. Mice were segregated into vehicle and I-BET 762 treatment groups and treated with either vehicle or drug for one week before the RT was initiated. Half of the mice in each treatment group (n = 10) received radiation (2 Gy per fraction for 5 days for a total of 10 Gy). The study endpoints were (1) tumor growth rates, (2) tumor size and weight at study termination, (3) immunohistochemical (IHC) staining for biomarkers of proliferation (Ki67), apoptosis (cleaved caspase 3, CC3), and DNA damage (γH2AX), and (4) RNA sequencing of PDXs from each experimental arm. Results: Significant tumor regression was observed in PRC2-mutant PDX tumors treated with I-BET 762 based on tumor growth kinetics over 45 days of treatment (p < 0.001). Tumor volume was significantly reduced by I-BET 762 compared to vehicle (p < 0.01). Combining I-BET 762 and RT resulted in significant tumor volume reduction (p <0.001). RNA sequencing and intersection of differentially expressed genes related to “DNA damage repair” and those repressed by I-BET 762 was performed for the MPNST007 PDXs. The expression of 259 genes related to DNA damage repair decreased after I-BET 762 treatment, including XRCC1, ERCC4, RAD50, RAD51D, and LIG4 (data not shown). IHC analysis prompted by the RNA sequencing results of the I-BET 762-treated PDXs revealed higher levels of γH2AX. An increase in necrotic and fibrotic tissue with increased CC3 in the BETi plus radiation group was observed. Conclusions: Genetic mutations in NF-1-associated MPNST tumors result in susceptibility to BETi treatment. In a PDX model of PRC2 wild-type tumors, BETi treatment resulted in tumor regression and sensitized MPNST xenografts to RT. Combining BETi and RT enhanced tumor death and increased expression of genes associated with DNA damage and apoptosis. Citation Format: Alcia A. Gingrich, Sharon Landers, Angela Bhalla, Cristian Rodriguez-Aguayo, Rossana Lazcano, Suresh Satpati, Alines Lebron-Torres, Emily Z. Keung, Christopher P. Scally, Christina L. Roland, Kelly K. Hunt, Heather Lyu, Heather Lillemoe, Ashleigh Guadagnolo, Alexander Lazar, John Slopis, Ian McCutcheon, John A. Livingston, Ahsan Farooqi, Kunal Rai, Keila E. Torres. Role of bromodomain extra terminal inhibitor (BETi) in combination with radiotherapy for the treatment of NF1-associated malignant peripheral nerve sheath tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7548.

Abstract A061: The LSD1 inhibitor iadademstat shows preclinical efficacy in malignant peripheral nerve sheath tumor cells and synergistic effects in combination

Abstract Background: Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive and rare malignancies accounting for 10% of all tissue sarcomas. Around 50% develop in patients with neurofibromatosis type 1 carrying mutations in the NF1 gene and the other 50% occur sporadically. NF1 is a tumor suppressor gene and a negative regulator of RAS signaling pathway. However, mutation of the NF1 gene is not sufficient to drive MPNST and a series of further mutational events must accumulate in genes other than NF1, such as in CDKN2A and PRC2 complex components. Mutations in p53 or PTEN and/or mutations or copy number variations in oncogenes, such as EGFR or c-Met can also be detected in MPNST. Herein we explore the effects of LSD1 inhibition with iadademstat as a single agent in a panel of MPNST cell lines, both NF1-related and sporadic, and in combination with inhibitors of the MEK-ERK and PI3K/AKT signaling pathways. Materials and Methods: The cell viability in 12 MPNST cell lines, both commercial and derived from patients’ primary tumors, was assessed after 6 days of treatment with iadademstat as a single agent. Synergisms between iadademstat and the MEK inhibitor selumetinib or the PI3K inhibitor copanlisib were also evaluated after 6 days of treatment in three selected responsive cell lines and analyzed with Calcusyn and Combenefit software. Additionally, the effects of iadademstat in RAS pathways (pAKT and pERK levels) were also evaluated in these cell lines. Results: Iadademstat displayed sub-nanomolar activity as a single agent in 8 out of 12 cell lines tested, both NF1-related and sporadic, with different degrees of viability reduction. This was further confirmed with two additional LSD1 inhibitors, with iadademstat being the most potent inhibitor tested. Highly-responsive cell lines showed a decrease in pAKT levels while medium- and low-responsive cell lines displayed no significant differences. pERK levels were not affected. Moreover, the combination of iadademstat and selumetinib or copanlisib displayed strong synergy in cell viability assays in both commercial and patient-derived iadademstat-sensitive cell lines. Conclusions: The LSD1 inhibitor iadademstat is efficacious as single agent in nearly 70% of the MPNST cell lines tested, both NF1-related and sporadic and this efficacy increases synergistically in combination with selumetinib or copanlisib. Therefore, LSD1 inhibitors alone or in combination emerge as a potential treatment for MPNST, an indication with high unmet needs with no approved targeted therapies available. Citation Format: Natalia Sacilotto, Cristina Mascaró, Edgar Creus, Juana Fernández, Conxi Lázaro, Ana Limón, Robert Soliva, Jordi Xaus. The LSD1 inhibitor iadademstat shows preclinical efficacy in malignant peripheral nerve sheath tumor cells and synergistic effects in combination [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A061.

Integrating analysis of proteome profile and drug screening identifies therapeutic potential of MET pathway for the treatment of malignant peripheral nerve sheath tumor

ABSTRACT Background Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma with a poor prognosis that requires novel therapeutic agents. Proteome information is useful for identifying new therapeutic candidates because it directly reflects the biological phenotype. Additionally, in vitro drug screening is an effective tool to identify candidate drugs for common cancers. Hence, we attempted to identify novel therapeutic candidates for MPNST by integrating proteomic analysis and drug screening. Methods We performed comprehensive proteomic analysis on 23 MPNST tumor samples using liquid chromatography – tandem mass spectrometry to identify therapeutic targets. We also conducted drug screening of six MPNST cell lines using 214 drugs. Results Proteomic analysis revealed that the MET and IGF pathways were significantly enriched in the local recurrence/distant metastasis group of MPNST, whereas drug screening revealed that 24 drugs showed remarkable antitumor effects on the MPNST cell lines. By integrating the results of these two approaches, MET inhibitors, crizotinib and foretinib, were identified as novel therapeutic candidates for the treatment of MPNST. Conclusions We successfully identified novel therapeutic candidates for the treatment of MPNST, namely crizotinib and foretinib, which target the MET pathway. We hope that these candidate drugs will contribute to the treatment of MPNST.

Experience of a single center in the treatment of rare malignant peripheral nerve sheath tumors during the years 1991–2021

Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma with a poor prognosis, as the aggressive types of this cancer tend to grow rapidly and metastasize frequently. MPNST is associated with neurofibromatosis type 1 gene mutation. The minority of cases arise secondary to radiation therapy or sporadically. The primary treatment for MPNST is early surgical resection of the tumor. The aim of this study was to retrospectively evaluate the outcome of the treatment of MPNST in Helsinki University Hospital from the years 1991 to 2021. Fourteen MPNST cases were evaluated in this study retrospectively. Descriptive statistical analysis was performed on the collected patient data. Marginal resection was completed in nine cases, wide margins were achieved in three cases, and in two cases the final histological examination of the specimen revealed intralesional removal. During the follow-up time of 36.7 ± 12.1 months, all patients who underwent wide margin resection were alive. One patient died 22 months after intralesional resection and six within 38.3 ± 30.9 months of marginal resection. Seventy-one percent of tumor surgeries resulted in Clavien-Dindo class 3b complications, reflecting the complexity of the surgeries. The aggressive nature of MPNST and the large size of these tumors requires extensive surgery, which can lead to complications. The prognosis of MPNST needs improvement.

Photonic hyperthermia of malignant peripheral nerve sheath tumors at the third near-infrared biowindow.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that typically carry a dismal prognosis. Given the insensitivity of these tumors to traditional chemotherapy and the absence of effective targeted drugs, new therapeutic strategies are urgently needed. Photothermal therapy (PTT) including near-infrared laser at the third biowindow (NIR-III) has demonstrated significant potential in cancer theranostics due to its minimally invasive nature and excellent therapeutic outcomes. However, the passive utilization of photothermal agents (PTAs) with poor target specificity and biocompatibility substantially hinders the clinical translation and application of this method. We evaluated the efficiency, safety, and underlying mechanisms of NIR-III without PTAs in the treatment of MPNSTs. The photothermal performance and tissue penetration capability of the NIR-III laser were evaluated in human MPNST cell lines using CCK-8, Calcein-AM and propidium iodide (PI) staining, and Annexin V-FITC/PI assays. The tumor xenografted mice model was used for evaluating the efficacy and biosafety of NIR-III photothermal ablation. Finally, the underlying mechanisms of NIR-III treatment, explored by whole-transcriptome sequencing, are further verified by RT-qPCR. We found that although the NIR-III photothermal treatment efficiency varied among individuals, which was possibly influenced by different endoplasmic reticulum stress responses, the expected antineoplastic effect was ultimately achieved after adjustment of the power density and radiation duration. The present study provides an intriguing noninvasive therapy for MPNSTs that accelerates the clinical translation of PTT while avoiding the biocompatibility issues arising from PTAs. This work was supported by grants from National Natural Science Foundation of China (82102344; 82172228); Shanghai Rising Star Program supported by Science and Technology Commission of Shanghai Municipality (20QA1405600); Natural Science Foundation of Shanghai (22ZR1422300); Science and Technology Commission of Shanghai Municipality (19JC1413) ; "Chenguang Program" supported by Shanghai Education Development Foundation (SHEDF) (19CG18); Shanghai Municipal Key Clinical Specialty (shslczdzk00901); Innovative research team of high-level local universities in Shanghai (SSMU-ZDCX20180700).

Preclinical Assessment of MEK Inhibitors for Malignant Peripheral Nerve Sheath Tumors Reveals Differences in Efficacy and Adaptive Response.

Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft-tissue sarcomas refractory to standard therapies. Inactivation of NF1 and subsequent upregulation of RAS/RAF/MEK/ERK signaling exist in the majority of MPNSTs. However, the lack of preclinical assessment of MEK inhibitors in MPNSTs hinders the clinical application as well as the development of combination therapy. To guide further clinical studies, we evaluated different MEK inhibitors in terms of efficacy, safety, and mechanism of adaptive response in treating MPNSTs. Using a MPNST tissue microarray, we found that p-ERK could serve as a biomarker for predicting the prognosis of MPNST patients as well as an effective therapeutic target. Through in vitro and in vivo experiments, we identified trametinib as the most potent MEK inhibitor for the treatment of MPNSTs. Mechanistically, reduced reactivation of the MAPK pathway and compensatory activation of the parallel pathways contributed to better efficacy. Our results provide a basis for the further clinical application of MEK inhibitors as single agents or combinational therapies.

Silver Nanoparticles Selectively Treat Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors in a Neurofibromin-Dependent Manner.

Neurofibromatosis type 1 (NF1) is among the most common neurogenic disorders, characterized by loss of function mutations in the neurofibromin gene (NF1). NF1 patients are extremely susceptible to developing neurofibromas, which can transform into deadly malignant peripheral nerve sheath tumors (MPNSTs). At the center of these tumors are NF1-null Schwann cells. Here, we found that nanomedicine shows promise in the treatment of NF1-associated MPNSTs. We assessed the cytotoxicity of silver nanoparticles (AgNPs) in NF1-null NF1-associated MPNSTs, NF1-wildtype sporadic MPNST, and normal Schwann cells. Our data show that AgNP are selectivity cytotoxic to NF1-associated MPNSTs relative to sporadic MPNST and Schwann cells. Furthermore, we found that sensitivity to AgNPs is correlated with the expression levels of functional neurofibromin. The restoration of functional neurofibromin in NF1-associated MPNSTs reduces AgNP sensitivity, and the knockdown of neurofibromin in Schwann cells increases AgNP sensitivity. This finding is unique to AgNPs, as NF1 restoration does not alter sensitivity to standard of care chemotherapy doxorubicin in NF1-associated MPNSTs. Using an in vitro model system, we then found that AgNP can selectively eradicate NF1-associated MPNSTs in co-culture with Schwann cells at doses tolerable to normal cells. AgNP represents a novel therapy for the treatment of NF1-associated MPNSTs and addresses significant unmet clinical need.

STAT3, VEGF, and PSMA Expression Patterns in Malignant Peripheral Nerve Sheath Tumors, Malignant Melanomas, and Glioblastomas: Does Staining Percentage and Intensity Have an Effect on Survival?

Malignant peripheral nerve sheath tumors (MPNSTs), glioblastomas (GBMs), and malignant melanomas (MMs) are neural crest-originating aggressive tumors with a poor prognosis. Signal transducer and transcription activator 3 (STAT3) plays a role in many biological processes, including cell life and proliferation, the acute phase response, chronic inflammation, autoimmunity, metabolism, and cancer progression, It is also known to be a prooncogenic transcription factor. Vascular endothelial growth factor (VEGF) is one of the most potent proangiogenic stimuli ever identified. It mediates tumor neovascularization, and is associated with angiogenesis and lymphangiogenesis. The prostate-specific membrane antigen (PSMA) folate hydrolase I, despite its name, has been found in tissues other than the prostate. It is overexpressed in prostate cancer cells and several other cancers, and has the potential to be a target for radioligand therapy. We investigated the value of STAT3, VEGF and PSMA immunohistochemical expression patterns and their effects on survival in MPNSTs, GBMs, and MMs. Their expression patterns were evaluated in 25 MPNSTs, 27 GBMs, and 25 MM cases. All GBM cases stained positively for STAT3 and VEGF. In the other groups, the staining patterns were heterogeneous. None of the cases showed positive staining with PSMA. There was no statistically significant difference in survival between cases with differing VEGF and STAT3 staining patterns in the MPSNT and MM groups, but there was an increase in mortality as the VEGF score increased in the GBM group. The suppression of VEGF and STAT3 may be a promising avenue for treatment of MPNSTs, GBMs, and MMs, although further research is needed.

Chromosomal translocations inactivating CDKN2A support a single path for malignant peripheral nerve sheath tumor initiation.

Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas with poor prognosis, developing either sporadically or in persons with neurofibromatosis type 1 (NF1). Loss of CDKN2A/B is an important early event in MPNST progression. However, many reported MPNSTs exhibit partial or no inactivation of CDKN2A/B, raising the question of whether there is more than one molecular path for MPNST initiation. We present here a comprehensive genomic analysis of MPNST cell lines and tumors to explore in depth the status of CDKN2A. After accounting for CDKN2A deletions and point mutations, we uncovered a previously unnoticed high frequency of chromosomal translocations involving CDKN2A in both MPNST cell lines and primary tumors. Most identified translocation breakpoints were validated by PCR amplification and Sanger sequencing. Many breakpoints clustered in an intronic 500bp hotspot region adjacent to CDKN2A exon 2. We demonstrate the bi-allelic inactivation of CDKN2A in all tumors (n = 15) and cell lines (n = 8) analyzed, supporting a single molecular path for MPNST initiation in both sporadic and NF1-related MPNSTs. This general CDKN2A inactivation in MPNSTs has implications for MPNST diagnostics and treatment. Our findings might be relevant for other tumor types with high frequencies of CDKN2A inactivation.

Surgical strategies and the use of functional reconstructions after resection of MPNST: An international survey on surgeons’ perspective

Malignant peripheral nerve sheath tumors (MPNST) are aggressive and possibly morbid sarcomas because of their tissue of origin. However, postoperative functional status of MPNST patients has been understudied. Reconstructions may play a role in restoring lost function, but are still infrequently carried out. This study investigated how surgical considerations and the use of functional reconstructions differed among surgeons treating MPNST. This survey was distributed among members of multiple surgical societies. Survey responses were analyzed overall and between surgical subspecialties (surgical oncology/neurosurgery/plastic surgery/other). A total of 30 surgical oncologists, 30 neurosurgeons, 85 plastic surgeons, and 29 ‘others’ filled out the survey. Surgical oncologists had the highest case load (p < 0.001). Functional status was usually considered preoperatively among all subspecialties (65.1%); 42.2% never considered performing less extensive resections to preserve function. Neuropathic pain and motor deficits are seen in 40.9 ± 22.9% and 36.7 ± 25.5% respectively. Functional reconstructions for motor and sensory deficits were more commonly considered by plastic surgeons and ‘others’. Relative contraindications for reconstructions did not differ between subspecialties (p > 0.05). Most surgeons would reconstruct directly or directly unless radiotherapy would be administered (62.7%). On average, surgeons would consider functional reconstructions when estimated survival is 3.0 ± 2.0 years. Surgical treatment of MPNSTs differs slightly among subspecialties. Neuropathic pain, motor deficits, and sensory deficits are commonly acknowledged postoperative morbidities. Functional reconstructions are varyingly considered by surgeons. Surgical oncologists and neurosurgeons treat most patients, yet may be least likely to consider functional reconstructions. A multidisciplinary surgical and reconstructive approach may be beneficial in MPNSTs. • Neuropathic pain, motor deficits, and sensory deficits are common postoperative morbidities after the resection of MPNSTs. • Surgical considerations for function preservation varies among surgeons. • Surgical oncologists and neurosurgeons treat most MPNST patients but are least likely to consider functional reconstructions. • Functional reconstructions can be considered in MPNST patients with a life expectancy of three or more years.

RECURRENCE OF MALIGNANT PERIPHERAL NERVE SHEATH TUMOR

Peripheral nerve sheath tumor (PNST) is known as a benign tumor called Schwannomas, developed from the Schwann cells that produce myelin and collagen, and can occur in a wide variety of locations. In some cases, it can take a malignant turn and grow as a pelvic mass known as malignant peripheral nerve sheath tumor (MPNST), malignant schwannoma, malignant neurofibroma, malignant mesenchynoma and neurogenic sarcoma. Our case report presents a female patient presenting dysuria and pelvic pain. The clinical examination revealed a palpable mass in the lower abdomen. The computer tomography (CT) scan of the abdomen and pelvic region showed a tumor mass that was in contact with the nearby organs, but not infiltrating them. After the surgery, histopathology confirmed the MPNST proliferation. A month after, the patient returned for a follow-up and presenting pelvic pain. The CT scan of the abdomen and pelvic region showed a tumoral mass compressing the nearby organs, but not infiltrating them. The patient was referred to oncology board for palliative treatment. The particularity of this case report is the short period of time recurrence of the MPNST, rather than metastases. The most important treatment for MPNSTs remains surgery, trying to achieve negative margins. However, there have been reported two cases of unresectable MPSNT with partial remission to chemo- and radiotherapy.&#x0D;

A rare case report of malignant peripheral nerve sheath tumor involving both the small bowel and large bowel

Malignant peripheral nerve sheath tumor (MPNST) contains properties and histologic markers of both neural crest cells and mesenchymal cells. It is a rare diagnosis, with an incidence of 1:100,000/year or 4%–10% of soft-tissue sarcomas. There are very few cases reported and studied. Therefore, establishing a proper diagnosis and treatment of MPNST provides a challenge. We present this unique and rare case of metastatic MPNST of the small and large bowel with bone, pulmonary, liver, and splenic metastases. The patient subsequently developed hemorrhagic brain metastases and died 6 months after THE initial diagnosis.

MALIGNANT PERIPHERAL NERVE SHEATH TUMOR SPREAD TO THE THORACIC CAVITY CAUSING OBSTRUCTIVE SHOCK

SESSION TITLE: Medical Student/Resident Lung Pathology SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Malignant peripheral nerve sheath tumor (MPNST) is a rare and aggressive subtype of sarcoma, which originates from peripheral nerves. MPNST can present sporadically or in association with neurofibromatosis type 1 (NF1). In this case we describe a patient with a rare spread of MPNST to her thoracic cavity resulting in a combination of obstructive and septic shock leading to death. CASE PRESENTATION: A 30 year old female with NF1 and MPNST presented with right flank pain of 5 days duration. The patient was found to have leukocytosis in the setting of hydronephrosis and was subsequently admitted. She quickly decompensated, becoming tachycardic and hypotensive. Computed tomography angiography of the abdomen and pelvis revealed severe hydronephrosis secondary to large abdominal mass effect and intrathoracic mass extending into the right middle lobe of the lung with invasion of the right and left atrium. Subsequently, she was transferred to the medical intensive care unit for mixed obstructive and septic shock requiring intubation and vasopressor support. Transthoracic echocardiogram revealed a small left ventricle cavity and an echogenic density 1.96 x 2.75 cm compressing the left atrium which appeared to be mass effect from the intrathoracic sarcoma. While awaiting hospice placement, she became bradycardic and was unable to be resuscitated, and ultimately succumbed to her condition. DISCUSSION: MPNST is defined as malignant tumors arising from peripheral nerves or as benign neurogenic tumors converted into malignant tumors. Although MPNST primarily affects extremities, it can rarely also occur in the thoracic cavity. The majority of MPNST occur on the right side of the heart, in close proximity to the interatrial septum, likely because of the origin of MPNST from cardiac branches of the vagus nerve and cardiac plexus. However, the presence of MPNST on the left side has also been reported. As with this patient, patients with Neurofibromatosis type I carry an increased risk for MPNST between 8-13%. In this case, the significant and severe spread of this patient’s MPNST caused multiple obstructions in the urinary system as well as within the heart, ultimately leading to the mixed shock. The most effective treatment for MPNST is complete excision, which unfortunately is not always possible in advanced stages. CONCLUSIONS: MPNST can be very difficult to treat due to its aggressive nature leading to terrible complications including obstruction and early death. In this case, the patient not only had MPNST, but also an even rarer spread to the thoracic cavity ultimately leading to her death. It is important to recognize that this disease process can escalate to a shock state and must be treated accordingly. Whenever possible, palliative care should be involved in patient care early to establish goals of care. Reference #1: Evans DG, Baser ME, McGaughran J, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet 2002; 39:311. Reference #2: Li S, Qiu Y, Yu J, Liang C, Peng L. Cardiac malignant peripheral nerve sheath tumor on computed tomography and magnetic resonance imaging: A case report. Medicine (Baltimore). 2019;98(44):e17463. doi:10.1097/MD.0000000000017463 Reference #3: Prifti E, Baboci A, Ikonomi M. A giant cardiac malignant peripheral nerve sheath tumor presenting with total obstruction of the superior vena cava. Ann Thorac Surg. 2014;97(1):e7-e9. doi:10.1016/j.athoracsur.2013.08.044 DISCLOSURES: No relevant relationships by Christopher Izzo, source=Web Response No relevant relationships by Nimeh Najjar, source=Web Response No relevant relationships by Spencer Streit, source=Web Response

HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis.

Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacological inhibition of HuR had potent cytostatic and cytotoxic effects on tumor growth, and strongly suppressed metastatic capacity in vivo. Importantly, we linked the profound tumorigenic function of HuR to its ability to simultaneously regulate multiple essential oncogenic pathways in MPNST cells, including the Wnt/β-catenin, YAP/TAZ, RB/E2F, and BET pathways, which converge on key transcriptional networks. Given the exceptional dependency of MPNST cells on HuR for survival, proliferation, and dissemination, we propose that HuR represents a promising therapeutic target for MPNST treatment.

Phase II clinical trial of pazopanib for patients with unresectable or metastatic malignant peripheral nerve sheath tumors.

e23569 Background: Malignant peripheral nerve sheath tumor (MPNST) is a malignant soft tissue tumor that does not respond well to chemotherapy and often develops on the basis of neurofibromatosis type 1 (NF1). The purpose of this study was to examine the effects of pazopanib on MPNST. Methods: This study was designed as a physician-initiated phase II clinical trial of pazopanib in patients with MPNST with unresectable or distant metastases. Eleven large hospitals were selected from the Japanese Musculoskeletal Oncology Group (JMOG), and patients were registered between July 2016 and August 2018. The primary endpoint was set to clarify the clinical benefit rate (CBR, including complete or partial response and stable disease) at 12 weeks for pazopanib according to Response Evaluation Criteria in Solid Tumors (RECIST1.1). Progression-free survival and overall survival were set as secondary endpoints along with the safety of this treatment. The clinical benefit rate based on Choi evaluation at week 12 was also set as the secondary endpoint. Results: The study enrolled twelve patients with MPNST. Grade 2 was 7 and grade 3 was 5 by according to the FNCLCC evaluation. Median follow-up period was 10.60 (1.74-22.85) months. Six were male, and six were female. Median age was 49 (20-76). After 12 weeks of pazopanib treatment, CBR was 50.0% (6 of 12 patients) and 50.0% (6 of 12 patients) at RECIST and Choi criteria, respectively. The median progression-free survival was 5.4 months for both RECIST and Choi. Interestingly, the median progression-free survival was 2.9 months for patients with FNCLCC Grade 2 and 10.2 months for Grade 3 for both RECIST and Choi. The median overall survival was 10.6 months. The adverse events of Grade 4 was neutropenia in one person and lipase elevation in one person. Grade 3 adverse events observed in ≥10% of patients were increase of AST and ALT, and decrease of white blood cells. Conclusions: The results of this pazopanib clinical trial were comparable to those of previous doxorubicin-based chemotherapy, and better than those of other molecular targeted therapy. Although accumulation of cases is necessary, pazopanib treatment for MPNST might be a safe and promising treatment, particularly for grade 3 MPNST. Clinical trial information: UMIN000019303 .

New Model Systems and the Development of Targeted Therapies for the Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors.

Neurofibromatosis Type 1 (NF1) is a common genetic disorder and cancer predisposition syndrome (1:3000 births) caused by mutations in the tumor suppressor gene NF1. NF1 encodes neurofibromin, a negative regulator of the Ras signaling pathway. Individuals with NF1 often develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage, some of which progress further to malignant peripheral nerve sheath tumors (MPNSTs). Treatment options for neurofibromas and MPNSTs are extremely limited, relying largely on surgical resection and cytotoxic chemotherapy. Identification of novel therapeutic targets in both benign neurofibromas and MPNSTs is critical for improved patient outcomes and quality of life. Recent clinical trials conducted in patients with NF1 for the treatment of symptomatic plexiform neurofibromas using inhibitors of the mitogen-activated protein kinase (MEK) have shown very promising results. However, MEK inhibitors do not work in all patients and have significant side effects. In addition, preliminary evidence suggests single agent use of MEK inhibitors for MPNST treatment will fail. Here, we describe the preclinical efforts that led to the identification of MEK inhibitors as promising therapeutics for the treatment of NF1-related neoplasia and possible reasons they lack single agent efficacy in the treatment of MPNSTs. In addition, we describe work to find targets other than MEK for treatment of MPNST. These have come from studies of RAS biochemistry, in vitro drug screening, forward genetic screens for Schwann cell tumors, and synthetic lethal screens in cells with oncogenic RAS gene mutations. Lastly, we discuss new approaches to exploit drug screening and synthetic lethality with NF1 loss of function mutations in human Schwann cells using CRISPR/Cas9 technology.

A Novel Treatment Modality for Malignant Peripheral Nerve Sheath Tumor Using a Dual-Effect Liposome to Combine Photodynamic Therapy and Chemotherapy.

Neurofibromatosis type 1 (NF1) is an inherited neurological disorder. Approximately 5–13% of NF1 patients may develop a malignant peripheral nerve sheath tumor (MPNST), which is a neurofibrosarcoma transformed from the plexiform neurofibroma or schwannoma. Given the large size and easy metastasis of MPNST, it remains difficult to be cured by either surgical or conventional chemotherapy. In this study, we investigated the possibility of combining photodynamic therapy (PDT) and chemotherapy to treat MPNST by using a dual-effect liposome (named as PL-cDDP-Ce6), in which a chemotherapeutic agent, cisplatin (cDDP), and photosensitizer, chlorine e6 (Ce6) were encapsulated in the same carrier. The cytotoxic effect of PL-cDDP-Ce6 against MPNST cells was significantly higher than cells treated with liposomal cDDP or Ce6 alone or in combination after light irradiation. Treatment with the dual-effect liposomes in mice bearing xenograft MPNST tumor reveals a significant increase in survival rate compared to those treated with liposomal cDDP and Ce6 in combination. Moreover, there is no weight loss or derangements of serum biochemistry. In conclusion, this study demonstrates the clinical potential and advantage of using this liposomal drug for the treatment of MPNST.

Malignant Peripheral Nerve Sheath Tumor of the Cervical Spine Treated with Surgical Resection Followed by X-ray Radiotherapy or Carbon Ion Radiotherapy: A Report of Three Cases.

Introduction Spinal malignant peripheral nerve sheath tumors (MPNSTs) are extremely rare. Because of vital surroundings, en bloc resection can be difficult in MPNSTs of the cervical spine. Herein, we report three cases of MPNST followed by radiotherapy or carbon ion radiotherapy (CIRT) after surgery. Technical Note In case 1, the patient underwent subtotal resection from both a posterior and anterior approach following by adjuvant X-ray radiotherapy. The patient died 13 years after surgery due to liver cancer unrelated to MPNST. In case 2, recurrence spread to the spinal canal in 10 months after primary CIRT. The patient underwent resection of the spinal canal lesion with the residual lesion treated by additional CIRT. Recurrence could be controlled for at least 1 year. In case 3, the patient underwent partial resection for the spinal canal lesion with the residual lesion treated by CIRT. Intradural and extradural recurrences from outside of the CIRT field were observed at 3 years after surgery. Conclusions Complete resection and adjuvant X-ray radiotherapy would be an effective treatment for MPNST of the cervical spine, even if en bloc resection with a wide margin is impossible. CIRT for the residual tumor after incomplete resection may have the potential to be an additional treatment option; however, further investigation is warranted.

Targeted therapy for malignant peripheral nerve sheath tumor: translational research and clinical application

Malignant peripheral nerve sheath tumor (MPNST) is a rare invasive soft tissue sarcoma that originates from peripheral nerve branches and peripheral nerve sheaths. Early radical surgery is an effective treatment for MPNST. Since it is insensitive to radiotherapy and chemotherapy, the disease manifests a rapid progression, poor prognosis and high mortality. In recent years, the translational researches on the driving factors and therapeutic targets of MPNST have been rapidly developed, including the pathways of NF1-Ras, Raf-MEK-ERK, PI3K-AKT-mTOR, Wnt signaling, and abnormal expressions of apoptotic proteins, the general loss of polycomb repressive complex 2 (PRC2), upregulation of the HDAC family, abnormal expressions of receptor tyrosine kinases, expressions of programmed cell death ligand (PD-L1), aurora kinase and various microRNAs.This review summarizes the current translational researches on potential therapeutic targets of MPNST, and the clinical trials which provide helpful information for MPNST targeted therapy.