Neurofibrosarcoma

Decorin-negative MPNST cells grew significantly larger tumor in vivo. Thus, depletion of Decorin may occur in CSCs in MPNSTs, serving possibly as a new therapeutic target.

Patients with NF1-mutant ERMS lacking TP53 alterations may benefit from dose-reduction chemotherapy. On the basis of the diagnostic challenges and significant treatment and prognostic differences, molecular profiling of challenging tumors with rhabdomyoblastic differentiation is recommended.

Moreover, in immunocompetent mouse models with MPNST-like allografts, CRAd injections induce a robust infiltration of CD8+ T cells into the tumor microenvironment (TME), indicating the potential to promote a pro-inflammatory response. These findings underscore oncolytic Ads as promising, selective, and minimally toxic agents for MPNST therapy, warranting further exploration.

P1, N=44, Recruiting, Seattle Children's Hospital | Trial completion date: Jun 2038 --> Jun 2040 | Trial primary completion date: Jun 2024 --> Jun 2025

AgNP was able to selectively remove pNF cells from a co-culture with patient-matched Schwann cells. Therefore, AgNPs represent a new approach for clinical management of NF1-associated pNF to address significant clinical need.

Melanoma-associated antigen, desmin, α-smooth muscle actin, CD18, CD31, ionized calcium binding adapter molecule-1 and CK8/18 were not expressed, which helped differentiate the tumour from other feline spindloid cell neoplasms. These features are characteristic of divergent epithelioid differentiation of MPNST.

P1/2, N=22, Terminated, Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | N=192 --> 22 | Trial completion date: Dec 2024 --> Feb 2024 | Recruiting --> Terminated; sponsor adjusts its research and development strategy

Mouse genetic and human xenograft MPNST models treated with STING agonist plus ICB exhibited growth delay via increased apoptotic cell death. This strategy offers a potential treatment regimen for MPNST.

P1, N=56, Active, not recruiting, University Health Network, Toronto | Recruiting --> Active, not recruiting

In response to MET, MEK and mTOR inhibition, we observed broad and heterogeneous activation of key differentiation genes in Trp53-deficient lines suggesting Trp53 loss also impacts lineage plasticity in MPNSTs. These results demonstrate the mechanisms by which p53 loss alters MET dependency and therapy resistance in MPNSTS through kinome reprogramming and phenotypic flexibility.

Furthermore, we review emerging evidence suggesting a dueling role of Nf1+/- immune cells along the neurofibroma to MPNST continuum, on one hand propitiating PNF initiation, while on the other, potentially impeding the malignant transformation of plexiform and atypical neurofibroma precursor lesions. Finally, we underscore the potential implications of these discoveries and advocate for further research directed at illuminating the contributions of various immune cells subsets in discrete stages of tumor initiation, progression, and malignant transformation to facilitate the discovery and translation of innovative diagnostic and therapeutic approaches to transform risk-adapted care.

P1/2, N=43, Active, not recruiting, Gulam Manji | Recruiting --> Active, not recruiting | Phase classification: P2 --> P1/2 | Trial completion date: Mar 2024 --> Jun 2024

Regarding BPNST + ANF vs. MPNST, best discrimination was obtained using an ADCdark cut-off value of 1.4 × 10-3 mm2/s (83.3% sensitivity, 94.5% specificity). DW-MRI using ADCdark allows specific and noninvasive discrimination of benign, atypical, and malignant nerve sheath tumors in NF1.

The interpretation criteria for FISH detection of MDM2 amplification are currently not unified. The signal characteristics need more attention when interpreting.

Targeting the PRRX1-TOP2A interaction in malignant tumours with high PRRX1 expression might provide a novel tumour-selective therapeutic strategy.

SOX9 increased collagen VI secretions by enhancing the activation of PCOLCE in neurofibroma cells. These findings might provide new perspectives on the pathophysiological significance of SOX9 in neurofibromas and elucidate a novel molecular mechanism underlying neurofibromas.

P1, N=14, Active, not recruiting, Jonsson Comprehensive Cancer Center | Trial completion date: Jan 2025 --> Jan 2026 | Trial primary completion date: Jan 2024 --> Jan 2025

P1, N=98, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Dec 2027 | Trial primary completion date: Dec 2024 --> Dec 2026

P2, N=148, Not yet recruiting, HRYZ Biotech Co.

Over time, the proportion of grade 3 MPNST and the malignant/premalignant ratio in screened individuals significantly decreased (p=0.03 and p<0.001, respectively). This study emphasizes the diagnostic and screening performances of whole-body 18F-FDG-PET/MRI in adults with NF1.

P1/2, N=20, Recruiting, Adaptimmune | Not yet recruiting --> Recruiting

P1/2, N=224, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P2/3, N=140, Active, not recruiting, National Cancer Institute (NCI)

Atypical neurofibromatous neoplasm with uncertain biologic potential is a newly defined entity, and it is important to discriminate it from low-grade MPNST, which requires more aggressive treatment methods. To the best of our knowledge, this is the first report describing synchronous GISTs, MPNST, and atypical neurofibromatous neoplasm with uncertain biologic potential developing in a single NF1 patient.

Therefore, the mass was diagnosed as a malignant peripheral nerve sheath tumor (MPNST). To our knowledge, this is the first report of primary renal MPNST in a dog.

These data suggest that a mechanism of YAP/TAZ activation by de novo synthesized adrenaline, as well as exogenous adrenaline, may exist in the maintenance of cancer stemness of MPNST cells. This mechanism not only helps to understand the pathology of MPNST, but could also contribute to the development of therapeutic strategies for MPNST.

P1, N=98, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

FT895, an HDAC11 inhibitor, exhibits potent anti-tumor effects on MPNST cells and enhances the cytotoxicity of cordycepin against MPNST...The RNA-seq analysis underscored the prominent role of the HIF-1α signaling pathway post-FT895 treatment, aligning with the observed impairment in mitochondrial respiration. In summary, the study pioneers the revelation that FT895 induces mitochondrial respiratory damage in MPNST cells.

Pan-TRK IHC shows some utility as a diagnostic and surrogate marker for NTRK screening however, physiologic or non-specific expression may lead to false-positive results.

Fusion-positive cases expressed significantly higher HTRA1 mRNA abundance, perhaps exploitable as a biomarker. In summary, we systematically characterize a series of 60 SH3PXD2A::HTRA1 fusion-positive schwannomas, showing their distinctive morphology and location-specific prevalence for the first time.

NF1 is associated with a substantially higher risk of all-cause and disease-specific mortality. This finding suggests that closer surveillance is required for NF1 patients at risk of developing MPNSTs.

Combinational, but not singular, in vivo treatment markedly suppressed the growth of S462TY xenografts established in the sciatic nerves of immune-deficient mice. Hence, prodrug farnesyl monophosphate FTIs can be rendered water-soluble by conjugation to PAMAM G4 dendrimers and exhibit potent anti-tumor activity when combined with clinically achievable statin concentrations.

DNAm profiling is a useful tool in diagnostic work-up of MPNSTs. Its application in a retrospective series collected during pre-molecular era contributed to classify morphologic mimics. The methylation group MPNST-like is a 'hybrid' category in pediatrics including high-grade and low-grade tumors mainly characterized by TRK alterations.

P2, N=41, Not yet recruiting, University of Alabama at Birmingham | Trial completion date: Jan 2030 --> Jun 2030 | Trial primary completion date: Jan 2029 --> Jun 2029

ONC201, ONC206, and ONC212 are imipridones showing pro-apoptotic anti-cancer response...Additionally, pediatric solid tumor cells were treated with single-agent therapy with histone deacetylase inhibitors (HDACi) vorinostat, entinostat, and panobinostat, showing cell killing with all 3 HDACi drugs, with panobinostat showing the greatest potency...Our results introduce a novel class of small molecules to treat pediatric solid tumors in a precision medicine framework. Use of impridones in pediatric oncology is novel and shows promising pre-clinical efficacy in pediatric solid tumors, including in combination with HDAC inhibitors.

Conclusion In conclusion, this study adds to our understanding of soft tissue sarcomas by emphasizing the crucial role of MUC4 in certain sarcoma subtypes while acknowledging the complex variety of the sarcoma landscape. Further research is needed to understand the molecular mechanism that governs marker expression patterns, as well as the therapeutic implications.

P2, N=21, Completed, Sarcoma Alliance for Research through Collaboration | Active, not recruiting --> Completed

The CD16a overexpression with CD68 positivity in the ANNUBPs potentially reflects that the TME immune modulation could be associated with NF progression to an ANNUBP. Further studies should explore the role of CD16a in immunomodulation for accelerating NF growth.

There are no approved drug treatments for adults with NF1-related inoperable plexiform neurofibromas, and only one drug (selumetinib), which is an FDA-approved targeted therapy for the treatment of symptomatic pediatric plexiform neurofibromas, highlighting the need for additional drug screening and development...The ΔS technique used here, in tandem with a supplemental ΔS web tool, simplifies HTS analysis and may provide a springboard for further investigations into drug response in NF1-related cancers. The tool may also prove useful for drug development in a variety of other cancers.

Additionally, SOX10 has been identified in various epithelial neoplasms, including breast, ovarian, salivary gland, nasopharyngeal, and bladder cancers, presenting itself as a potential diagnostic and prognostic marker. However, despite these associations, further research is imperative to elucidate its precise role in these malignancies.

Most patients (n = 42, 87.5%) received a combination of doxorubicin, ifosfamide, or etoposide as first-line chemotherapy. Salvage chemotherapy regimens and their TTP varied greatly, with irinotecan/temozolomide-based regimens having the longest average TTP (255.5 days, among 4 patients). Patients with advanced or metastatic MPNST often succumb to their disease despite multiple lines of therapy. These data may be used as comparative information in decision-making for future patients and clinical trials.

If validated prospectively in future studies, these signatures may serve as molecular diagnostic tools to augment conventional histopathological diagnosis by identifying neurofibromas at high risk of undergoing malignant transformation, facilitating risk-adapted care.