-
Methods in Molecular Biology (Clifton,... 2024Oncogenic fusion genes are attractive therapeutic targets because of their tumor-specific expression and central "driver" roles in various human cancers. However,...
Oncogenic fusion genes are attractive therapeutic targets because of their tumor-specific expression and central "driver" roles in various human cancers. However, oncogenic fusions involving transcription factors such as PAX3-FOXO1 in alveolar fusion gene-positive rhabdomyosarcoma (FP-RMS) have been difficult to inhibit due to the apparent lack of tractable drug-like binding sites comparable to that recognized by Gleevec (imatinib mesylate) on the BCR-ABL1 tyrosine kinase fusion protein. Toward the identification of novel small molecules that selectively target PAX3-FOXO1, we used CRISPR-Cas9-mediated knock-in to append the pro-luminescent HiBiT tag onto the carboxy terminus of the endogenous PAX3-FOXO1 fusion protein in two human FP-RMS cell lines (RH4 and SCMC). HiBiT is an 11-amino acid peptide derived from the NanoLuc luciferase that produces a luminescence signal which is ~100-fold brighter than firefly or Renilla luciferases through high-affinity binding to a complementary NanoLuc peptide fragment called LgBiT. To facilitate single-cell clonal isolation of knock-ins, the homology-directed repair template encoding HiBiT was followed by a P2A self-cleaving peptide for coexpression of an mCherry fluorescent protein as a fluorescence-activated cell sorter (FACS)-selectable marker. HiBiT tagging thus allows highly sensitive luminescence detection of endogenous PAX3-FOXO1 levels permitting quantitative high-throughput screening of large compound libraries for the discovery of PAX3-FOXO1 inhibitors and degraders.
Topics: Humans; Paired Box Transcription Factors; CRISPR-Cas Systems; Rhabdomyosarcoma; Peptides; Oncogene Proteins, Fusion; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Red Fluorescent Protein
PubMed: 38526790
DOI: 10.1007/978-1-0716-3738-8_12 -
Journal of Medical Case Reports Mar 2024Primary brain rhabdomyosarcoma is a rare primary brain malignancy with few case reports. The vast majority of cases of primary brain rhabdomyosarcoma occur in pediatric...
BACKGROUND
Primary brain rhabdomyosarcoma is a rare primary brain malignancy with few case reports. The vast majority of cases of primary brain rhabdomyosarcoma occur in pediatric patients, and immunohistochemistry can distinguish it from embryonal subtypes; however, few cases of primary brain rhabdomyosarcoma in adults have been reported in the literature.
CASE PRESENTATION
We report the case of a 26-year-old White male patient who was found to have primary brain alveolar rhabdomyosarcoma after developing headaches for several months. A brain MRI revealed a mixed cystic and solid tumor along the vermis of the cerebellum. The patient underwent a gross total surgical resection, which confirmed the diagnosis of alveolar rhabdomyosarcoma. Further staging workup for another primary focus or disseminated disease yielded negative results, confirming the diagnosis of primary alveolar rhabdomyosarcoma of the brain.
CONCLUSION
The standard of care for managing this rare type of brain tumor involves surgery with adjuvant chemoradiotherapy. Further studies should be conducted for a better diagnostic and therapeutic understanding.
Topics: Adult; Humans; Male; Brain; Brain Neoplasms; Magnetic Resonance Imaging; Rhabdomyosarcoma; Rhabdomyosarcoma, Alveolar; Rhabdomyosarcoma, Embryonal
PubMed: 38520005
DOI: 10.1186/s13256-024-04471-w -
Cureus Feb 2024Background and objective Rhabdomyosarcoma (RMS) is a rare and malignant mesenchymal tumor characterized by skeletal muscle differentiation. While it is a common soft...
Background and objective Rhabdomyosarcoma (RMS) is a rare and malignant mesenchymal tumor characterized by skeletal muscle differentiation. While it is a common soft tissue sarcoma in children, its incidence significantly decreases with advancing age, rendering it exceptionally rare in individuals aged more than 45 years. This study aimed to shed light on the clinicopathological diversity and subtypes of RMS, thereby providing a comprehensive overview for enabling diagnostic precision and therapeutic strategies in treating this infrequently encountered malignancy in adults. Methodology This was a hospital-based cross-sectional study conducted in the Department of Pathology. Patients who were diagnosed with RMS over a period of three years were included in the study. The demographic features such as age and sex and aspects related to the tumor site, size, subtypes of RMS, and immunohistochemical expression were studied. Results A total of 14 cases were included in our study. The age at diagnosis ranged from four months to 65 years with a male-to-female ratio of 1:2.5. The sites of presentation were head and neck, trunk, pelvis, genitourinary tract, and retroperitoneum. The histological types were embryonal, alveolar, pleomorphic, and mixed and spindle cell types. The tumor cells were positive for immunohistochemistry markers desmin, MyoD1, and vimentin. Conclusion This study delved into the clinicopathological intricacies of RMS, offering comprehensive insights into its diverse subtypes. Our findings underscore the unique presentation of RMS in adults, with trunk and genitourinary tracts emerging as primary sites and alveolar and pleomorphic RMS observed as the predominant histological subtypes. Furthermore, the study sheds light on rare subtypes with distinct anatomical distributions.
PubMed: 38500901
DOI: 10.7759/cureus.54341 -
International Journal of Surgical... Mar 2024Rhabdomyosarcoma is a highly malignant tumor with striated muscle differentiation, which is histologically classified as alveolar, embryonal, pleomorphic, and spindle...
Rhabdomyosarcoma is a highly malignant tumor with striated muscle differentiation, which is histologically classified as alveolar, embryonal, pleomorphic, and spindle cell/sclerosing histological subtype. Rhabdomyosarcoma with rearrangement, which usually occurs in the bone, is a newly identified rare spindle and epithelioid rhabdomyosarcoma with characteristic clinicopathological features and molecular alterations. We report a 39-year-old female patient who underwent local excision of the mandibular lesion. Microscopically, the intraosseous tumor was composed of spindle-shaped, epithelioid, and rhabdomyoblastic cells with atypical nuclei and atypical mitotic figures. In addition, rearrangement was revealed by the fluorescence in situ hybridization. The tumor was thus correctly diagnosed as rhabdomyosarcoma with rearrangement. The patient was scheduled to undergo radiotherapy, and triple-agent chemotherapy after surgery, and no tumor recurrence or metastasis was detected during the 3-month postoperative follow up. Since this tumor is relatively rare and newly recognized, it can be easily misdiagnosed or missed and might be a conundrum of pathological diagnosis. Familiarity with its clinicopathological features and molecular alterations is essential for its correct diagnosis. Therefore, we summarized the clinicopathological, immunohistochemical, and molecular alterations of 43 cases of this rare rhabdomyosarcoma variant in the English-language literature. In addition, the differential diagnosis of this lesion is crucial either.
PubMed: 38500382
DOI: 10.1177/10668969241239676 -
BMC Cancer Mar 2024Adult head and neck rhabdomyosarcoma (HNRMS) is an exceptionally rare malignancy, and there is a paucity of data and research dedicated to understanding its...
BACKGROUND
Adult head and neck rhabdomyosarcoma (HNRMS) is an exceptionally rare malignancy, and there is a paucity of data and research dedicated to understanding its characteristics and management in adult populations. This study aimed to assess the outcomes and identify survival predictors in adult HNRMS.
METHODS
We retrospectively evaluated 42 adult patients (> 16 years) with HNRMS who received radiotherapy (RT)-based treatment at our institute between 2008 and 2022. We analysed the clinical characteristics and prognosis of these patients, including the locoregional recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS), using the Kaplan-Meier method. The chi-square and Fisher's exact tests were used to analyse differences between groups for dichotomous and categorical variables, respectively. Survival rates were calculated using the Kaplan-Meier method. Prognostic variables were assessed through univariate Cox analyses.
RESULTS
The median patient age was 28 years (range, 16-82 years). Alveolar RMS was the most common histological type, observed in 21 patients (50.0%), followed by embryonal in 16 patients (38.1%). The anatomic sites of origin were orbital in one (2.4%), parameningeal in 26 (61.9%), and non-orbital/non-parameningeal in 15 (35.7%) patients. Nineteen patients (45.2%) had regional lymph node metastasis, and five patients (11.9%) presented with distant metastatic disease. Distant metastasis (n = 17) was the primary cause of treatment failure. At a median follow-up of 47.0 months, the 5-year LRFS, PFS, and OS rates were 69.0%, 39.7%, and 41.0%, respectively. Univariate analysis revealed that tumour size, lymph node involvement, and the local treatment pattern (surgery and RT vs. RT alone) were significant predictors of survival.
CONCLUSIONS
The main failure pattern in patients with HNRMS receiving RT-based treatment was distant metastasis. Tumour size > 5 cm and lymph node involvement were predictors of worse LRFS. Multimodality local treatment, combining surgery and RT, is effective and provides survival benefits.
Topics: Adult; Humans; Adolescent; Young Adult; Middle Aged; Aged; Aged, 80 and over; Retrospective Studies; Head; Neck; Rhabdomyosarcoma; Combined Modality Therapy
PubMed: 38486204
DOI: 10.1186/s12885-024-12079-y -
International Journal of Molecular... Feb 2024Alveolar rhabdomyosarcoma (ARMS), an invasive subtype of rhabdomyosarcoma (RMS), is associated with chromosomal translocation events resulting in one of two oncogenic... (Review)
Review
Alveolar rhabdomyosarcoma (ARMS), an invasive subtype of rhabdomyosarcoma (RMS), is associated with chromosomal translocation events resulting in one of two oncogenic fusion genes, or . ARMS patients exhibit an overexpression of the pleiotropic cytokine transforming growth factor beta (TGF-β). This overexpression of TGF-β1 causes an increased expression of a downstream transcription factor called SNAIL, which promotes epithelial to mesenchymal transition (EMT). Overexpression of TGF-β also inhibits myogenic differentiation, making ARMS patients highly resistant to chemotherapy. In this review, we first describe different types of RMS and then focus on ARMS and the impact of TGF-β in this tumor type. We next highlight current chemotherapy strategies, including a combination of the FDA-approved drugs vincristine, actinomycin D, and cyclophosphamide (VAC); cabozantinib; bortezomib; vinorelbine; AZD 1775; and cisplatin. Lastly, we discuss chemotherapy agents that target the differentiation of tumor cells in ARMS, which include all-trans retinoic acid (ATRA) and 5-Azacytidine. Improving our understanding of the role of signaling pathways, such as TGF-β1, in the development of ARMS tumor cells differentiation will help inform more tailored drug administration in the future.
Topics: Humans; Rhabdomyosarcoma, Alveolar; Transforming Growth Factor beta; Transforming Growth Factor beta1; Paired Box Transcription Factors; Epithelial-Mesenchymal Transition; Rhabdomyosarcoma; Oncogene Proteins, Fusion
PubMed: 38474036
DOI: 10.3390/ijms25052791 -
Indian Journal of Otolaryngology and... Feb 2024Paediatric rhabdomyosarcoma most commonly occurs in the head and neck region. Its treatment is complex, including multi-drug chemotherapy, surgery and radiotherapy....
Paediatric rhabdomyosarcoma most commonly occurs in the head and neck region. Its treatment is complex, including multi-drug chemotherapy, surgery and radiotherapy. Here, we report a case of alveolar rhabdomyosarcoma of the temporal region with a metastatic cervical lymph node, in a 15-year-old girl, and its management. The patient received ne-adjuvant chemotherapy, followed by surgery and post operative radiotherapy. Literature was also reviewed for the various treatment modalities for these rare tumours. Rhabdomyosarcoma of the temporal region has rarely been reported in the literature. Due to the rarity of these tumours, there are difficulties in creating standardized therapeutic protocols. However, multimodality treatment, including chemotherapy, surgery and radiotherapy, has been shown to improve the overall survival rate.
PubMed: 38440594
DOI: 10.1007/s12070-023-04120-6 -
Cancer Genomics & Proteomics 2024Chemoresistance in rhabdomyosarcoma (RMS) is associated with poor survival, necessitating the development of novel anticancer drugs. Auranofin (AUR), an anti-rheumatic...
BACKGROUND/AIM
Chemoresistance in rhabdomyosarcoma (RMS) is associated with poor survival, necessitating the development of novel anticancer drugs. Auranofin (AUR), an anti-rheumatic drug, is a thioredoxin reductase (TXNRD) inhibitor with anticancer properties. Although patient-derived xenograft (PDX) models are essential for studying cancer biology, reports on sarcomas using the PDX model are scarce because of their rarity. This study aimed to investigate the effectiveness of AUR treatment in RMS using a PDX model to evaluate its impact on local progression.
MATERIALS AND METHODS
A 20-year-old woman who was diagnosed with alveolar RMS was used to generate the PDX model. RMS PDX tumors were implanted in nude mice and divided into non-treated (vehicle) and treated (AUR) groups. Tumor volume and weight were evaluated, and immunohistochemical staining was performed to evaluate local progression of the sarcoma. The relationship between the TXNRD-1 expression and survival probability of patients with RMS was evaluated using publicly available expression cohorts.
RESULTS
AUR significantly suppressed RMS tumor progression over time. It also significantly suppressed the tumor size and weight at the time of excision. Histological evaluation showed that AUR induced oxidative stress in the PDX mouse models and inhibited the local progression of RMS by inducing apoptosis. High TXNRD-1 expression was found to be a negative prognostic factor for overall survival in patients with RMS.
CONCLUSION
AUR-induced inhibition of TXNRDs can significantly impede the local progression of RMS through the oxidative stress-apoptosis pathway as demonstrated in PDX models. Thus, targeting TXNRD inhibition may be a promising therapeutic strategy for the treatment of RMS.
Topics: Female; Humans; Animals; Mice; Young Adult; Adult; Thioredoxin-Disulfide Reductase; Mice, Nude; Rhabdomyosarcoma; Sarcoma; Auranofin; Disease Models, Animal; Xenograft Model Antitumor Assays; Cell Line, Tumor
PubMed: 38423598
DOI: 10.21873/cgp.20439 -
Nature Communications Feb 2024Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1...
Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1 are lacking. Here, we screen 62,643 compounds using an engineered cell line that monitors PAX3-FOXO1 transcriptional activity identifying a hitherto uncharacterized compound, P3FI-63. RNA-seq, ATAC-seq, and docking analyses implicate histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirm the inhibition of multiple KDMs with the highest selectivity for KDM3B. Structural similarity search of P3FI-63 identifies P3FI-90 with improved solubility and potency. Biophysical binding of P3FI-90 to KDM3B is demonstrated using NMR and SPR. P3FI-90 suppresses the growth of FP-RMS in vitro and in vivo through downregulating PAX3-FOXO1 activity, and combined knockdown of KDM3B and KDM1A phenocopies P3FI-90 effects. Thus, we report KDM inhibitors P3FI-63 and P3FI-90 with the highest specificity for KDM3B. Their potent suppression of PAX3-FOXO1 activity indicates a possible therapeutic approach for FP-RMS and other transcriptionally addicted cancers.
Topics: Child; Humans; Paired Box Transcription Factors; Rhabdomyosarcoma, Alveolar; Cell Line, Tumor; Rhabdomyosarcoma; Forkhead Box Protein O1; Oncogene Proteins, Fusion; Gene Expression Regulation, Neoplastic; PAX3 Transcription Factor; Jumonji Domain-Containing Histone Demethylases; Histone Demethylases
PubMed: 38402212
DOI: 10.1038/s41467-024-45902-y -
Medical Oncology (Northwood, London,... Feb 2024Alveolar soft-part sarcoma (ASPS) is a rare soft tissue tumor with a broad morphologic differential diagnosis. While histology and immunohistochemistry can be...
Alveolar soft-part sarcoma (ASPS) is a rare soft tissue tumor with a broad morphologic differential diagnosis. While histology and immunohistochemistry can be suggestive, diagnosis often requires exclusion of other entities followed by confirmatory molecular analysis for its characteristic ASPSCR1-TFE3 fusion. Current stain-based biomarkers (such as immunohistochemistry for cathepsin K and TFE3) show relatively high sensitivity but may lack specificity, often showing staining in multiple other entities under diagnostic consideration. Given the discovery of RNA in situ hybridization (RNA-ISH) for TRIM63 as a sensitive and specific marker of MiTF-family aberration renal cell carcinomas, we sought to evaluate its utility in the workup of ASPS. TRIM63 RNA-ISH demonstrated high levels (H-score greater than 200) of expression in 19/20 (95%) cases of ASPS (average H-score 330) and was weak or negative in cases of paraganglioma, clear cell sarcoma, rhabdomyosarcoma, malignant epithelioid hemangioendothelioma, as well as hepatocellular and adrenal cortical carcinomas. Staining was also identified in tumors with known subsets characterized by TFE3 alterations such as perivascular epithelioid cell neoplasm (PEComa, average H-score 228), while tumors known to exhibit overexpression of TFE3 protein without cytogenetic alterations, such as melanoma and granular cell tumor, generally showed less TRIM63 ISH staining (average H-scores 147 and 96, respectively). Quantitative assessment of TRIM63 staining by RNA-ISH is potentially a helpful biomarker for tumors with molecular TFE3 alterations such as ASPS.
Topics: Humans; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Biomarkers, Tumor; Carcinoma, Renal Cell; In Situ Hybridization; Muscle Proteins; RNA; Sarcoma, Alveolar Soft Part; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 38393424
DOI: 10.1007/s12032-024-02305-9