Is gene therapy a treatment for rhabdomyosarcoma?

Gene Therapy in Rhabdomyosarcoma: Current Status and Future Directions

Gene therapy is not currently an established treatment for rhabdomyosarcoma according to current guidelines and evidence. 1, 2

Current Standard Treatment Approaches

The management of rhabdomyosarcoma involves a multimodality approach that includes:

1. Surgery: Excision of the primary tumor when possible without causing major functional or cosmetic deficits
2. Chemotherapy: Standard backbone includes vincristine, actinomycin D, and cyclophosphamide (VAC) or ifosfamide (IVA)
3. Radiation therapy: Often used for incompletely resected tumors

High-Dose Chemotherapy Status

The most recent evidence from a 2024 systematic review by the Australia and New Zealand Sarcoma Association indicates that high-dose chemotherapy with autologous stem cell transplant (HDT/ASCT) has no proven survival benefit for rhabdomyosarcoma in:

• Primary localized disease
• Metastatic disease
• Relapsed disease 1

Molecular Understanding and Targeted Approaches

While gene therapy is not yet established, molecular diagnostics have become increasingly important in rhabdomyosarcoma management:

• Molecular Classification: Rhabdomyosarcoma can be classified based on characteristic genetic aberrations, including chromosomal translocations 1
• Fusion Transcripts: Alveolar rhabdomyosarcoma is characterized by PAX-FKHR fusion genes (PAX3-FKHR or PAX7-FKHR) 1
• Prognostic Implications: In metastatic alveolar rhabdomyosarcoma, PAX7-FKHR fusion is associated with more favorable prognosis compared to PAX3-FKHR 1

Emerging Research Directions

Current research is focusing on several potential approaches that may lead to gene therapy applications:

1. TRK Fusions: While TRK fusions have been identified in rhabdomyosarcoma, they occur at lower frequencies compared to other pediatric cancers 1

2. Clinical Trials: The National Comprehensive Cancer Network recommends enrollment in clinical trials for children with rhabdomyosarcoma, including those studying targeted agents 2

3. Future Directions: Risk-adapted classification of rhabdomyosarcoma will likely be based on biological features, including chromosomal translocations and gene expression profiles 3

Treatment Recommendations

For optimal management of rhabdomyosarcoma:

• Treatment at specialized centers with extensive experience in pediatric sarcomas 2
• Enrollment in clinical trials whenever possible, as this is considered part of optimal management 2, 3
• Adolescent and Young Adult (AYA) patients have superior outcomes when treated with pediatric protocols 2

Challenges and Limitations

Several factors have limited progress in gene therapy for rhabdomyosarcoma:

• Low enrollment rates in clinical trials, particularly among older adolescents and young adults 2
• Limited understanding of the pathogenesis at molecular, genetic, and pathological levels 4
• Lack of targeted therapies specifically designed for rhabdomyosarcoma 4

Future Perspectives

The future of gene therapy in rhabdomyosarcoma may include:

• Development of therapies directed at specific molecular genetic defects 3
• Immunotherapy approaches including vaccination, antigen-mediated therapy, and immune checkpoint inhibitors 5
• Improved molecular classification to better guide treatment selection 1, 3

Despite advances in understanding the molecular basis of rhabdomyosarcoma, standard treatment approaches remain centered on conventional modalities, with gene therapy still in the investigational phase.