Oncolytic Viruses in Rhabdomyosarcoma Treatment
Introduction to Rhabdomyosarcoma
Rhabdomyosarcoma (RMS) is the most common form of soft tissue sarcoma accounting for 5% of all cases of cancers in children and adolescents. It can occur either as a primary malignancy or as a component of a heterogeneous malignancy, such as a malignant teratomatous tumor. Derived from primitive mesenchymal stem cells directed towards myogenesis, RMS can arise in a variety of anatomic sites throughout the body, including but not limited to head and neck, genitourinary tract, and trunk. In general, the presentation of RMS is site-dependent. Diagnosis of RMS often needs both open incisional biopsy and image-guided core needle (Tru-Cut) biopsies.
Treatment for Rhabdomyosarcoma
Treatment with RMS focuses on achieving "local control" and "systemic control". Local control refers to the permanent eradication of the "primary tumor". Systemic control refers to the permanent control of invisible "micrometastases" or visible "metastases". To achieve this goal, RMS is treated with a combination of surgery, chemotherapy and radiation. Chemotherapy drugs are given in the hospital to kill cancer cells everywhere. Radiation is a series of x-ray treatments given to kill cancer cells in a specific area. Surgery is intended to remove entire cancer, part of it, or for diagnosis by obtaining a biopsy of the lump or an involved lymph node. However, how each type of treatment helps to cure this cancer is unclear.
Fig.1 Oncolytic virus-mediated primary and secondary tumor cell lysis. (Masemann, 2017)
Oncolytic Viral Therapy for Rhabdomyosarcoma
- Myxoma Virus (MYXV)
- HSV-1
MYXV is a member of the genus Leporipoxvirus, subfamily Chordopoxvirinae, belonging to the family of Poxviridae. The virus does not cause disease in humans or other vertebrates, except for rabbits and European Brown Hares (only occasionally with clinical signs). Despite its species specificity in vivo and in nonneoplastic cells in vitro, MYXV productively infects cultured cancer cells from several animal species. Given its essentially harmless to non-lagomorphs, MYXV is considered a promising oncolytic virus for the treatment of cancer. Studies have shown that fluorescent protein could be expressed in four RMS cell lines when inoculated with MYXV-red, indicating that these cells were semi permissive to MYXV infection. The oncolytic effects of MYXV have also been studied in nude mice injected with CCL-136 cells to establish RMS xenografts. Results have suggested that the average final tumor volume and rate of tumor growth of MYCV treated mice were significantly decreased, while median survival time was significantly increased.
HSV-1 is an enveloped, double-stranded DNA virus with a genome of 152 kb that allows for the delivery of multiple transgenes, and the use of heterologous promoters. G207 is a genetically engineered oncolytic herpes simplex virus (oHSV) with both copies of the γ134.5 gene deleted to decrease neurovirulence. Experimental studies demonstrated that G207 is effective against human carcinoma cell lines of breast, prostate, colon, the ovaries, and head and neck SCC, malignant melanoma, as well as pediatric embryonal tumor cell lines such as neuroblastoma. An in vitro study suggested that human embryonal (KF-RMS-1, RD, and CCA) and alveolar RMS (KFR, Rh28, Rh30, and Rh41) cell lines were highly sensitive to cytotoxic and replicative effects of G207. Additionally, G207 could reduce xenograft tumor growth and increase animal survival in both embryonal (ERMS) and alveolar rhabdomyosarcoma (ARMS) animal models. Moreover, animals receiving repeat doses of G207 coupled with low-dose radiation had improved tumor response in RMS.
Reference
- Masemann, D.; et al. Employing RNA viruses to fight cancer: novel insights into oncolytic virotherapy. Biological chemistry. 2017, 398(8), pp.891-909.