Characterization of Mechanisms Driving Muscle Disease and Identification of Novel Therapeutics

Alveolar rhabdomyosarcoma is a cancer of the muscle lineage. Nemaline myopathy is associated with defects in sarcomere structure and function. We are investigating disease progression and performing screens to identify novel therapeutics for these diseases.

Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is a rare tumor, yet it is the most common pediatric soft tissue sarcoma, representing 3 to 5 percent of all childhood cancers. Patients with alveolar rhabdomyosarcoma (ARMS), an aggressive form of RMS, often have poor prognosis, particularly with metastatic disease. There are no targeted treatments for this cancer.

Figure 9: Expression of human PAX7::FOXO1A oncoprotein in Drosophila muscle leads to metastatic cells that populate the Central Nervous system. -- Magnified view of the central nerve cord of a 3rd instar larva, top panel control, bottom panel PAX7::FOXO1A positive. i & iii) brightfield image, ii & iv) GFP fluorescence. Note the GFP positive, neoplastic cells that invaded the central nerve cord (arrows).

ARMS uniquely associates with chromosomal translocations t(2;13)(q35;q14) and t(1;13)(p36;q14), leading to the production of the fusion oncoproteins PAX3::FOXO1A or PAX7::FOXO1A. Expression of a human PAX7::FOXO1A fusion protein alone in Drosophila mesoderm leads to a population of free larval myoblasts that transform into aggressive cells that leave the muscle compartment, migrate, and invade nonadjacent tissues, including the central nervous system (CNS).

This cellular behavior is reminiscent of metastatic disease in which transformed cells invade and integrate into adjacent tissues. We are studying this Drosophila ARMS model to better understand metastatic behaviors. A screen for new therapeutics to treat this disease is underway.

Nemaline myopathy

Nemaline myopathy (NM) is the most common form of non-dystrophic congenital myopathy, with an incidence of 1/20,000 in some populations. It is a slow or non-progressive disease, characterized by the presence of nemaline bodies in the affected muscle tissue, muscle weakness, and the absence of muscle regeneration. There is no effective treatment for this disease.

Mutations in nine different genes have been linked to NM, six of which encode skeletal muscle sarcomere thin filament-associated proteins. Using the human mutations as a guide, we have developed Drosophila models for the disease. We are currently investigating how NM develops and are identifying novel therapeutics to treat it.