Joseph G. Pressey

Molecular Pathogenesis of Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is a family of soft tissue tumors that are associated with the skeletal muscle lineage and generally occur in the pediatric population. Based on histopathologic features, two subtypes, embryonal (ERMS) and alveolar (ARMS), were identified and associated with distinct clinical characteristics and genetic alterations. ARMS is associated with 2;13 or 1;13 chromosomal translocations, which generate PAX3-FKHR and PAX7-FKHR fusion products, respectively. These translocations result in altered expression, function, and subcellular localization of the fusion products relative to the wild-type proteins, and ultimately contribute to oncogenic behavior by modifying growth, differentiation, and apoptosis pathways. In contrast to the specific translocations found in ARMS, most ERMS cases have allelic loss at chromosome 11p15.5. Chromosome fragment transfer studies demonstrated that this region represses tumor cell growth, suggesting the presence of tumor suppressor gene(s) in this region. In both ERMS and ARMS, there is evidence of collaborating alterations that affect common targets, such as the p53 and RB pathways. One mechanism for perturbing these pathways involves amplification of genes such as MDM2 and CDK4; these amplification events occur frequently in ARMS but only rarely in ERMS. Therefore, despite similarities in the downstream targets of these genetic alterations, the striking cytogenetic and molecular differences between ARMS and ERMS indicate distinct molecular etiologies in these two subtypes.

Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4

Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is an extremely rare, aggressive cancer affecting children and young women. We identified germline and somatic inactivating mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 69% (9/13) of SCCOHT cases in addition to SMARCA4 protein loss in 82% (14/17) of SCCOHT tumors but in only 0.4% (2/485) of other primary ovarian tumors. These data implicate SMARCA4 in SCCOHT oncogenesis.

Current concepts on the surgical and medical management of osteosarcoma

Although advances have been made in both surgical and medical management of patients with osteosarcoma, the overall survival of patients with osteosarcoma has remained constant, with no substantial improvement in the past 15 years. Advances in imaging have had a substantial impact on surgical planning and staging. These advances have, in turn, had a major impact on the surgeon’s ability to perform limb-sparing surgery. Surgical techniques have improved in terms of instrumentation, modularity of implants and availability. Limb salvage has proven to be an acceptable method of treatment both with respect to oncologic and functional outcome in those patients where a wide resection may be achieved. The use of massive allografts has been largely replaced with the use of modern oncologic endoprostheses. Biologic targets that will enable new therapies to have maximum effect on tumor cells while minimizing toxicity to the host tissues need to be identified.

Hedgehog Pathway Activity in Pediatric Embryonal Rhabdomyosarcoma and Undifferentiated Sarcoma: A Report from the Children’s Oncology Group

Aberrant activation of the hedgehog (Hh) signaling pathway is implicated widely in both pediatric and adult malignancies. Inactivation of the Hh regulator PTCH is responsible for the Gorlin cancer predisposition syndrome. The spectrum of tumors found in Gorlin Syndrome includes basal cell carcinoma, medulloblastoma, and rarely, rhabdomyosarcoma (RMS). A previous report utilizing in situ hybridization has provided initial evidence for the expression of Hh targets GLI1 and PTCH in RMS tumors.

Herpes Simplex Virus Oncolytic Therapy for Pediatric Malignancies

Despite improving survival rates for children with cancer, a subset of patients exist with disease resistant to traditional therapies such as surgery, chemotherapy, and radiation. These patients require newer, targeted treatments used alone or in combination with more traditional approaches. Oncolytic herpes simplex virus (HSV) is one of these newer therapies that offer promise for several difficult to treat pediatric malignancies. The potential benefit of HSV therapy in pediatric solid tumors including brain tumors, neuroblastomas, and sarcomas is reviewed along with the many challenges that need to be addressed prior to moving oncolytic HSV therapy from the laboratory to the beside in the pediatric population.

Targeting wild-type and mutant p53 with small molecule CP-31398 blocks the growth of rhabdomyosarcoma by inducing reactive oxygen species-dependent apoptosis.

Rhabdomyosarcoma (RMS) is a common soft-tissue sarcoma of childhood in need of more effective therapeutic options. The expression of p53 in RMS is heterogeneous such that some tumors are wild-type whereas others are p53 mutant. The small molecule CP-31398 modulates both the wild-type and the mutant p53 proteins. Here, we show that CP-31398 blocks the growth of RMS cells that have either wild-type or mutant p53 status. In wild-type A204 cells, CP-31398 increased the expression of p53 and its downstream transcriptional targets, p21 and mdm2; enhanced the expression of apoptosis-related proteins; and reduced proliferation biomarkers. Flow profiling of CP-31398-treated cells indicated an enhancement in sub-G(0) and G(1) populations. CP-31398 inhibited proliferation in a manner associated with co-induction of SOX9 and p21. Apoptosis induced by CP-31398 occurred with translocation of p53 to mitochondria, leading to altered mitochondrial membrane potential, cytochrome c release, and reactive oxygen species release. In vivo, CP-31398 decreased the growth of tumor xenografts composed of wild-type or mutant p53 tumor cells, increasing tumor-free host survival. Our findings indicate that the ability of CP-31398 to modulate wild-type and mutant p53 results in the inhibition of RMS growth and invasiveness.

Sirolimus therapy for fibromatosis and multifocal renal cell carcinoma in a child with tuberous sclerosis complex

A male with tuberous sclerosis complex (TSC) developed a chest wall fibromatosis and bilateral multifocal renal cell carcinoma (RCC). The fibromatosis tumor was initially resected during infancy but recurred 5 years later. At that time, bilateral RCC was also detected, leading to the resection of the more extensively affected right kidney. In an attempt to avoid bilateral nephrectomies, the patient was treated with the mTOR inhibitor sirolimus. Within 6 months of therapy, the fibromatosis and remaining RCC tumors responded substantially with minimal adverse effects. Pediatr Blood Cancer 2010;54:1035–1037

Single institution series of nodular fasciitis in children.

Nodular fasciitis often resembles malignant sarcomas from a clinical and pathologic perspective. We describe the case of an infant that presented with a supraclavicular nodular fasciitis that recurred after an initial gross total resection. A review of pathology records at the Childrens Hospital of Alabama led to the identification of 18 nodular fasciitis cases between 1997 and 2009, all of which underwent surgical excisions. Patient characteristics were similar to previous studies that detected a broad range of ages at diagnosis, a male predominance, and a predilection for the head and neck. Only one tumor recurred after the initial surgical intervention. All patients ultimately recovered with minimal morbidity.

CD133 Marks a Myogenically Primitive Subpopulation in Rhabdomyosarcoma Cell Lines that are Relatively Chemoresistant but Sensitive to Mutant HSV

Rhabdomyosarcoma (RMS) is characterized by features of skeletal muscle and is comprised of two major histological subtypes, embryonal (E‐RMS), and alveolar (A‐RMS). Subsets of each RMS subtype demonstrate resistance to multimodal therapy leading to treatment failure. Cancer stem cells or cancer‐initiating cells (CIC) represent a theorized population of cells that give rise to tumors and are responsible for treatment resistance.

Rapamycin targeting mTOR and hedgehog signaling pathways blocks human rhabdomyosarcoma growth in xenograft murine model

Rhabdomyosarcomas (RMS) represent the most common childhood soft-tissue sarcoma. Over the past few decades outcomes for low and intermediate risk RMS patients have slowly improved while patients with metastatic or relapsed RMS still face a grim prognosis. New chemotherapeutic agents or combinations of chemotherapies have largely failed to improve the outcome. Based on the identification of novel molecular targets, potential therapeutic approaches in RMS may offer a decreased reliance on conventional chemotherapy. Thus, identification of effective therapeutic agents that specifically target relevant pathways may be particularly beneficial for patients with metastatic and refractory RMS. The PI3K/AKT/mTOR pathway has been found to be a potentially attractive target in RMS therapy. In this study, we provide evidence that rapamycin (sirolimus) abrogates growth of RMS development in a RMS xenograft mouse model. As compared to a vehicle-treated control group, more than 95% inhibition in tumor growth was observed in mice receiving parenteral administration of rapamycin. The residual tumors in rapamycin-treated group showed significant reduction in the expression of biomarkers indicative of proliferation and tumor invasiveness. These tumors also showed enhanced apoptosis. Interestingly, the mechanism by which rapamycin diminished RMS tumor growth involved simultaneous inhibition of mTOR and hedgehog (Hh) pathways. Diminution in these pathways in this model of RMS also inhibited epithelial mesenchymal transition (EMT) which then dampened the invasiveness of these tumors. Our data provide bases for using rapamycin either alone or in combination with traditional chemotherapeutic drugs to block the pathogenesis of high risk RMS.