Developing cancer therapies – think global

a disease that afflicts individuals regardless of age. It may occur in children, adolescents, or young adults who are born with genetic mutations that predispose them to the disease. It also occurs in the elderly where a lifetime of exposure to environmental or age-related stressors facilitates the acquisition of oncogenic mutations. Regardless of the age of onset, cancer is a multifaceted and deeply complex disease that results from the accumulation of multiple genetic alterations that allow cells to evade normal regulatory safeguards to develop into a metastatic tumor. Many times the cascade of genetic alterations leading to the metastatic state is initiated by a single driver mutation, a single genetic event that facilitates or promotes the generation of subsequent mutations culminating in the oncogenic state. In a recent publication we identified a known oncogenic protein to be one such driving mutation [1]. Alveolar Rhabdomyosarcoma (ARMS), an aggressive pediatric muscle tumor, is primarily characterized by the somatically acquired t(2;13)(q35;q14) balanced chromosomal translocation, which generates the oncogenic fusion protein PAX3-FOXO1. We determined that the sole expression of PAX3-FOXO1 is sufficient to promote aneuploidy and overcome aneuploidy-dependent cell cycle arrest in the progression to the oncogenic state, thereby serving as a driver mutation in ARMS. More importantly, we showed that PAX3-FOXO1 achieves this by globally altering mRNA and miRNA expression levels to negatively affect all aspects of chromosomal segregation and stability (leading to aneuploidy) while positively affecting at least five different growth factor related signaling pathways (leading to overcoming proliferative arrest). Given the global nature of PAX3-FOXO1 induced expression changes (in which over 100 genes are directly or indirectly affected to promote aneuploidy and proliferative effects), it is not surprising that present experimental therapeutic strategies are proving ineffective in clinical trials. Many of these therapies focus on inhibiting a single gene or pathway located genetically downstream of the oncogenic fusion protein. However, our results highlight the fact that ARMS tumor cells have altered the expression of multiple genes involved in redundant biological processes (e.g., Editorial growth factor related proliferation). As such ARMS tumor cells can easily compensate for the loss or inhibition of a single gene or pathway under present experimental therapeutic approaches. Based on this information we proposed the development of a multifaceted treatment regimen in which we suggest using small molecules to inhibit three essential biological pathways important for the development of ARMS: 1) prevent phosphorylation of PAX3-FOXO1 at the key …