Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children and makes up 3% of all childhood cancers. Aveloar Rhabdomyosarcoma is the most aggressive subtype and is primarily established through a chromosomal translocation resulting in the fusion protein PAX3-FOXO1. Despite aggressive therapy, the 5-year survival rate for patients with high risk or recurrent Fusion Positive RMS (FP-RMS) is low (~30% and ~17%, respectively). Therefore, new therapies targeting the PAX3-FOXO1 oncogenic driver are urgently needed.  

To identify inhibitors of PAX3-FOXO1, scientists at the National Cancer Institute (NCI) developed a novel cell-based reporter assay of PAX3-FOXO1 activity. Using this system NCI scientists screened a 62,643 small molecule chemical library and found compounds with unknown function that disrupt PAX3-FOXO1 activity. Further studies of these compounds showed that they were inhibitors of histone lysine demethylases (KDMs), with enhanced selectivity for KDM3B. Treatment of RMS cell lines with these compounds resulted in cytotoxicity and apoptosis, highlighting their potential as therapeutics for RMS. These compounds were also found to be cytotoxic to other sarcoma cell lines, such as Ewing’s sarcoma and osteosarcoma. Screening of the NCI-60 cancer cell panel with one of these compounds resulted in growth inhibition of a range of cancer cell types, including leukemias, CNS cancers, melanoma, prostate cancer, colon cancer, ovarian cancers, breast cancers, and renal caners. In the case of renal cancer, treatment resulted in growth inhibition followed by cell death. Thus, these compounds may be effective therapeutics for a variety of cancers outside of RMS.

The NCI seeks research co-development partners and/or licensees to help increase the potencies of the compounds and further develop them as cancer therapeutics.

Competitive Advantages:

• First-in-class inhibitors of the histone lysine demethylase KDM3B
• The ability of the compounds to target multiple histone demethylases (KDMs) has two main advantages: 1) may upregulate myogenesis and apoptosis, while at the same time downregulating PAX3-FOXO1 oncogenic targets, and 2) may reduce the frequency of acquired drug resistance resulting from the acquisition of mutations in a single therapeutic KDM target  

Commercial Applications:

• Therapeutic for Rhabdomyosarcoma and other cancers – including, but perhaps not limited to:
  • breast cancer
  • melanoma
  • leukemias
  • prostate cancer
  • colon cancer
  • renal cancer
• Therapeutic for diseases involving aberrant histone lysine methylation, such as neurodevelopmental disorders