Rhabdomyosarcoma is a pediatric tumor that originates from immature cells originally destined to become skeletal muscle cells. Current chemotherapies used to treat rhabdomyosarcoma have many toxic side effects and are not very effective. The most aggressive subtype of rhabdomyosarcoma contains a fusion of the PAX3/7 and FOXO1 genes. The oncogenic protein product of the PAX3-FOXO1 fusion could be an attractive therapeutic target for this type of rhabdomyosarcoma. The PAX3-FOXO1 protein, however, is a transcription factor, and transcription factors are difficult to target through traditional drug discovery approaches. Benjamin Stanton of Nationwide Children’s Hospital and Jun Qi of the Dana-Farber Cancer Institute have discovered small molecules that induce degradation of the SWI/SNF chromatin remodeling complex via the ubiquitination machinery and unexpectedly cause the destabilization of PAX3-FOXO1. The two investigators are combining chemical biology and genetic approaches to build upon these findings and develop precision therapies that target PAX3-FOXO1 signaling in rhabdomyosarcoma.
This project has two primary aims: to define the mechanism of the PAX3-FOXO1 fusion protein degradation; and to assess the therapeutic potential of SWI/SNF degraders in rhabdomyosarcoma. After deciphering the impact of PAX3-FOXO1 function on the chromatin landscape, the investigators also aim to develop small molecules to optimally disrupt its activity. They will use in vitro pharmacodynamic studies and xenograft mouse models to assess efficacy of candidate compounds and identify a lead compound that can be moved forward into clinical trials.
Sunkel BD, Wang M, LaHaye S, Kelly BJ, Fitch JR, Barr FG, White P, Stanton BZ. Evidence of pioneer factor activity of an oncogenic fusion transcription factor. iScience. 2021.
Tallan A, Stanton BZ. Inducible Protein Degradation to Understand Genome Architecture. Biochemistry. 2021.
Sunkel BD, Stanton BZ. Pioneer factors in development and cancer. iScience. 2021.
Laubscher D, Gryder BE, Sunkel BD, Andresson T, Wachtel M, Das S, Roschitzki B, Wolski W, Wu XS, Chou HC, Song YK, Wang C, Wei JS, Wang M, Wen X, Ngo QA, Marques JG, Vakoc CR, Schäfer BW, Stanton BZ, Khan J. BAF complexes drive proliferation and block myogenic differentiation in fusion-positive rhabdomyosarcoma. Nat Commun. 2021.
Popova LV, Nagarajan P, Lovejoy CM, Sunkel BD, Gardner ML, Wang M, Freitas MA, Stanton BZ, Parthun MR. Epigenetic regulation of nuclear lamina-associated heterochromatin by HAT1 and the acetylation of newly synthesized histones. Nucleic Acids Res. 2021.
Wang M, Sunkel BD, Ray WC, Stanton BZ. Chromatin structure in cancer. BMC Mol Cell Biol. 2022.