Resetting the epigenetic addiction in leiomyosarcomas: a therapeutic perspective

Leiomyosarcomas (LMS) are rare highly malignant tumors of mesenchymal origin. Standard treatment is surgery and adjuvant radiotherapy. Unfortunately, local recurrence and metastasis develop in approximately 40% of cases, which drastically reduce overall survival. In order to provide better perspective to patients, new therapeutic strategy are urgently needed. The reset of the epigenetic status of the neoplastic cells is a promising strategy to impact on tumor aggressiveness. Class IIa HDACs are important epigenetic regulators which are overexpressed in 25% of LMS. Gene editing by CRISPR/Cas9 has proved that LMS cells (SK-UT-1) depends on HDAC9 for survival. HDAC9 can buffer the level of death receptor FAS and in its absence, apoptosis is induced by engagement of the extrinsic apoptotic pathway. Moreover several drugs increase they ability to kill LMS cells in the absence of HDAC9. Through a designed screening for small molecule that could impact on HDAC9-dependent repressive influence, we have found that NKL54 can mimic the deletion of HDAC9. Expression of FAS and other genes repressed by HDAC9 is up-regulated by NKL54 and cell death is induced in LMS cells. With this proposal we aim: a) To expand our initial observation on NKL54 efficiency on additional LMS cell lines, including patient-derived LMS cells; b) To generate and test an optimized versions of NKL54, for in vivo delivery, on PDX (Patient-Derived Xenograft), as single agent or in combination with doxorubicin; c) To obtain omic patterns of sensitivity and resistance to NKL54, for a comparison with those for doxorubicin and olaratumab.