Clinical Evaluation of BET and HDAC Inhibition in Canine Sarcoma

Targeting chromatin-remodeling enzymes holds great promise for treating soft tissue sarcomas (STS) since 1) the key oncogenic drivers in many sarcomas are translocation-derived chimeric transcription factors whose activities critically depend on chromatin remodeling factors; and 2) recent work from our group and others has highlighted the role of epigenetic deregulation and chromatin status in sarcomagenesis. Together these finding suggest that epigenetic therapy may be a particularly effective approach against these tumors. Recent data from our group reveal the dramatic in vivo effects of the BET bromodomain inhibitor, JQ1, and the histone deacetylase (HDAC) inhibitor Vorinostat, in multiple sarcoma subtypes suggesting that sarcomas may be generally sensitive to this class of drugs. Our current hypothesis supported by in vitro and autochthonous mouse model data suggests that the Hippo pathway is a critical tumor suppressive node in muscle tissues, which is inactivated during sarcomagenesis. Regaining control of the Hippo pathway and its transcriptional effector YAP1 through pharmacological treatment with JQ1 and vorinostat effectively inhibits sarcomagenesis in multiple subtypes and restores de-differentiated cells to a discernible mesenchymal lineage. Based on our pre-clinical data my team of veterinary clinicians and basic researchers is pursuing a clinical trial of combination epigenetic modulators in adult dogs suffering from STS. STS occur more commonly in dogs than in humans, representing 15% of all canine tumors with an estimated incidence of 35 per 100,000 dogs/year. Moreover, the commonly diagnosed STS subtypes in adults are identical in humans and canines (i.e. Undifferentiated, Pleomorphic Sarcomas). Relevant to this approach, JQ1 is cytostatic in canine sarcoma cell lines with an IC50 that is comparable to that of human sarcoma cell lines and within the tolerable range when used in murine models. Furthermore, Vorinostat induces histone acetylation and is cytotoxic to canine sarcoma cell lines and has been successfully used in a dog with a highly aggressive sarcoma. Although preliminary, these findings strongly indicate that dogs with spontaneous sarcomas will provide an excellent resource for clinical evaluation of BET bromodomain inhibitors +/- Vorinostat and that if successful, will serve to accelerate the translation of this approach into the human sarcoma clinic. We will use the more stable clinical BET inhibitor CPI-0610 +/- Vorinostat for best results. Moreover, I will validate Hippo pathway markers in pre- and post-treatment biopsy tissues and investigate novel pathways with unbiased screening approaches to characterize the utility and mechanism of action of this therapeutic strategy in the canine system.