SUN-337 Anti-tumorigenic Effects Of The Maternal Leucine Zipper Kinase (MELK) Inhibitor, OTSSP167, In Pre-clinical In Vivo Models Of Adrenocortical Carcinomas (ACC)

Abstract

ACC is an aggressive endocrine cancer with limited therapeutic options and poor survival rates. In patients with progressive disease, standard EDP (etoposide, doxorubicin and cisplatin) chemotherapy is associated with only a modest response and progression free survival of 5 months. Mitotane, the only adjuvant FDA approved therapy for ACC is associated with 30% stable disease or partial response, as well as an association with toxicity and intolerability. The lack of pre-clinical models has also contributed to slow progress in the field. Previously, we developed CU-ACC1 and CU-ACC2 patient derived xenografts (PDX) and their corresponding ACC cell lines to study potential targets in ACC tumorigenesis. In this study we characterized a third ACC PDX, CU-ACC9. CU-ACC9 PDX was derived from a mild cortisol producing 15 cm primary ACC tumor involving adrenal, kidney, distal pancreas with an inferior vena cava (IVC) thrombus in a 55 year-old female patient. On analysis, the CU-ACC9 tumor had a T53 p.R248W mutation, intermediate microsatellite instability, and loss of MSH2 and MSH6 staining by immunohistochemistry, all suggestive of Lynch syndrome. Despite the initial poor prognosis associated with IVC thrombus, the patient underwent radical resection and subsequent therapy with anti-PD1 checkpoint inhibitor and mitotane, and survived for 2 years. STR profiling confirmed a 96% match between the CU-ACC9 PDX and the original tumor tissue. Immunohistochemistry of the PDX revealed positive expression of the adrenal markers, inhibin alpha and SF-1. Further gene expression studies using RNA seq revealed that CU-ACC9 PDX and CU-ACC1 PDX had high MELK expression, a kinase we previously identified as a potential therapeutic target in ACC. Our prior studies demonstrated a dose dependent induction of apoptosis by the MELK inhibitor, OTSSP167, in H295R, CU-ACC1 and CU-ACC2 cells which correlated with endogenous MELK expression. To test effects of the MELK inhibitor in vivo, we treated the F13 generation of CU-ACC1 and F7 generation of CU-ACC9 PDX with OTSSP167. Accounting for the variable tumor growth rate between the two PDXs, OTSSP167 treatment for 18 days and 28 days in CU-ACC1 and CU-ACC9 PDXs, respectively resulted in a 4 fold (p= 0.02) and 2.2-fold ( p<0.001) inhibition in tumor growth. The tumor inhibitory growth index (TGII) for both explants were <20 % suggesting a response to the single agent therapy with OTSSP167. There was no evidence of systemic toxicity as assessed by changes in body weight. These data establish the therapeutic potential of OTSSP167 in ACC and suggest that targeting MELK could have efficacy in a subset ACC patients. Future studies will focus on enhancing the therapeutic efficacy by combining OTSSP167 with other rational based therapies in our ACC PDX models, towards Phase I studies in patients with ACC. Funding: CLC grants, K08, Doris Duke CU-FRCS, VA Merit Review