Abstract LB196: SPR965, a PI3K/mTORC1/C2 inhibitor for treatment of chordoma
Authors: Dugar Sundeep , Sen Somdutta , Maffuid Paul , Freed Dan , Sommer Josh , Anderson Edward , Hickey Anthony 
Published: June 2022

Abstract
Introduction: Chordoma is a rare tumor with a median survival of 7 years in US. At present, standard treatment involves surgery and/or radiation. Complete surgical resection, however, can be challenging as the tumor is located on the skull base or spine. Moreover, there is currently no approved systemic therapy for advanced chordoma. These challenges have resulted in significant morbidity and a dismal cure rate of approximately 30%, highlighting the need for development of new therapeutic strategies for this orphan disease. Emerging evidence suggests a key role for the PI3K/mTOR pathway in chordoma and numerous reports point to an enrichment of chordoma cases in individuals with tuberous sclerosis syndrome, which is driven by dysregulated mTOR activity. Another study of chordoma tumors from 111 patients demonstrated that the mTOR pathway was activated in 46% of the tumors, and sequencing studies have revealed oncogenic alterations to the PI3K/mTOR pathway in approximately 15-20% of chordomas. We surmised that dual inhibition of both the mTOR and the PI3K pathways may represent a desirable profile as it will not only have the potential to address the effects of activation of both these targets, but also prevent feedback reactivation of the pathway resulting from the inhibition of one or the other. Previously, SPR965 was shown as a potent, selective and orally bioavailable PI3K and mTOR C1/C2 inhibitor with an excellent PK/ADME profile.
Methods: SPR965 and comparator compounds were evaluated in vitro in the chordoma cell lines JHC7, U-CH1, and U-CH2 by (Resarufin assay). SPR965 was evaluated in vivo in multiple chordoma PDX models.
Results: SPR965 in vitro showed significant effect on cell proliferation with EC50 of 50-90nM. SPR965 was more active at 1uM than PI3K/mTOR inhibitors VS-5584, Bimiralisib, PF-04691502, WYE-687, Dactolisib, and Voxtalisib in the Kinase Chemogenomic Set. SPR965 in vivo monotherapy in SF8894 PDX at 3mg/kg had similar tumor growth inhibition (TGI) to CDK4/6 inhibitor Palbociclib at 50mg/kg. SPR965 combination with Palbocicilib had similar TGI to PI3K inhibitor Buparlisib at 35mg/kg. In CF459 PDX, SPR965 potently inhibited tumor growth at 10mg/kg. TGI% was statistically significant with SPR965 versus untreated controls in both models.
Conclusion: In SF8894 PDX model SPR965 was more efficacious as it produced similar tumor growth inhibition at 12- and 17-fold lower dose than Buparlisib (PI3K) and Palbociclib (CDK4/6) respectively, both these compounds are in phase 2 clinical trials. In CF459 PDX model SPR965 exhibited dose-dependent tumor growth inhibition, and at 10mg/kg profoundly slowed tumor growth compared to Palbociclib. Studies are underway to elucidate potential mechanisms of SPR965 sensitivity. SPR965 represents a significant opportunity for development of a targeted therapeutic for chordoma patients.
Citation Format: Sundeep Dugar, Somdutta Sen, Paul Maffuid, Dan Freed, Josh Sommer, Edward Anderson, Anthony Hickey. SPR965, a PI3K/mTORC1/C2 inhibitor for treatment of chordoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB196.