Abstract 1755: TORK/DNA-PK inhibitor CC-115 is effective as a single agent in a subset of glioblastoma patient-derived cancer stem cells and xenografts and potentiates temozolomide therapy
Authors: Bergman Kimberly , Irtenkauf Susan M. , Hasselbach Laura A. , Mueller Claudius , Petricoin Emanuel , Raymon Heather , Mikkelsen Tom , Decarvalho Ana C. 
Published: August 2015

Glioblastoma (GBM) cells are highly invasive and respond poorly to radiation and chemotherapy. The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase signals through protein complexes mTORC1 and mTORC2 to regulate several essential processes such as cell growth, proliferation, metabolism, survival, and autophagy. mTOR is activated by oncogenic signaling, including PI3K which is frequently deregulated in high grade glioma. Using GBM patient-derived neurospheres and xenograft tumors (PDX), we have tested CC-223 (Celgene), an ATP-competitive TOR kinase inhibitor (TORKi), and CC-115 (Celgene), a dual TORK/ DNA-PK inhibitor. The latter is also an attractive drug target because of its role in the repair of double stranded DNA breaks, conferring resistance to radiation and temozolomide (TMZ), used in the standard of care for GBMs.

Neurospheres enriched in cancer stem cells (CSCs) were cultured from freshly resected GBM tumors. Dose-response curves for both compounds were obtained for nine GBM neurosphere lines, resulting in stratification into sensitive and resistant groups. CC-115 single agent presented higher efficacy than CC-223 for all GBM CSC lines. Sensitivity to TORKi was not correlated with PTEN status in this sample set. To investigate the changes in CSC signaling pathways in response to TORK/DNA-PK inhibition, CC-115 dose-dependent changes in the levels of 70 proteins and phosphoproteins in 4 CSC lines presenting variable sensitivities were determined by reverse phase protein arrays (RPPA) The levels of p-mTOR, several downstream targets of both mTORC1 (e.g. p-S6K, p-4EBP1, p-RPS6K) and mTORC2 (p-AKT), and cyclin B1 were decreased in response to CC-115 IC30 dose in all CSC lines.

Four CSC lines from the CC-115 sensitive group were implanted intracranially in nude mice. PDXs were administered CC-115 (2.5 - 5mg/kg) and CC-223 (10mg/kg), or vehicle control 5 days/week by oral gavage (n&gt;7/group) for a minimum of 4 weeks. CC-115 monotherapy significantly increased survival of one PDX line. Combination therapy significantly increased survival of GBM PDX lines that did not respond to either CC-115 or TMZ monotherapy. Toxicity associated with CC-115 treatment in nude mice prevented a dose-escalation study. We conclude that the TORK/DNA-PK inhibitor CC-115 is a promising targeted therapy for GBMs, particularly in combination with DNA-targeting treatments. Our results underline the molecular diversity in GBMs reflected in the variable chemosensitivity, and the need to stratify patients for targeted therapies to increase the chance of success.

Citation Format: Kimberly Bergman, Susan M. Irtenkauf, Laura A. Hasselbach, Claudius Mueller, Emanuel Petricoin, Heather Raymon, Tom Mikkelsen, Ana C. Decarvalho. TORK/DNA-PK inhibitor CC-115 is effective as a single agent in a subset of glioblastoma patient-derived cancer stem cells and xenografts and potentiates temozolomide therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1755. doi:10.1158/1538-7445.AM2015-1755