Detection of tissue and bone marrow clearance of systemically engrafted hematologic tumors by ABT-199 and navitoclax using bioluminescent imaging

Leukemias and lymphomas are characterized by disseminated disease burden in the circulation, lymphoid tissues and bone marrow. Although anti-cancer agents that can effectively target all of these compartments are associated with better prognosis, there is a paucity of established, longitudinal pre-clinical models that can faithfully reproduce the system-wide disease state of these malignancies. To address this limitation, we induced stable expression of the fusion construct of luc2, a firefly luciferase optimized for expression in mammalian cells, and mCherry, a far red fluorescent protein (named LMC), in an acute lymphoblastic leukemia (ALL) cell line, RS4;11, and a mantle cell lymphoma (MCL) cell line, Granta 519. Intravenous (IV) inoculation of these engineered lines in mice results in reliable tumor engraftment of the bone marrow and other tissues. Additionally, we demonstrate that Granta 519, a cell line harvested from a patient with a highly aggressive blastoid lymphoma, invades the central nervous system (CNS) similar to that observed in some MCL patients. Administration of the Bcl-2 inhibitors ABT-199 or navitoclax to established RS4;11-LMC tumor bearing mice significantly reduced tumor load in all compartments. This reflected the clinical activity achieved with navitoclax and, in particular, ABT-199, in recent clinical trials. Further, ABT-199 and navitoclax combined with bendamustine-rituximab (BR) induces significant regression of Granta 519-LMC tumors in the bone marrow and CNS, demonstrating that the Bcl-2 agents can access MCL cells which have invaded the CNS. Taken together, these data demonstrate that IV inoculation of RS4;11-LMC and Granta 519-LMC leads to engraftment of tumor cells in clinically relevant sites. The ability to both model systemic disease and monitor drug treatment in a longitudinal fashion constitutes a translational advantage for the study and development of anticancer therapeutics. Disclosures: SA, AO, JChen, BJC, JClarin, KF, TM, SM, SS, MLS, SKT, JL, AJS, ERB and JH are employees of AbbVie. This study was sponsored by AbbVie. AbbVie contributed to the study design, research and interpretation of data, writing, reviewing and approving the publication. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C249. Citation Format: Scott L. Ackler, Anatol Oleksijew, Jun Chen, Brenda J. Chyla, Jerry Clarin, Kelly Foster, Thomas McGonigal, Sasmita Mishra, Sally Schlessinger, Morey L. Smith, Stephen K. Tahir, Joel Leverson, Andrew J. Souers, Erwin R. Boghaert, Jonathan Hickson. Detection of tissue and bone marrow clearance of systemically engrafted hematologic tumors by ABT-199 and navitoclax using bioluminescent imaging. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C249.