Abstract PR09: Synergistic activity of CRLX101, a nanopharmaceutical in Phase II clinical trials, with antiangiogenic therapies mediated through HIF-1alpha inhibition: A translational research program.

Background: Antiangiogenic drugs reduce blood flow to tumors and thereby inhibit tumor growth by starving tumors of oxygen and nutrients. However, antiangiogenic drugs have achieved limited success as monotherapies, in part because of their induction of hypoxia and the concomitant up-regulation of hypoxia-inducible factor 1α (HIF-1α), now well implicated in the promotion of tumor angiogenesis, invasion, metastasis, and cancer stem cell formation. We describe here a translational research program to investigate whether the efficacy of antiangiogenic drugs can be improved through combination with CRLX101, a camptothecin (CPT) containing nanopharmaceutical that inhibits both topoisomerase-1 and HIF-1α. Material and methods: We will present preclinical and clinical projects conducted across several major research institutions intended to demonstrate the anti-HIF-1α activity of CRLX101, the capacity of this drug to block the epithelial-mesenchymal transition (EMT) and the formation of cancer stem cells, and the synergistic activity of CRLX101 given in combination with antiangiogenic drugs. We will further describe two ongoing clinical trials evaluating these hypotheses, one at the University of Pennsylvania in advanced renal cell carcinoma (RCC) and one at the Massachusetts General Hospital in relapsed ovarian cancer following progression through prior platinum-containing chemotherapy. Results: A single dose of CRLX101 durably inhibits HIF-1α protein levels across multiple tumor types. Evaluation of CRLX101 in combination with bevacizumab, aflibercept or pazopanib in the A2780 ovarian xenograft tumor model demonstrates synergistic inhibition of tumor growth inhibition as well as increases in the rate of long-term survivorship. While all three antiangiogenic drugs alone increased HIF-1α protein levels, levels were inhibited in response to combination with CRLX101. In clinical evaluations, a CRLX101-bevacizumab combination appears safe and well tolerated with no dose limiting toxicities observed to date. Notable tumor decreases and long periods of progression free survival have been noted among patients treated with CRLX101-based mono and combination therapy. Conclusions: Results generated through this translational research program suggest that CRLX101 can overcome HIF-1α-mediated acquired resistance to antiangiogenic drugs, supporting the use of CRLX101 in combination with antiangiogenic drugs as an exciting new paradigm for the treatment of cancer. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PR09. Citation Format: Scott Eliasof, Sarah Conley, Stephen M. Keefe, Robert Kerbel, Carolyn N. Krasner, Douglas Lazarus, Christian Peters, Elizabeth Pham, Max S. Wicha, Edward G. Garmey. Synergistic activity of CRLX101, a nanopharmaceutical in Phase II clinical trials, with antiangiogenic therapies mediated through HIF-1alpha inhibition: A translational research program. [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 PR09.