Abstract 376: CRLX101, a nanopharmaceutical in phase 2 clinical trials, is synergistic with antiangiogenic treatment through HIF-1α inhibition in an ovarian cancer xenograft model

Antiangiogenic drugs reduce blood flow to tumors and thereby inhibit tumor growth by starving tumors of oxygen and nutrients. However, antiangiogenic agents have achieved limited success as monotherapies. This may be in part because the reduced blood flow that follows this therapy induces tumor hypoxia and up-regulates hypoxia-inducible factor 1α (HIF-1α), well implicated in the promotion of tumor angiogenesis, invasion, and metastasis. We investigated whether the efficacy of antiangiogenic drugs could be improved by combining them with an inhibitor of HIF-1α. Previous investigators showed that HIF-1α can be inhibited by camptothecin (CPT). Therefore, we sought to demonstrate that CRLX101, a self-assembling nanopharmaceutical that delivers the topoisomerase-1 inhibitor CPT, is an inhibitor of HIF-1α and that CRLX101 efficacy is synergistic with antiangiogenic treatment. CRLX101 is designed to deliver therapeutically relevant concentrations of CPT to tumors over an extended period of time. We have previously presented data demonstrating dramatic CRLX101-mediated inhibition of tumor growth in 20 different xenograft models and CRLX101 is currently being evaluated in phase 2 clinical trials as a monotherapy for NSCLC, ovarian and gastric cancer and in combination with bevacizumab in renal cell carcinoma. First, we demonstrated that CRLX101 is an inhibitor of HIF-1α. A single administration of CRLX101 inhibited HIF-1α protein in 7/8 different xenograft models tested, representing ovarian, lung, renal, colorectal and prostate tumor types. In the HCT-116 colon xenograft tumor, for example, HIF-1α was inhibited up to 90% for at least 7 days. Treatment by CRLX101 also decreased the mRNA of all HIF-1α-regulated genes analyzed, including VEGF, CA9, GLUT-1, GLUT-3 and CD31. Inhibition of these genes occurred only in tumors in which HIF-1α levels were inhibited. Second, combining CRLX101 with bevacizumab (BEV) demonstrated a synergistic effect on tumor growth inhibition and improved survival in the A2780 ovarian xenograft tumor model. Specifically, CRLX101 alone, at a sub-maximal dose of 5 mg/kg, produced 2/10 complete responses (CRs), BEV alone at 5 mg/kg produced 2/10 CRs and the combination of the two resulted in 6/9 CRs. BEV alone increased HIF-1α protein, consistent with BEV-induced hypoxia, whereas CRLX101 alone inhibited HIF-1α protein. When the two drugs were combined, inhibition of HIF-1α was significantly greater than CRLX101 monotherapy. The synergistic acti