Anticancer effect of a combination of CXCR4 antagonist CTCE-9908 and Docetaxel in a murine model of human prostate cancer

C20 The role that the SDF-1/CXCR4 axis plays in tumor metastasis and angiogenesis is now well recognized. The chemokine SDF-1 (stromal cell derived factor-1) is the sole chemokine ligand for the receptor CXCR4. Recent work has also demonstrated that CXCR4 is involved in the establishment of the microenvironment and vasculature that support tumor cell proliferation. Thus, an inhibitor of this pathway may exhibit both cancer stasis in addition to anti-metastatic properties. A large and growing number of cancer types have been reported to express CXCR4, prostate cancer being one of them. The literature indicates that the expression of CXCR4 by prostate cancer correlates with its metastatic potential. As is the case with most cancers, the cure rate declines once the cancer metastasizes from the prostate gland to distant sites. We synthesized and tested a large number of CXCR4 antagonists. The lead product, designated CTCE-9908, is a modification of the N-terminal of human SDF-1. We have previously shown the anti-metastatic activity of this compound in five murine cancer models. Of note, CTCE-9908 alone reduced the total amount of metastases and especially distant metastases in a human prostate cancer model in mice. In the present study, we examined the effect of combination treatment of chemotherapy (Docetaxel) and CTCE-9908 in this prostate cancer model which has been previously described. Briefly, GFP transfected CXCR4 expressing PC-3 tumor cells were grown in subcutaneous site of host nude mice. Two 1mm 3 viable pieces of tumor were retrieved and sutured between the two ventral lobes of the prostate of host nude mice. In a pilot study, we treated mice implanted with PC-3 using various doses of Docetaxel on days 4 and 7 and determined a subtherapeutic dose. This dose was used in the subsequent combination study involving both adjuvant and consolidation treatment regimes. In the adjuvant setting, CTCE-9908 was given daily starting from day 3, on every day when Docetaxel was not given (days 5, 6, and 8 onwards). In the consolidation setting, CTCE-9908 was given daily starting the day after the last Docetaxel treatment (day 8) until the animals were euthanized. Metastasis was quantitated by measuring the fluorescent area. Survival of animals was also assessed. We observed no significant change in metastatic area with Docetaxel alone compared to the control group treated with vehicle. The adjuvant group showed a 34% reduction of metastatic area, while the consolidation group showed a 47% reduction compared to the vehicle control. The number of animals with distant metastasis to the diaphragm was reduced by 50% in both the adjuvant and consolidation groups. Survival analysis showed a significant increase in the average number of survival days from 35 days (vehicle) to 115 days (consolidation). By the end of the study, one mouse in the Docetaxel alone group and three mice in the consolidation group were free of primary tumor and metastases. The use of CTCE-9908 as a consolidation therapy used in combination with chemotherapy suggests a possible clinical application. The safety of CTCE-9908 was established in a Phase I clinical trial. Both safety and preliminary efficacy are being assessed in an ongoing Phase I/II study. Further development of CTCE-9908 in Phase II studies is underway.