Abstract A99: Docetaxel-resistance can be overcome by enhancing intratumoral taxane concentrations to a threshold level for efficacy.

Abstract

Abstract Introduction / objectives: Metastatic castration resistant prostate cancer (mCRPC) patients are treated with docetaxel (DOC) as a first line of treatment. Although DOC improves survival of mCRPC patients, resistance to DOC is commonly developed, hampering clinical efficacy. We hypothesized that there is a minimum exposure level for antitumor activity and therefore investigated the relation between intratumoral concentrations and antitumor activity for DOC and second-line treatment cabazitaxel (CABA) in DOC-naive and DOC-resistant patient-derived prostate cancer (PC) xenograft models. Materials and methods: DOC-resistant PC xenografts were generated previously by treatment of tumor-bearing mice with a single dose of DOC (33 mg/kg) followed by additional dosing at growth recurrence and upon subsequent passaging. Intratumoral concentrations of DOC and CABA were measured in the following xenografts: PC374 (DOC-sensitive), PC339 (poorly sensitive) and in the PC339-DOC resistant xenograft. Naïve PC339 and PC374 bearing mice were treated with a single injection of DOC or CABA of 8.3; 16.5 or 33 mg/kg. PC339-DOC -bearing mice, resistant to DOC at 33 mg/kg, were treated with a single injection of DOC 16.5; 33 or 50 mg/kg and sacrificed at 7 days post treatment. Intratumoral concentrations of DOC and CABA were correlated to the log ratio of tumor volume (TV) at start of treatment (day 0) divided by TV at sacrifice (day 7). Results: In mice dosed with DOC 33 mg /kg, intratumoral concentrations were higher in PC374 compared to PC339: 1.6 ± 05ng/mg tissue and 0.28 ± 0.13 ng/mg tissue, respectively (P =0.001). Moreover, CABA levels were higher than those of DOC in both PC374 and PC339 tumors: 5.3 ± 1.3 ng/mg tissue and 4.1 ± 1.8 ng/mg tissue, respectively (P= 0.0005, P= 0.005). In PC339 tumors, CABA antitumor activity and intratumoral concentrations were strongly correlated (r = -0.87, P <0.0001). Although DOC at 33 mg/kg was inactive in PC339-DOC bearing mice, increased dosing to 50 mg/kg may overcame drug resistance, resulting in a significant increase in intratumoral concentrations from 0.29 ± 0.09 ng/mg after dosing with 33 mg/kg to 1.1 ± 0.25 ng/mg after treatment with 50 mg/kg (P=0.005). In this xenograft antitumor response and intratumoral concentrations were strongly correlated (r=-0.84, P=0.004). For both DOC and CABA, a minimum exposure level (or ‘threshold’ concentration) for anti-tumor efficacy of 1.5 ng taxane/mg tumor tissue was found for naïve and DOC-resistant PC xenografts. Conclusions: These preclinical data pinpoint a sustained relationship between intratumoral concentrations and antitumor activity of taxanes in DOC resistant PC models. A minimum exposure level for effective intratumoral concentrations for both taxanes was defined that still applies in DOC-resistance. These data indicate that efforts to improve taxane uptake in DOC-resistant tumors may still be a relevant strategy to improve treatment outcome of mCRPC patients. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A99. Citation Format: Ellen S. de Morree, Corrina M. de Ridder, Peter de Bruijn, Herman Burger, Erik A.C. Wiemer, Ron H.J. Mathijssen, Ronald de Wit, Wytske van Weerden. Docetaxel-resistance can be overcome by enhancing intratumoral taxane concentrations to a threshold level for efficacy. [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 A99.