Abstract P4-06-15: Mifepristone modifies the tumor microenvironment increasing the therapeutic efficiency of low doses of Doxorubicin liposomes or paclitaxel-albumin nanoparticles in a murine model of breast cancer.

Abstract

Abstract Chemotherapy is the standard treatment for metastatic breast cancer today. To overcome undesired side effects and improve drug efficacy in tumor cells, different nanoparticle formulations have been developed. Paclitaxel has been bound with human albumin (Nab-paclitaxel), and pegylated liposomes have been developed for doxorubicin delivery (PEG-LD). The aim of our study was to evaluate the effect of these therapeutic agents in experimental mammary carcinomas expressing different ratios of progesterone receptor (PR) isoforms and to evaluate the effect of combined treatments of chemotherapeutic agents with the antiprogestin mifepristone (MFP). Nab-paclitaxel (Abraxane, Abraxis), at a dosage of 30 and 60 mg/kg body weight administered in three doses every four days, completely inhibited the growth of the antiprogestin-resistant C4-2-HI mouse mammary carcinoma, which is associated with high levels of PR isoform B (PR-B) expression. C4-HI, an antiprogestin-responsive mouse tumor that shows high levels of PR isoform A (PR-A) expression, was not inhibited by the low Nab-paclitaxel dose. However, the combination of MFP (6 mg silastic pellet) with Nab-paclitaxel improved the efficacy of both single treatments. Similar experiments were conducted using PEG-LD (Doxopeg; Laboratorios Raffo). In this case, all tumors tested (C4-HI, CC4-3-HI, 59–2-HI and C4-2-HI) were all highly responsive to high (18 mg/kg/week) or low (9 mg/kg/week) PEG-LD doses. When PEG-LD concentrations were lowered to 4.5 mg/kg/week and they were combined with MFP, an improved response was observed with combined treatments only in tumors with high PR-A levels (p <0.001). Using BALB/c-GFP mice, we demonstrated that MFP treatment induced tissue remodeling in PR-A positive tumors, increasing the stromal/tumor cell ratio and the number of vessels (as shown by CD31 positive cells; p < 0.001). Taking advantage of doxorubicin's red autofluorescence, we showed increased levels of drug accumulation in tumor cells surrounding the stromal tissue. Using a human albumin antibody we demonstrated nab-paclitaxel accumulation in similar locations. However, because increased areas (p < 0.001) of stromal tissue were observed in the antiprogestin-treated mice, the total amount of PEG-LD or Nab-paclitaxel was much higher in the combined-treated tumors. We propose that antiprogestins have the potential to enhance the efficacy of nanotherapeutics in patients with breast tumors with a high PR-A/PR-B ratio. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-06-15.