| dc.description.abstract | Background: Prostate cancer not responding to androgen deprivation therapy is known as castration-resistant prostate cancer (CRPC). Despite rapid increase of treatment options, the disease remains incurable, when metastases appear, which might be due to the diverse mechanisms and the heterogeneity and multifocal nature of the disease. For this reason, novel and highly effective therapy approaches against metastatic CRPC (mCRPC) are required. Exploring combination therapy using existing and novel agents provide better response than treatments with single agents. The progression of treated-naïve- prostate cancer is shown to be driven by androgen-receptor (AR), along with bromodomain and extra terminal domain (BET) proteins. Thus, inhibition of such proteins is an alternative, promising anticancer therapy. Treatments of mCRPC with BET inhibitors, JQ1, AZD5153 or AR inhibitor, Enzalutamide (ENZA) in combination with radiopharmaceuticals, are not being investigated.
Aim: Evaluating the preclinical therapeutic efficacy of combining BET or AR inhibitors with radiopharmaceuticals, α-emitting 223Ra targeting bone metastases or ẞ-emitting 177Lu-PSMA-617 in the prostate cancer C4-2 cells grown in cell monolayers (2D) and multicellular spheroids (3D).
Methods: Prostate cancer C4-2 cells growing 2D and 3D culture models were treated with selected concentrations of JQ1, AZD5153 or ENZA in combination with various activities of 223Ra. In 2D model, the treatment effects were assessed by counting colonies after 10-14 days and assessing cell survival fraction curves. Growth rates of the spheroids after treatments were evaluated by following the morphological changes and measurement of the cross-sectional area of the spheroids. Flow cytometry analysis was used to study cell apoptosis/necrosis, DNA damage and cell cycle distribution 72 h after combination treatment. In addition, C4-2 spheroids were treated with a combination of a selected concentration of AZD5153 and various activities of 177Lu-PSMA-617).
Results: The studied BET inhibitors, JQ1, AZD5153 had antiproliferative effects as mono-treatment in C4-2 monolayer cells and decreased C4-2 spheroid growth in a dose and time-dependent manner. ENZA did not inhibit C4-2 cell survival in a dose-dependent manner. The combination of AZD5153, JQ1 or ENZA with 223Ra showed the synergistic decrease in C4-2 spheroid growth. The combination treatments reduced the percentage of C4-2 cells in S and M phases of the cell cycle. However, the reduction was not statistically significant. However, the combination treatments had no proapoptotic activity. Additionally, the combination of AZD5153 with 177Lu-PSMA-617, synergistically decreased C4-2 spheroid growth.
Conclusion: The combination treatments of JQ1, AZD5153 or ENZA and 223Ra or AZD5153 and177Lu-PSMA-617 induced synergistic inhibition of C4-2 spheroids growth. These preclinical combination therapies provide rational for clinical evaluation of these combinations for treatment of mCRPC patients. | en_US |
