This study is focused on evaluating the pre-clinical therapeutic efficacy of using Lu-177 labeled GRP (BB2 bombesin receptor subtype) receptor targeting peptides in combination with conventional chemotherapy for the treatment of human estrogen receptor positive (ER+) breast cancer SCID mouse xenografts. Xenografts of human ER+ breast cancer (T47D cell line) were created using a SCID mouse model. SCID mice were bilaterally inoculated subcutaneously with 5X106 cells per flank. DOTA-8-AOC-BBN(7-14)NH2 was synthesized via solid phase peptide synthesis. This compound has been demonstrated to target the BB2 or GRP receptor with nanomole affinity. Lu-177-DOTA-8-AOC-BBN(7-14)NH2 was prepared and purified by HPLC prior to i.v. administration. Docetaxel was administered singly or in combination with the GRP receptor targeted radiotherapy agent (TRT). Studies in our laboratory involving the use of docetaxel (DOC) and targeted radiotherapy in prostate cancer models demonstrated superior efficacy as compared to the use of either agent alone. Docetaxel has also been previously been shown to function as a radiation sensitizer. Combination Lu-177-DOTA-8-AOC-BBN(7-14)NH2/DOC studies were begun 50 days and 32 days post inoculation for ER+ xenografts, respectively. Lu-177- DOTA-8-AOC-BBN(7-14)NH2 dosing occurred biweekly for a total of 3 doses, and DOC chemotherapy administration occurred weekly for 5 consecutive weeks. Tumor size, body weight, and body condition score were evaluated twice weekly. Tumor volume measurements at 60 days post study initiation for the ER+ tumors demonstrated a 97%, 86%, and 20% tumor suppression for the combined Lu-177 TRT/DOC group, the DOC group, and the Lu-177-TRT group, respectively, as compared to the non-treated control group. Mean survival analysis demonstrated a increasing survival with respect to treatment where the mean survival times for the control group, the DOC group, the TRT group, and the DOC+TRT group was 81 days, 96 days, 108 days, and 125 days, respectively. Lu-177-TRT combined with DOC provided the greatest sustained tumor growth suppression and survival of all experimental groups evaluated. These data demonstrate that GRP receptor targeted radiation therapy combined with selective chemotherapy agents significantly inhibit the growth of human ER+ tumors using a preclinical xenograft model.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]