PSMA ligands for diagnosis and therapy of prostate cancer

Abstract

Since the prostate-specific membrane antigen (PSMA) is frequently over-expressed in prostate cancer (PCa) several PSMA-targeting molecules are under development to detect and treat metastatic castration resistant prostate cancer. In 82.8% of 319 patients investigated with 68Ga-PSMAHBEDPET/ CT at least one lesion indicative for PCa was detected. Tumor detection was positively associated with PSA level and androgen deprivation therapy. Amongst lesions investigated by histology, 30 were false-negative in 68Ga-PSMAHBED-PET/CT (one local relapse in one patient and 29 lymph nodes in another patient), all other lesions (n=416) were diagnosed true-positive or -negative. Fifty of 116 patients available for follow-up received local therapy after 68Ga-PSMAHBED-PET/CT. A comparison of 68Ga-PSMA-ligand with 18Ffluoromethylcholine PET/CT revealed 78 PC-suspicious lesions in 32 patients using 68Ga-PSMA-PET/CT and 56 lesions in 26 patients using Choline-PET/CT. The higher detection rate in 68Ga-PSMA-PET/CT concerning PC-suspicious lesions was significant (p=0.04). All lesions detected by 18Ffluoromethylcholine- PET/CT were also seen by 68Ga-PSMAPET/ CT. In 68Ga-PSMA-PET/CT SUVmax was clearly (>10%) higher in 62 of 78 lesions (79.1%) and tumor-to-background ratio was clearly (>10%) higher in 73 of 78 lesions (93.6%) when compared to 18F-fluoromethylcholine-PET/CT. Since the ligand bound to PSMA is internalized, the target may also be used for endoradiotherapy. We used a small molecule inhibitor of PSMA ((S)-2-(3-((S)-1-carboxy-5-(3-(4- [131I]-iodophenyl)ureido)-pentyl)ureido)-pentanedioic-acid; MIP-1095) for therapy in men with mCRPC. Dosimetry estimates for I-131-MIP-1095 revealed that the highest absorbed doses were delivered to the salivary glands (3.8 mSv/MBq, liver (1.7 mSv/MBq) and kidneys (1.4 mSv/MBq). The absorbed dose calculated for the red marrow was 0.37 mSv/MBq. PSA values decreased by >50% in 60.7% of the men treated. 84.6 % of men with bone pain showed complete or moderate reduction in pain. Hematological toxicities were mild. 25% of men treated had a transient slight to moderate dry mouth. No adverse effects on renal function were observed. In order to increase the therapeutic flexibilty we designed a novel theranostic PSMA ligand coupled to DOTA which allows coupling to Ga-68 for diagnostic use or to Lu-177 or Ac-225 for therapy. Especially for alpha therapy with Ac-225 promising results were found in the first 10 patients.