Abstract
Anti-prostate specific membrane antigen (PSMA) radioligand therapy is promising but not curative in castration resistant prostate cancer. One way to broaden the therapeutic index could be to administer higher doses in combination with radioprotectors, since administered radioactivity is kept low today in order to avoid side-effects from a high absorbed dose to healthy tissue. Here, we investigated the human radical scavenger α1-microglobulin (A1M) together with 177-Lutetium (177Lu) labeled PSMA-617 in preclinical models with respect to therapeutic efficacy and kidney toxicity. Nude mice with subcutaneous LNCaP xenografts were injected with 50 or 100 MBq of [177Lu]Lu-PSMA-617, with or without injections of recombinant A1M (rA1M) (at T = 0 and T = 24 h). Kidney absorbed dose was calculated to 7.36 Gy at 4 days post a 100 MBq injection. Activity distribution was imaged with Single-Photon Emission Computed Tomography (SPECT) at 24 h. Tumor volumes were measured continuously, and kidneys and blood were collected at termination (3–4 days and 3–4 weeks after injections). In a parallel set of experiments, mice were given [177Lu]Lu-PSMA-617 and rA1M as above and dynamic technetium-99m mercaptoacetyltriglycine ([99mTc]Tc-MAG3) SPECT imaging was performed prior to injection, and 3- and 6-months post injection. Blood and urine were continuously sampled. At termination (6 months) the kidneys were resected. Biomarkers of kidney function, expression of stress genes and kidney histopathology were analyzed. [177Lu]Lu-PSMA-617 uptake, in tumors and kidneys, as well as treatment efficacy did not differ between rA1M and vehicle groups. In mice given rA1M, [99mTc]Tc-MAG3 imaging revealed a significantly higher slope of initial uptake at three months compared to mice co-injected with [177Lu]Lu-PSMA-617 and vehicle. Little or no change compared to control was seen in urine albumin, serum/plasma urea levels, RT-qPCR analysis of stress response genes and in the kidney histopathological evaluation. In conclusion, [99mTc]Tc-MAG3 imaging presented itself as a sensitive tool to detect changes in kidney function revealing that administration of rA1M has a potentially positive effect on kidney perfusion and tubular function when combined with [177Lu]Lu-PSMA-617 therapy. Furthermore, we could show that rA1M did not affect anti-PSMA radioligand therapy efficacy.
Highlights
Prostate cancer (PCa) is among the most common malignancies in men
We investigated the effects of [177 Lu]Lu-prostate specific membrane antigen (PSMA)-617, 50 and 100 MBq/mouse, alone or co-administered with recombinant as α1 -microglobulin (A1M) in two preclinical mouse models
Lu]Lu-PSMA-617 in our preclinical model of prostate cancer as no significant effect of [177Lu]Lu-PSMA-617 in our preclinical model of prostate cancer as no significant differences could be seen between mice given vehicle or recombinant A1M (rA1M) together with [177
Summary
Prostate cancer (PCa) is among the most common malignancies in men. Initially all PCa tumors are androgen responsive and androgen deprivation therapy (ADT) is the first line therapy of choice with a high response rate in metastatic disease. ADT progresses the disease to a castration resistant state called castration resistant prostate cancer (CRPC). In the STAMPEDE trial, the median failure free survival for patients with metastatic androgen sensitive PCa treated with ADT alone was 11.2 months [1]. PSMA radioligand therapy has been successful in prolonging the life and temporarily reducing the tumor burden in terminally ill prostate cancer patients with limited observed toxicity, it is not curative in metastatic CRPC [5,6,7]. All published clinical studies to date have been conducted as salvage therapy or followed patients with an overall survival of approximately one year; the relatively good toxicity data reported do not necessarily take into account eventual late effects of the treatment. Uptake in kidney and salivary glands must be seen as a potential obstacle for the realization of broader use of PSMA specific radioligands
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
