Preclinical positron emission computed tomography of prolonged tumor growth after lutetium-177 prostate-specific membrane antigen treatment in xenograft model of human prostate cancer

Abstract

BACKGROUND: New treatment methods of castration-resistant prostate cancer with radionuclide therapy are needed. They will optimize personalized strategy for radionuclide therapy of metastatic castrate-resistant prostate cancer using low molecular weight ligands to prostate-specific membrane antigen (PSMA) labeled with lutetium-177.

AIM: To define the long-term effects and effectiveness of the treatment experimental animals with PET imaging to refine the research strategy.

METHODS: The study was performed in nu/nu male mice with PSMA-expressing 22Rv1 prostate cancer xenografts. Positron emission computed tomography with 18F-PSMA-1007 was used to confirm the tumor regrowth after a single therapeutic dose of [177Lu]Lu-PSMA-I&T.

RESULTS: Positron emission tomography imaging with 18F-PSMA-1007 showed the possibility of prolonged 22Rv1 tumor regrowth after a single injection of 9.2 MBq of [177Lu]Lu-PSMA-I&T, which is equivalent to minimal human therapeutic dose (28.6 MBq/kg).

CONCLUSIONS: The study confirmed the short period of the observed therapeutic effect after a single injection of 9.2 MBq of [177Lu]Lu-PSMA-I&T. The tumor regrowth in 2.5 months after the reduction of 22Rv1 xenografts to a non-palpable state was confirmed by positron emission computed tomography with 18F-PSMA-1007. These results confirm the need to study the frequency of repeated administrations of radiopharmaceuticals based on ligands to PSMA labeled with lutetium-177 to achieve a stable therapeutic effect in cases where a single dose reduction is necessary.

Keywords

radiopharmaceuticals / xenograft / tumor / castration-resistant prostate cancer / lutetium-177 / fluorine-18

References

[1] Crowley F, Sterpi M, Buckley C, et al. A Review of the Pathophysiological Mechanisms Underlying Castration-resistant Prostate Cancer. Research and Reports in Urology. 2021;13:457–472. doi: 10.2147/RRU.S264722

[2] Crowley F., Sterpi M., Buckley C., et al. A Review of the Pathophysiological Mechanisms Underlying Castration-resistant Prostate Cancer // Research and Reports in Urology. 2021. Vol. 13. P. 457–472. doi: 10.2147/RRU.S264722

[3] Pituskin E, Fairchild A. Prostate Cancer with Bone Metastases: Addressing Chronic Pain from the Perspective of the Radiation Oncology Nurse Practitioner. Seminars in Oncology Nursing. 2021;37(4):151175. doi: 10.1016/j.soncn.2021.151175

[4] Pituskin E., Fairchild A. Prostate Cancer with Bone Metastases: Addressing Chronic Pain from the Perspective of the Radiation Oncology Nurse Practitioner // Seminars in Oncology Nursing. 2021. Vol. 37, N 4. P. 151175. doi: 10.1016/j.soncn.2021.151175

[5] Mirshahvalad SA, Farzanefar S, Abbasi M. Therapeutic Outcomes of 177Lu-PSMA Targeted Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer: A Single-Center Study. Asia Oceania Journal of Nuclear Medicine & Biology. 2023;11(1):23–29. doi: 10.22038/AOJNMB.2022.64964.1454

[6] Mirshahvalad S.A., Farzanefar S., Abbasi M. Therapeutic Outcomes of 177Lu-PSMA Targeted Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer: A Single-Center Study // Asia Oceania Journal of Nuclear Medicine & Biology. 2023. Vol. 11, N 1. P. 23–29. doi: 10.22038/AOJNMB.2022.64964.1454

[7] ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine. [cited 2023 Oct 1]. Available from: https://clinicaltrials.gov/ct2/results?cond=&term=177Lu+PSMA&cntry=&state=&city=&dist=&Search=Search

[8] ClinicalTrials.gov [Internet]. Bethesda (MD) : National Library of Medicine. [дата обращения: 01.10.2023]. Доступ по ссылке: https://clinicaltrials.gov/ct2/results?cond=&term=177Lu+PSMA&cntry=&state=&city=&dist=&Search=Search

[9] Committee for Medicinal Products for Human Use (CHMP). Assessment report Pluvicto. 2022 Oct. EMA/871459/2022.

[10] Helmich LPH, de Arruda MAM, Sapienza MT. PSMA-directed radioligand therapy (PSMA-RLT) with Lutetium-177 (177Lu-PSMA) as a treatment to metastatic resistant prostate cancer: a systematic review. Revista De Medicina. 2021;100(4):391–402. doi: 10.11606/issn.1679-9836.v100i4p391-402

[11] Helmich L.P.H., de Arruda M.A.M., Sapienza M.T. PSMA-directed radioligand therapy (PSMA-RLT) with Lutetium-177 (177Lu-PSMA) as a treatment to metastatic resistant prostate cancer: a systematic review // Revista De Medicina. 2021. Vol. 100, N 4. P. 391–402. doi: 10.11606/issn.1679-9836.v100i4p391-402

[12] Yusufi N, Wurzer A, Herz M, et al. Comparative Preclinical Biodistribution, Dosimetry, and Endoradiotherapy in Metastatic Castration-Resistant Prostate Cancer Using 19F/177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T. Journal of Nuclear Medicine. 2021;62(8):1106–1111. doi: 10.2967/jnumed.120.254516

[13] Yusufi N., Wurzer A., Herz M., et al. Comparative Preclinical Biodistribution, Dosimetry, and Endoradiotherapy in Metastatic Castration-Resistant Prostate Cancer Using 19F/177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T // Journal of Nuclear Medicine. 2021. Vol. 62, N 8. P. 1106–1111. doi: 10.2967/jnumed.120.254516

[14] Kuo H-T, Merkens H, Zhang Zh, et al. Enhancing Treatment Efficacy of 177Lu-PSMA-617 with the Conjugation of an Albumin-Binding Motif: Preclinical Dosimetry and Endoradiotherapy Studies. Molecular Pharmaceutics. 2018;15(11):5183–5191. doi: 10.1021/acs.molpharmaceut.8b00720

[15] Kuo H.-T., Merkens H., Zhang Zh., et al. Enhancing Treatment Efficacy of 177Lu-PSMA-617 with the Conjugation of an Albumin-Binding Motif: Preclinical Dosimetry and Endoradiotherapy Studies // Molecular Pharmaceutics 2018. Vol. 15, N 11. P. 5183–5191. doi: 10.1021/acs.molpharmaceut.8b00720

[16] Weineisen M, Schottelius M, Simecek J, et al. 68Ga- and 177Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies. Journal of Nuclear Medicine. 2015;56(8):1169–1176. doi: 10.2967/jnumed.115.158550

[17] Weineisen M., Schottelius M., Simecek J., et al. 68Ga- and 177Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies // Journal of Nuclear Medicine. 2015. Vol. 56, N 8. P. 1169–1176. doi: 10.2967/jnumed.115.158550

[18] Wang F (Nanjing First Hospital, Nanjing Medical University). 177Lu-PSMA-I&T PSMA Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer. National Library of Medicine (US), ClinicalTrials.gov; 2019 Jun. ID NCT04188587.

[19] Wang F. (Nanjing First Hospital, Nanjing Medical University). 177Lu-PSMA-I&T PSMA Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer. National Library of Medicine (US), ClinicalTrials.gov; 2019 Jun. ID NCT04188587.

[20] Lückerath K, Wei L, Fendler WP, et al. Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer. EJNMMI Research. 2018;8. doi: 10.1186/s13550-018-0451-z

[21] Lückerath K., Wei L., Fendler W.P., et al. Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer // EJNMMI Research. 2018. Vol. 8. doi: 10.1186/s13550-018-0451-z

[22] Tomayko MM, Reynolds CP. Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemotherapy and Pharmacology. 1989;24:148–154. doi: 10.1007/BF00300234

[23] Tomayko M.M., Reynolds C.P. Determination of subcutaneous tumor size in athymic (nude) mice // Cancer Chemotherapy and Pharmacology. 1989. Vol. 24. P. 148–154. doi: 10.1007/BF00300234

[24] Mironov AN, editor. Rukovodstvo po provedeniyu doklinicheskikh issledovanii lekarstvennykh sredstv. Part 1. Moscow: Grif i K; 2012. (In Russ).

[25] Руководство по проведению доклинических исследований лекарственных средств. Часть 1 / под ред. А.Н. Миронова. Москва : Гриф и К, 2012.

[26] Khabriev RU, editor. Rukovodstvo po eksperimental’nomu (doklinicheskomu) izucheniyu novykh farmakologicheskikh veshchestv. 2nd edition. Moscow: Izdatelstvo Meditsina; 2008. (In Russ).

[27] Руководство по экспериментальному (доклиническому) изучению новых фармакологических веществ. 2-е издание / под ред. Р.У. Хабриева. Москва : Издательство «Медицина», 2008.

[28] IAEA Radioisotopes And Radiopharmaceuticals Series. Guidance for Preclinical Studies with Radiopharmaceuticals. 2021.

[29] Dupont P, Warwick J. Kinetic modelling in small animal imaging with PET. Methods. 2009;48(2):98–103. doi: 10.1016/j.ymeth.2009.03.008

[30] Dupont P., Warwick J. Kinetic modelling in small animal imaging with PET // Methods. 2009. Vol. 48, N 2. P. 98–103. doi: 10.1016/j.ymeth.2009.03.008

[31] Kuntner C. Kinetic modeling in pre-clinical positron emission tomography. Zeitschrift für Medizinische Physik. 2014;24(4):274–285. doi: 10.1016/j.zemedi.2014.02.003

[32] Kuntner C. Kinetic modeling in pre-clinical positron emission tomography // Zeitschrift für Medizinische Physik. 2014. Vol. 24, N 4. P. 274–285. doi: 10.1016/j.zemedi.2014.02.003

[33] Khmelinskii A, Baiker M, Kaijzel EL, et al. Articulated Whole-Body Atlases for Small Animal Image Analysis: Construction and Applications. Molecular Imaging and Biology. 2011;13:898–910. doi: 10.1007/s11307-010-0386-x

[34] Khmelinskii A., Baiker M., Kaijzel E.L., et al. Articulated Whole-Body Atlases for Small Animal Image Analysis: Construction and Applications // Molecular Imaging and Biology. 2011. Vol. 13. P. 898–910. doi: 10.1007/s11307-010-0386-x

[35] Israeli RS, Powell CT, Corr JG, Fair WR, Heston WD. Expression of the prostate-specific membrane antigen. Cancer Research. 1994;54(7):1807–1811.

[36] Israeli R.S., Powell C.T., Corr J.G., Fair W.R., Heston W.D. Expression of the prostate-specific membrane antigen // Cancer Research. 1994. Vol. 54, N 7. P. 1807–1811.

[37] Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clinical cancer research. 1997;3(1):81–85.

[38] Silver D.A., Pellicer I., Fair W.R., Heston W.D., Cordon-Cardo C. Prostate-specific membrane antigen expression in normal and malignant human tissues // Clinical cancer research. 1997. Vol. 3, N 1. P. 81–85.

[39] Malik D, Sood A, Mittal BR, et al. Nonspecific Uptake of 68Ga-Prostate-Specific Membrane Antigen in Diseases other than Prostate Malignancy on Positron Emission Tomography/Computed Tomography Imaging: A Pictorial Assay and Review of Literature. Indian Journal of Nuclear Medicine. 2018;33(4):317–325. doi: 10.4103/ijnm.IJNM_81_18

[40] Malik D., Sood A., Mittal B.R., et al. Nonspecific Uptake of 68Ga-Prostate-Specific Membrane Antigen in Diseases other than Prostate Malignancy on Positron Emission Tomography/Computed Tomography Imaging: A Pictorial Assay and Review of Literature // Indian Journal of Nuclear Medicine. 2018. Vol. 33, N 4. P. 317–325. doi: 10.4103/ijnm.IJNM_81_18

[41] de Galiza Barbosa F, Queiroz MA, Nunes RF, et al. Nonprostatic diseases on PSMA PET imaging: a spectrum of benign and malignant findings. Cancer imaging. 2020;20. doi: 10.1186/s40644-020-00300-7

[42] de Galiza Barbosa F., Queiroz M.A., Nunes R.F., et al. Nonprostatic diseases on PSMA PET imaging: a spectrum of benign and malignant findings // Cancer imaging. 2020. Vol. 20. doi: 10.1186/s40644-020-00300-7

[43] European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes. European Treaty Series — No. 123. Strasbourg. (Mar 18, 1986).

[44] European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes. European Treaty Series - No. 123. Strasbourg. (Mar 18, 1986).

[45] Bol’shakov OP, Neznanov NG, Babakhanyan RV. Didakticheskie i eticheskie aspekty provedeniya issledovanii na biomodelyakh i na laboratornykh zhivotnykh. Kachestvennaya Klinicheskaya Praktika (Good Clinical Practice). 2002;(1):58–61. (In Russ).

[46] Большаков О.П., Незнанов Н.Г., Бабаханян Р.В. Дидактические и этические аспекты проведения исследований на биомоделях и на лабораторных животных // Качественная клиническая практика. 2002. № 1. С. 58–61.

[47] Directive 2010/63/EU of the European Parliament and of the Council on the protection of animals used for scientific purposes. (Sep 22, 2010).

Funding

ООО «ЦМИ-Медицина»CMI-Medicine LLC(14-8/36-2021)

ФГБУ ГНЦ ФМБЦ им. А.И. Бурназяна ФМБА РоссииState Research Center–Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency(14-8/36-2021)

RIGHTS & PERMISSIONS

Eco-Vector