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Targeted α-Therapy in Cancer Management: Synopsis of Preclinical and Clinical Studies.

ABSTRACT: The approval of ²²³Ra dichloride (²²³RaCl₂) in 2013 was a principal event in introducing targeted α-therapy as a form of safe and effective management strategy in cancer. There is an increasing interest in research and development of new targeted α-therapy agents spearheaded by advancements in cancer biology, radiochemistry, and availability of clinically relevant α particles. There are active clinical studies on sequencing or combining ²²³RaCl₂ with other drug regimens in the setting of metastatic prostate cancer and in other cancers such as osteosarcoma and bone-dominant breast cancer. Targeted α-therapy strategy is also being actively explored through many preclinical and few early clinical studies using ²²⁵Ac, ²¹³Bi, ²¹¹At, ²²⁷Th, and ²¹²Pb. Investigations incorporating ²²⁵Ac are more robust and active at this time with promising results. The author provide a brief synopsis of the preclinical and clinical studies in the rapidly evolving field of targeted α-therapy in cancer management.

SUBMITTER: Jadvar H

PROVIDER: S-EPMC7475102 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Targeted α-Therapy in Cancer Management: Synopsis of Preclinical and Clinical Studies.

Jadvar Hossein H

Cancer biotherapy & radiopharmaceuticals 20200323 7

The approval of 223Ra dichloride (223RaCl2) in 2013 was a principal event in introducing targeted α-therapy as a form of safe and effective management strategy in cancer. There is an increasing interest in research and development of new targeted α-therapy agents spearheaded by advancements in cancer biology, radiochemistry, and availability of clinically relevant α particles. There are active clinical studies on sequencing or combining 223RaCl2</ ...[more]

PMID: 32202923

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Project description:PurposeProstate-specific membrane antigen (PSMA) continues to be the hallmark biomarker for prostate cancer as it is expressed on nearly all prostatic tumors. In addition, increased PSMA expression correlates with castration resistance and progression to the metastatic stage of the disease. Recently, we combined both an albumin-binding motif and an irreversible PSMA inhibitor to develop the novel PSMA-targeted radiotherapeutic agent, CTT1403. This molecule was novel in the field of PSMA-targeted agents as its key motifs resulted in extended blood circulation time and tumor uptake, rapid and extensive internalization into PSMA+ cells, and promising therapeutic efficacy. The objective of this study was to perform IND-enabling translational studies on CTT1403 in rodent models.ProceduresA dose optimization study was performed in PC3-PIP (PSMA+) tumor-bearing mice. Treatment groups were randomly selected to receive one to three 14-MBq injections of CTT1403. Control groups included (1) saline, (2) non-radioactive [175Lu]CTT1403, or (3) two injections of 14 MBq CTT1751, a Lu-177-labeled non-targeted albumin-binding moiety. Tumor growth was monitored up to 120 days. Small-animal single photon emission tomography/X-ray computed tomography imaging was performed with CTT1403 and CTT1751 in PC3-PIP tumor-bearing mice to visualize infiltration of the Lu-177-labeled agent into the tumor. In preparation for a first-in-human study, human absorbed doses were estimated based on rat biodistribution out to 5 weeks to determine a safe CTT1403 therapy dose in humans.ResultsTwo to 3 injections of 14 MBq CTT1403 yielded significant tumor growth inhibition and increased survival compared with all control groups and mice receiving 1 injection of 14 MBq CTT1403. Five of 12 mice receiving 2 or 3 injections of CTT1403 survived to the 120-day post-treatment study endpoint. Dosimetry identified the kidneys as the dose-limiting organ, with an equivalent dose of 5.18 mSv/MBq, resulting in a planned maximum dose of 4.4 GBq for phase 1 clinical trials.ConclusionsThe preclinical efficacy and dosimetry of CTT1403 suggest that this agent has significant potential to be safe and effective in humans.

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Targeted α-Therapy in Cancer Management: Synopsis of Preclinical and Clinical Studies.

Publications

Targeted α-Therapy in Cancer Management: Synopsis of Preclinical and Clinical Studies.

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