Dataset Information

Novel PSMA-Targeting Radionuclide Peptidomimetics for Treating Prostate Cancer.

ABSTRACT: Prostate cancer is the third-most commonly diagnosed cancer and is one of the leading causes of cancer-related deaths in men worldwide. Although an armamentarium of approved drugs exists, treatment options become severely limited when resistance develops against last-line taxane chemotherapeutics. In March 2022, the FDA approved a first-in-class targeted radionuclide therapy, lutetium Lu 177 vipivotide tetraxetan (Pluvicto), for treating metastatic castration-resistant prostate cancer. The drug constitutes a prostate-specific membrane antigen-targeting peptidomimetic moiety conjugated to a radionuclide chelator via a linker. This Patent Highlight reveals the structure-activity relationship of key compounds against prostate cancer cells.

SUBMITTER: Chia CSB

PROVIDER: S-EPMC9841587 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Novel PSMA-Targeting Radionuclide Peptidomimetics for Treating Prostate Cancer.

Chia C S Brian CSB

ACS medicinal chemistry letters 20221223 1

Prostate cancer is the third-most commonly diagnosed cancer and is one of the leading causes of cancer-related deaths in men worldwide. Although an armamentarium of approved drugs exists, treatment options become severely limited when resistance develops against last-line taxane chemotherapeutics. In March 2022, the FDA approved a first-in-class targeted radionuclide therapy, lutetium Lu 177 vipivotide tetraxetan (Pluvicto), for treating metastatic castration-resistant prostate cancer. The drug ...[more]

PMID: 36655127

Similar Datasets

Project description:PurposeVarious radiolabeled prostate-specific membrane antigen (PSMA)-targeting tracers are clinically applied for prostate cancer (PCa) imaging and targeted radionuclide therapy. The PSMA binding affinities, biodistribution, and DNA-damaging capacities of these radiotracers have not yet been compared in detail. A major concern of PSMA-targeting radiotracers is the toxicity in other PSMA-expressing organs, such as the salivary glands, thus demanding careful evaluation of the most optimal and safest radiotracer. In this extensive preclinical study, we evaluated the clinically applied PSMA-targeting small molecule inhibitors DOTA-PSMA-617 (PSMA-617) and DOTAGA-PSMA-I&T (PSMA-I&T) and the PSMA nanobody DOTA-JVZ-007 (JVZ-007) using PSMA-expressing cell lines, a unique set of PCa patient-derived xenografts (PDX) and healthy human tissues.Methods and resultsIn vitro displacement studies on PSMA-expressing cells and cryosections of a PSMA-positive PDX revealed high and specific binding affinity for all three tracers labeled with lutetium-177 with IC50 values in the nanomolar range. Interestingly, [177Lu]Lu-JVZ-007 could not be displaced by PSMA-617 or PSMA-I&T, suggesting that this tracer targets an alternative binding site. Autoradiography assays on cryosections of human salivary and renal tissues revealed [177Lu]Lu-PSMA-617 to have the lowest binding to these healthy organs compared with [177Lu]Lu-PSMA-I&T. In vivo biodistribution assays confirmed the in vitro results with comparable tumor uptake of [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T at all timepoints, resulting in induction of similar levels of DNA double-strand breaks in the tumors. However, [177Lu]Lu-PSMA-I&T demonstrated approximately 40× higher renal uptake at 4 and 8 h post injection resulting in an unfavorable tumor-to-kidney ratio.Conclusion[177Lu]Lu-PSMA-617 has the most favorable biodistribution in mice as well as more favorable binding characteristics in vitro in PSMA-positive cells and human kidney and salivary gland specimens compared with [177Lu]Lu-PSMA-I&T and [177Lu]Lu-JVZ-007. Based on our preclinical evaluation, [177Lu]Lu-PSMA-617 is the best performing tracer to be taken further into clinical evaluation for PSMA-targeted radiotherapeutic development although with careful evaluation of the tracer binding to PSMA-expressing organs.

Project description:BackgroundProstate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) has demonstrated efficacy and tolerability with a dose-response effect in phase I/II trials in men with metastatic castration-resistant prostate cancer (mCRPC). The need for positive PSMA imaging before PSMA-TRT to select patients is largely practiced, but its utility is not proven. Given target heterogeneity, developing a biomarker to identify the optimal patient population remains an unmet need. The aim of this study was to assess PSMA uptake by imaging and response to PSMA-TRT.MethodsWe performed an analysis of men with mCRPC enrolled in sequential prospective phase I/II trials of PSMA-TRT. Each patient had baseline PSMA imaging by planar 111 In and/or 177 Lu SPECT (N = 171) or 68 Ga-PSMA-11 PET/CT (N = 44), but the results were not used to include/exclude treatment. Semiquantitative imaging scores (IS) on a 0-4 scale were assigned based on PSMA uptake in tumors compared to liver uptake. We compared the ≥50% PSA decline response proportions between low (0-1) and high (2-4) PSMA IS using the χ2 -test. We used multivariable logistic regression analysis to understand the relationship between independent and dependent variables, including IS, radionuclide activity (dose) administered, CALGB (Halabi) prognostic risk score, prior taxane use.Results215 men with progressive mCRPC received PSMA-TRT as follows: 177 Lu-J591 (n = 137), 177 Lu-PSMA-617 (n = 44), 90 Y-J591 (n = 28), 177 Lu-J591 + 177 Lu-PSMA-617 (n = 6). High PSMA expression (IS 2-4) was found in 160 (74.4%) patients and was significantly associated with more frequent ≥ 50% PSA reduction (26.2 vs. 7.3%, p = .006). On multivariate logistic regression analysis, higher IS was associated with a ≥50% decrease in PSA, even after accounting for CALGB (Halabi) prognostic score, the dose administered, and previous taxane use (OR, 4.72; 95% CI, 1.71-16.85; p = .006). Patients with low PSMA expression (N = 55, 24.7%) were less likely to respond. Thirteen of 26 (50%) with no PSMA uptake (IS = 0) had post-PSMA-TRT PSA decline with 2 (7.7%) having ≥ 50% PSA declines.ConclusionCollectively, the data provide evidence in favor of the hypothesis that patients with high PSMA uptake and high administered radionuclide dose correlate with a higher chance of response.

Dataset Information

Novel PSMA-Targeting Radionuclide Peptidomimetics for Treating Prostate Cancer.

Publications

Novel PSMA-Targeting Radionuclide Peptidomimetics for Treating Prostate Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets