Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer

Juzeniene, Asta; Stenberg, Vilde Yuli; Bruland, Øyvind S.; Larsen, Roy H.

doi:10.3390/cancers13040779

Cited by 57 publications

(62 citation statements)

References 204 publications

(339 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The alpha particles emitted by 225 Ac have a much higher LET than electrons emitted by 177 Lu, leading to clusters of irreparable double-strand DNA breaks. In contrast, beta radiation by 177 Lu alone produces primarily single-strand breaks, which are more easily repaired by cell mechanisms [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of [225Ac]Ac-PSMA-617 Augmented [177Lu]Lu-PSMA-617 Radioligand Therapy in Patients with Highly Advanced mCRPC with Poor Prognosis

et al. 2021

View full text Add to dashboard Cite

The use of 225Ac in prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), either as monotherapy or in combination with 177Lu, is a promising therapy approach in patients with metastatic castration-resistant prostate carcinoma (mCRPC). In this study, we report the efficacy and safety of [225Ac]Ac-PSMA-617 augmented [177Lu]Lu-PSMA-617 RLT in 177Lu-naive mCRPC patients (n = 15) with poor prognosis (presence of visceral metastases, high total tumor burden with diffuse bone metastases or a short PSA doubling time of <2 months). Biochemical (by PSA serum value) and molecular imaging response (by [68Ga]Ga-PSMA-11 PET/CT) was assessed after two cycles of [177Lu]Lu-PSMA-617 RLT, with at least one [225Ac]Ac-PSMA-617 augmentation. In addition, PSA-based progression-free survival (PSA-PFS), overall survival (OS) and toxicity (according to CTCAE) were analyzed. We observed a biochemical- and molecular imaging-based partial remission in 53.3% (8/15) and 66.7% (10/15) of patients, respectively. The median PSA-PFS and OS was 9.1 and 14.8 months, respectively. No serious acute adverse events were recorded. Two out of fifteen patients experienced grade 3 anemia. No other grade 3/4 toxicities were observed. RLT-related xerostomia (grade 1/2) was recorded in 2/15 patients. Our data showed a high clinical efficacy with a favorable side effects profile of [225Ac]Ac-PSMA-617 augmented [177Lu]Lu-PSMA-617 RLT in this highly challenging patient cohort.

show abstract

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of [225Ac]Ac-PSMA-617 Augmented [177Lu]Lu-PSMA-617 Radioligand Therapy in Patients with Highly Advanced mCRPC with Poor Prognosis

et al. 2021

View full text Add to dashboard Cite

show abstract

“…TAT using 213 Bi-labelled PSMA-617 has also shown considerable antitumour activity in a mCRPC patient [ 17 ]. A recently published review provides a comprehensive overview of the preclinical and clinical status of PSMA-TAT for mCRPC [ 18 ]. However, several limitations are associated with the use of 225 Ac and 213 Bi, including availability, logistics related to the short half-life of 213 Bi (t 1/2 = 46 min) and toxicity in salivary glands of 225 Ac [ 12 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the PSMA-Binding Ligand 212Pb-NG001 in Multicellular Tumour Spheroid and Mouse Models of Prostate Cancer

Stenberg

Larsen²,

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

Radioligand therapy targeting the prostate-specific membrane antigen (PSMA) is rapidly evolving as a promising treatment for metastatic castration-resistant prostate cancer. The PSMA-targeting ligand p-SCN-Bn-TCMC-PSMA (NG001) labelled with 212Pb efficiently targets PSMA-positive cells in vitro and in vivo. The aim of this preclinical study was to evaluate the therapeutic potential of 212Pb-NG001 in multicellular tumour spheroid and mouse models of prostate cancer. The cytotoxic effect of 212Pb-NG001 was tested in human prostate C4-2 spheroids. Biodistribution at various time points and therapeutic effects of different activities of the radioligand were investigated in male athymic nude mice bearing C4-2 tumours, while long-term toxicity was studied in immunocompetent BALB/c mice. The radioligand induced a selective cytotoxic effect in spheroids at activity concentrations of 3–10 kBq/mL. In mice, the radioligand accumulated rapidly in tumours and was retained over 24 h, while it rapidly cleared from nontargeted tissues. Treatment with 0.25, 0.30 or 0.40 MBq of 212Pb-NG001 significantly inhibited tumour growth and improved median survival with therapeutic indexes of 1.5, 2.3 and 2.7, respectively. In BALB/c mice, no signs of long-term radiation toxicity were observed at activities of 0.05 and 0.33 MBq. The obtained results warrant clinical studies to evaluate the biodistribution, therapeutic efficacy and toxicity of 212Pb-NG001.

show abstract

“…Alpha particle emission from 149 Tb is associated with high recoil energy that is sufficient to cause bond breakage leading to the systemic dissemination of daughter radionuclides and consequently whole-body radiation in general and bone marrow damage from the long-term accumulation of these free daughter radionuclides in the functional bone marrow [29]. 212 Pb decays by beta emission (physical halflife = 10.6 h) via its short-lived daughter radionuclides, 212 Bi (T 1/2 = 60.6 min) and 212 Po (T 1/2 = 0.3 µs) [25]. Two major limitations with the clinical application of 212 Pb for targeted radioligand therapy relate to the high initial kidney uptake and consequently imparting a high renal dose as well as the high recoil energy, which is high enough to cause to up to 36% of 212 Bi, one of its daughter radionuclides, to dissociate from the complexes [25,30,31].…”

Section: Alpha-emitting Radionuclides For Psma Therapymentioning

confidence: 99%

Global experience with PSMA-based alpha therapy in prostate cancer

Sathekge

Bruchertseifer

Vorster

et al. 2021

Eur J Nucl Med Mol Imaging

View full text Add to dashboard Cite

Purpose This review discusses the current state of prostate-specific membrane antigen (PSMA)-based alpha therapy of metastatic castration-resistant prostate cancer (mCRPC). With this in-depth discussion on the growing field of PSMA-based alpha therapy (PAT), we aimed to increase the interactions between basic scientists and physician–scientists in order to advance the field. Methods To achieve this, we discuss the potential, current status, and opportunities for alpha therapy and strategies, attempted to date, and important questions that need to be addressed. The paper reviews important concepts, including whom to treat, how to treat, what to expect regarding treatment outcome, and toxicity, and areas requiring further investigations. Results There is much excitement about the potential of this field. Much of the potential exists because these therapies utilize unique mechanisms of action, difficult to achieve with other conventional therapies. Conclusion A better understanding of the strengths and limitations of PAT may help in creating an effective therapy for mCRPC and design a rational combinatorial approach to treatment by targeting different tumor pathways.

show abstract

Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer

Cited by 57 publications

References 204 publications

Efficacy and Safety of [225Ac]Ac-PSMA-617 Augmented [177Lu]Lu-PSMA-617 Radioligand Therapy in Patients with Highly Advanced mCRPC with Poor Prognosis

Efficacy and Safety of [225Ac]Ac-PSMA-617 Augmented [177Lu]Lu-PSMA-617 Radioligand Therapy in Patients with Highly Advanced mCRPC with Poor Prognosis

Evaluation of the PSMA-Binding Ligand 212Pb-NG001 in Multicellular Tumour Spheroid and Mouse Models of Prostate Cancer

Global experience with PSMA-based alpha therapy in prostate cancer

Contact Info

Product

Resources

About