Optimizing the Schedule of PARP Inhibitors in Combination with 177Lu-DOTATATE: A Dosimetry Rationale

Hallqvist, Andreas; Svensson, Johanna; Hagmarker, Linn; Marin, Ida; Rydén, Tobias; Beauregard, Jean-Mathieu; Bernhardt, Peter

doi:10.3390/biomedicines9111570

Cited by 6 publications

(4 citation statements)

References 25 publications

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“…Independent from HRD, the combination of PRRT and PARPi seems to be an interesting option to induce synthetic lethality and to enhance treatment efficacy. A study tried to optimize the treatment combination of PRRT and PARPi [ 14 ]. Two phase-1 studies PARLuNET for NET G2 (NCT05053854) and LuPARP for NET G2/G3 (NCT04375267) are ongoing to evaluate the feasibility and toxicity.…”

Section: Discussionmentioning

confidence: 99%

Successful Combination of Olaparib and 225Ac-Dotatate in a Patient with Neuroendocrine Tumor G3 and BRCA Mutation

Kröcher,

Folprecht,

Winzer

et al. 2023

Case Rep Oncol

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Based on the results of the NETTER-1 trial, peptide receptor radionuclide therapy with Lutetium-177 (177Lu) – DOTATATE is authorized for the treatment of neuroendocrine tumors (NET) grade 1 (G1) and grade 2 (G2) of the intestine. After the failure of 177Lu-DOTATATE therapy, targeted alpha-particle therapy (TAT) may be a possible treatment option. Here, we present a patient with cancer of unknown primary NET G2 later G3. The patient was referred to our hospital with urosepsis due to a second-degree urinary retention. After stent insertion, a contrast-enhanced computed tomography revealed a huge pelvic tumor without metastases. Initially, the patient had undergone surgical treatment. Later the patient developed liver metastasis and was treated by 177Lu-DOTATATE therapy and four lines of systemic therapy. A disease progression was observed and with the knowledge of a germline BRCA1 mutation, the patient was treated with TAT (Actinium-225 [225Ac]-DOTATATE) combined with olaparib. The patient achieved a significant treatment response for 12 months indicating that a combination therapy with an alpha emitter and olaparib demands further investigations in clinical trials.

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Section: Discussionmentioning

confidence: 99%

Successful Combination of Olaparib and 225Ac-Dotatate in a Patient with Neuroendocrine Tumor G3 and BRCA Mutation

Kröcher,

Folprecht,

Winzer

et al. 2023

Case Rep Oncol

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“…Indeed, the full radiosensitizing potential of olaparib is likely to be achieved using distinct schedules and doses. For 177 Lu-DOTATATE, a dosimetry-based schedule rationale is to start the PARP inhibitor 24 h after the infusion of 177 Lu-DOTATATATE and continue for 4 weeks at each cycle [ 8 ]. As for EBRT, Verhagen et al suggested that a short 7 h exposure (1 h before and 6 h after irradiation) of the PARP inhibitor is sufficient for radiosensitization [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…Such data are needed to fully exploit RNT potential, including in the context of treatment combination strategies. For example, DNA repair targeting strategies (i.e., using poly (ADP-ribose) polymerase (PARP) inhibitors) have shown promise in combination with EBRT and were therefore also tested in combination with RNT; however, different radiobiological considerations may need to be applied for efficient radiosensitization [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Understanding the Radiobiological Mechanisms Induced by 177Lu-DOTATATE in Comparison to External Beam Radiation Therapy

Delbart

Karabet

Marin

et al. 2022

IJMS

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Radionuclide Therapy (RNT) with 177Lu-DOTATATE targeting somatostatin receptors (SSTRs) in neuroendocrine tumours (NET) has been successfully used in routine clinical practice, mainly leading to stable disease. Radiobiology holds promise for RNT improvement but is often extrapolated from external beam radiation therapy (EBRT) studies despite differences in these two radiation-based treatment modalities. In a panel of six human cancer cell lines expressing SSTRs, common radiobiological endpoints (i.e., cell survival, cell cycle, cell death, oxidative stress and DNA damage) were evaluated over time in 177Lu-DOTATATE- and EBRT-treated cells, as well as the radiosensitizing potential of poly (ADP-ribose) polymerase inhibition (PARPi). Our study showed that common radiobiological mechanisms were induced by both 177Lu-DOTATATE and EBRT, but to a different extent and/or with variable kinetics, including in the DNA damage response. A higher radiosensitizing potential of PARPi was observed for EBRT compared to 177Lu-DOTATATE. Our data reinforce the need for dedicated RNT radiobiology studies, in order to derive its maximum therapeutic benefit.

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“…Combining TRT with potentially synergistic agents (chemotherapy, immune checkpoint inhibitors, PARP inhibitors, etc.) or with other radiopharmaceuticals is being evaluated in ongoing clinical trials (14)(15)(16)(17). The focus of this paper is to describe and explore a novel technology platform that may improve the therapeutic effect of TRT by combining two radionuclides from the same decay chain; one TAT component targeting the stromal elements of osteoblastic skeletal metastases and the other by selective cell-surface binding to cancer cells in extraskeletal and skeletal metastases.…”

Section: Introductionmentioning

confidence: 99%

Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach

Juzeniene

Stenberg²,

Bruland³

et al. 2023

Front. Med.

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Metastases are the primary cause of death among cancer patients and efficacious new treatments are sorely needed. Targeted alpha-emitting radiopharmaceuticals that are highly cytotoxic may fulfill this critical need. The focus of this paper is to describe and explore a novel technology that may improve the therapeutic effect of targeted alpha therapy by combining two radionuclides from the same decay chain in the same solution. We hypothesize that the dual targeting solution containing bone-seeking 224Ra and cell-directed complexes of progeny 212Pb is a promising approach to treat metastatic cancers with bone and soft tissue lesions as well as skeletal metastases of mixed lytic/osteoblastic nature. A novel liquid 224Ra/212Pb-generator for rapid preparation of a dual targeting solution is described. Cancer cell targeting monoclonal antibodies, their fragments, synthetic proteins or peptides can all be radiolabeled with 212Pb in the 224Ra-solution in transient equilibrium with daughter nuclides. Thus, 224Ra targets stromal elements in sclerotic bone metastases and 212Pb-chelated-conjugate targets tumor cells of metastatic prostate cancer or osteosarcoma. The dual targeting solution may also be explored to treat metastatic breast cancer or multiple myeloma after manipulation of bone metastases to a more osteoblastic phenotype by the use of bisphosphonates, denosumab, bortezomib or hormone therapy prior to treatment. This may improve targeting of bone-seeking 224Ra and render an augmented radiation dose deposited within metastases. Our preliminary preclinical studies provide conceptual evidence that the dual 224Ra-solution with bone or tumor-targeted delivery of 212Pb has potential to inhibit cancer metastases without significant toxicity. In some settings, the use of a booster dose of purified 212Pb-conjugate alone could be required to elevate the effect of this tumor cell directed component, if needed, e.g., in a fractionated treatment regimen, where the dual targeting solution will act as maintenance treatment.

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Optimizing the Schedule of PARP Inhibitors in Combination with 177Lu-DOTATATE: A Dosimetry Rationale

Cited by 6 publications

References 25 publications

Successful Combination of Olaparib and <sup>225</sup>Ac-Dotatate in a Patient with Neuroendocrine Tumor G3 and BRCA Mutation

Successful Combination of Olaparib and <sup>225</sup>Ac-Dotatate in a Patient with Neuroendocrine Tumor G3 and BRCA Mutation

Understanding the Radiobiological Mechanisms Induced by 177Lu-DOTATATE in Comparison to External Beam Radiation Therapy

Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach

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