<sup>177</sup>Lu-DOTATATE for the treatment of gastroenteropancreatic neuroendocrine tumors

Das, Satya; Al‐Toubah, Taymeyah; El-Haddad, Ghassan; Strosberg, Jonathan R.

doi:10.1080/17474124.2019.1685381

Cited by 80 publications

(52 citation statements)

References 48 publications

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“…Based on the NETTER-1 randomized clinical trial, peptide receptor radiotherapy (PRRT) using Lu-177-DOTATATE has been approved for somatostatin receptor 2 (SSTR2)-positive, nonresectable or metastatic, progressive, well-differentiated G1 and G2 NENs due to significantly increased progression-free survival (median time-to-progression was 36 months) [8] , [9] , [10] . The suggested mechanism is that after binding of the Lu-177 labeled ligand to SSTR, the emitted beta particles induce DNA single- and double-strand breaks (SSB and DSB) in SSTR2-positive tumor cells [11] .…”

Section: Introductionmentioning

confidence: 99%

Does the proteasome inhibitor bortezomib sensitize to DNA-damaging therapy in gastroenteropancreatic neuroendocrine neoplasms? – A preclinical assessment in vitro and in vivo

et al. 2021

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Background: Well-differentiated gastroenteropancreatic neuroendocrine neoplasms are rare tumors with a slow proliferation. They are virtually resistant to many DNA-damaging therapeutic approaches, such as chemo- and external beam therapy, which might be overcome by DNA damage inhibition induced by proteasome inhibitors such as bortezomib. Methods and results: In this study, we assessed several combined treatment modalities in vitro and in vivo . By cell-based functional analyses, in a 3D in ovo and an orthotopic mouse model, we demonstrated sensitizing effects of bortezomib combined with cisplatin, radiation and peptide receptor radionuclide therapy (PRRT). By gene expression profiling and western blot, we explored the underlying mechanisms, which resulted in an impaired DNA damage repair. Therapy-induced DNA damage triggered extrinsic proapoptotic signaling as well as the induction of cell cycle arrest, leading to a decreased vital tumor volume and altered tissue composition shown by magnetic resonance imaging and F-18-FDG-PET in vivo , however with no significant additional benefit related to PRRT alone. Conclusions: We demonstrated that bortezomib has short-term sensitizing effects when combined with DNA damaging therapy by interfering with DNA repair in vitro and in ovo . Nevertheless, due to high tumor heterogeneity after PRRT in long-term observations, we were not able to prove a therapeutic advantage of bortezomib-combined PRRT in an in vivo mouse model.

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Section: Introductionmentioning

confidence: 99%

Does the proteasome inhibitor bortezomib sensitize to DNA-damaging therapy in gastroenteropancreatic neuroendocrine neoplasms? – A preclinical assessment in vitro and in vivo

et al. 2021

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“…Clinical success has been demonstrated with the β − emitters 90 Y and 131 I conjugated with anti-CD20 monoclonal antibodies in follicular B-cell non-Hodgkin lymphoma [6], 177 Lu-labeled prostate-specific membrane antigen (PSMA) peptides in metastatic, castrationresistant prostate cancer (CRPC) and 177 Lu-DOTATATE for neuroendocrine tumors [7,8].…”

Section: Radioactive Particle Decay Characteristics Clinical Cancer Applications Referencementioning

confidence: 99%

Targeted Alpha Therapy: Progress in Radionuclide Production, Radiochemistry, and Applications

2020

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This review outlines the accomplishments and potential developments of targeted alpha (α) particle therapy (TAT). It discusses the therapeutic advantages of the short and highly ionizing path of α-particle emissions; the ability of TAT to complement and provide superior efficacy over existing forms of radiotherapy; the physical decay properties and radiochemistry of common α-emitters, including 225Ac, 213Bi, 224Ra, 212Pb, 227Th, 223Ra, 211At, and 149Tb; the production techniques and proper handling of α-emitters in a radiopharmacy; recent preclinical developments; ongoing and completed clinical trials; and an outlook on the future of TAT.

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“…Aminopeptidases represent one rational target in tumor cells for PDCs, catalyzing the hydrolysis of terminal amino acid residues from proteins or peptides and operating downstream of the ubiquitin–proteasome system [ 1 , 2 ]. PDCs targeting peptide hormone receptors that are overexpressed on tumor cells are another mechanism for delivering a cytotoxic payload into the tumor [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…177 Lu-dotatate has a different mechanism of action. 177 Lu-dotatate is a peptide receptor radionuclide therapy that is a targeted form of radiotherapy, allowing the delivery of a radionuclide payload directly to tumor cells that are expressing receptors and binding the homing peptide [ 3 ]. We also briefly cover some selected examples of PDCs currently under clinical development.…”

Section: Introductionmentioning

confidence: 99%

Progress and Future Directions with Peptide-Drug Conjugates for Targeted Cancer Therapy

et al. 2021

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We review drug conjugates combining a tumor-selective moiety with a cytotoxic agent as cancer treatments. Currently, antibody-drug conjugates (ADCs) are the most common drug conjugates used clinically as cancer treatments. While providing both efficacy and favorable tolerability, ADCs have limitations due to their size and complexity. Peptides as tumor-targeting carriers in peptide-drug conjugates (PDCs) offer a number of benefits. Melphalan flufenamide (melflufen) is a highly lipophilic PDC that takes a novel approach by utilizing increased aminopeptidase activity to selectively increase the release and concentration of cytotoxic alkylating agents inside tumor cells. The only other PDC approved currently for clinical use is 177Lu-dotatate, a targeted form of radiotherapy combining a somatostatin analog with a radionuclide. It is approved as a treatment for gastroenteropancreatic neuroendocrine tumors. Results with other PDCs combining synthetic analogs of natural peptide ligands with cytotoxic agents have been mixed. The field of drug conjugates as drug delivery systems for the treatment of cancer continues to advance with the application of new technologies. Melflufen provides a paradigm for rational PDC design, with a targeted mechanism of action and the potential for deepening responses to treatment, maintaining remissions, and eradicating therapy-resistant stem cells.

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¹⁷⁷Lu-DOTATATE for the treatment of gastroenteropancreatic neuroendocrine tumors

Cited by 80 publications

References 48 publications

Does the proteasome inhibitor bortezomib sensitize to DNA-damaging therapy in gastroenteropancreatic neuroendocrine neoplasms? – A preclinical assessment in vitro and in vivo

Does the proteasome inhibitor bortezomib sensitize to DNA-damaging therapy in gastroenteropancreatic neuroendocrine neoplasms? – A preclinical assessment in vitro and in vivo

Targeted Alpha Therapy: Progress in Radionuclide Production, Radiochemistry, and Applications

Progress and Future Directions with Peptide-Drug Conjugates for Targeted Cancer Therapy

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177Lu-DOTATATE for the treatment of gastroenteropancreatic neuroendocrine tumors

Cited by 80 publications

References 48 publications

Does the proteasome inhibitor bortezomib sensitize to DNA-damaging therapy in gastroenteropancreatic neuroendocrine neoplasms? – A preclinical assessment in vitro and in vivo

Does the proteasome inhibitor bortezomib sensitize to DNA-damaging therapy in gastroenteropancreatic neuroendocrine neoplasms? – A preclinical assessment in vitro and in vivo

Targeted Alpha Therapy: Progress in Radionuclide Production, Radiochemistry, and Applications

Progress and Future Directions with Peptide-Drug Conjugates for Targeted Cancer Therapy

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Product

Resources

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¹⁷⁷Lu-DOTATATE for the treatment of gastroenteropancreatic neuroendocrine tumors