The radiosensitizer Onalespib increases complete remission in 177Lu-DOTATATE-treated mice bearing neuroendocrine tumor xenografts

Lindström, Sara; Spiegelberg, Diana; Raval, Nakul Ravi; Nestor, Marika

doi:10.1007/s00259-019-04673-1

Cited by 23 publications

(14 citation statements)

References 35 publications

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“…To further evaluate the mechanisms and molecular effects of selected combination treatments, western blot analysis was performed on 3D tumor lysates 24 h posttreatment ( Figure 7 ). The results validated previously known onalespib-mediated effects, such as downregulation of EGFR and upregulation of HSP70 ( 70 , 71 ), demonstrating clear effects of HSP90 inhibition on a molecular level. Interestingly, in the high CEA-expressing spheroid model SNU1544, a combination with 177 Lu-DOTA-M5A reduced EGFR levels even more than onalespib alone, indicating an even more efficient block of the EGFR pathway in this group, which is in line with a previous study ( 46 ).…”

Section: Discussionsupporting

confidence: 87%

“…HSP90 inhibitors have previously demonstrated preclinical and clinical potential both as a single drug and in combination with external radiation and/or chemotherapy for GI tumors ( 65 – 69 ). The HSP90 inhibitor onalespib was recently demonstrated to have radiosensitizing properties when combined with either external beam radiation ( 45 ) or molecular radiotherapy through 177 Lu-DOTATATE in tumor xenografts ( 70 ).…”

Section: Discussionmentioning

confidence: 99%

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In Vitro Characterization of 177Lu-DOTA-M5A Anti-Carcinoembryonic Antigen Humanized Antibody and HSP90 Inhibition for Potentiated Radioimmunotherapy of Colorectal Cancer

Mohajershojai

Jha

Boström³

et al. 2022

Front. Oncol.

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Carcinoembryonic antigen (CEA) is an antigen that is highly expressed in colorectal cancers and widely used as a tumor marker. 131I and 90Y-radiolabeled anti-CEA monoclonal antibodies (mAbs) have previously been assessed for radioimmunotherapy in early clinical trials with promising results. Moreover, the heat shock protein 90 inhibitor onalespib has previously demonstrated radiotherapy potentiation effects in vivo. In the present study, a 177Lu-radiolabeled anti-CEA hT84.66-M5A mAb (M5A) conjugate was developed and the potential therapeutic effects of 177Lu-DOTA-M5A and/or onalespib were investigated. The 177Lu radiolabeling of M5A was first optimized and characterized. Binding specificity and affinity of the conjugate were then evaluated in a panel of gastrointestinal cancer cell lines. The effects on spheroid growth and cell viability, as well as molecular effects from treatments, were then assessed in several three-dimensional (3D) multicellular colorectal cancer spheroid models. Stable and reproducible radiolabeling was obtained, with labeling yields above 92%, and stability was retained at least 48 h post-radiolabeling. Antigen-specific binding of the radiolabeled conjugate was demonstrated on all CEA-positive cell lines. Dose-dependent therapeutic effects of both 177Lu-DOTA-M5A and onalespib were demonstrated in the spheroid models. Moreover, effects were potentiated in several dose combinations, where spheroid sizes and viabilities were significantly decreased compared to the corresponding monotherapies. For example, the combination treatment with 350 nM onalespib and 20 kBq 177Lu-DOTA-M5A resulted in 2.5 and 2.3 times smaller spheroids at the experimental endpoint than the corresponding monotreatments in the SNU1544 spheroid model. Synergistic effects were demonstrated in several of the more effective combinations. Molecular assessments validated the therapy results and displayed increased apoptosis in several combination treatments. In conclusion, the combination therapy of anti-CEA 177Lu-DOTA-M5A and onalespib showed enhanced therapeutic effects over the individual monotherapies for the potential treatment of colorectal cancer. Further in vitro and in vivo studies are warranted to confirm the current study findings.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

In Vitro Characterization of 177Lu-DOTA-M5A Anti-Carcinoembryonic Antigen Humanized Antibody and HSP90 Inhibition for Potentiated Radioimmunotherapy of Colorectal Cancer

Mohajershojai

Jha

Boström³

et al. 2022

Front. Oncol.

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“…administration) and 177 Lu-DOTATATE on days 2-4 (.0037 GBq IV), demonstrated improved tumor growth slowing, survival and tumor regression compared to monotherapy with either agent. Specifically, complete responses were increased from 8% in xenografts treated with 177 Lu-DOTATATE monotherapy to 29% in xenografts treated with onalespib and 177 Lu-DOTATATE (Lundsten et al 2020).…”

Section: Combination Therapiesmentioning

confidence: 99%

Somatostatin receptor radionuclide therapy in neuroendocrine tumors

Haider

Das

Al‐Toubah

et al. 2021

Endocrine-Related Cancer

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Peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTATATE has been approved for the treatment of gastroenteropancreatic NETs. An understanding of benefits and risks is important for the appropriate implementation of this therapy. This review summarizes study data supporting the use of radiolabeled somatostatin analogs for the treatment of advanced NETs and highlights risks, including potential toxicities in specific populations. Key ongoing clinical trials, including randomized studies, are designed to better define the position of PRRT within the broader therapeutic landscape. Preclinical and early-phase human studies are focused on the development of novel somatostatin-receptor agonists and antagonists, new radionuclides, and radiosensitizing combination therapies.

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“…Another Hsp90 inhibitor, onalespib, enhanced the in vivo treatment effect of PRRT as well. It also induced the expression of Hsp70, which could reduce the renal toxicity [ 85 ]. No clinical trials have been performed in NEN patients or in combination with PRRT yet.…”

Section: Treatment Optimizationmentioning

confidence: 99%

Strategies Towards Improving Clinical Outcomes of Peptide Receptor Radionuclide Therapy

et al. 2021

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Purpose of Review Peptide receptor radionuclide therapy (PRRT) with [177Lu-DOTA0,Tyr3] octreotate is an effective and safe second- or third-line treatment option for patients with low-grade advanced gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN). In this review, we will focus on possible extensions of the current use of PRRT and on new approaches which could further improve its treatment efficacy and safety. Recent Findings Promising results were published regarding PRRT in other NENs, including lung NENs or high-grade NENs, and applying PRRT as neoadjuvant or salvage therapy. Furthermore, a diversity of strategic approaches, including dosimetry, somatostatin receptor antagonists, somatostatin receptor upregulation, radiosensitization, different radionuclides, albumin binding, alternative renal protection, and liver-directed therapy in combination with PRRT, have the potential to improve the outcome of PRRT. Also, novel biomarkers are presented that could predict response to PRRT. Summary Multiple preclinical and early clinical studies have shown encouraging potential to advance the clinical outcome of PRRT in NEN patients. However, at this moment, most of these strategies have not yet reached the clinical setting of randomized phase III trials.

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The radiosensitizer Onalespib increases complete remission in 177Lu-DOTATATE-treated mice bearing neuroendocrine tumor xenografts

Cited by 23 publications

References 35 publications

In Vitro Characterization of 177Lu-DOTA-M5A Anti-Carcinoembryonic Antigen Humanized Antibody and HSP90 Inhibition for Potentiated Radioimmunotherapy of Colorectal Cancer

In Vitro Characterization of 177Lu-DOTA-M5A Anti-Carcinoembryonic Antigen Humanized Antibody and HSP90 Inhibition for Potentiated Radioimmunotherapy of Colorectal Cancer

Somatostatin receptor radionuclide therapy in neuroendocrine tumors

Strategies Towards Improving Clinical Outcomes of Peptide Receptor Radionuclide Therapy

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