A Targeted Thorium-227 Conjugate Demonstrates Efficacy in Preclinical Models of Acquired Drug Resistance and Combination Potential with Chemotherapeutics and Antiangiogenic Therapies Article Swipe

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Sabine Zitzmann-Kolbe , Alexander Kristian , Dieter Zopf , Claudia Kamfenkel , Oliver Politz , Christine Ellingsen , Jochen Hilbig , Mark U. Juul , Jesper Fonslet , Carsten H. Nielsen , Christoph A. Schatz , Roger M. Bjerke , Alan Cuthbertson , Dominik Mumberg , Urs B. Hagemann ·

YOU? · · 2023 · Open Access · · DOI: https://doi.org/10.1158/1535-7163.mct-22-0808

Targeted alpha therapies (TAT) are an innovative class of therapies for cancer treatment. The unique mode-of-action of TATs is the induction of deleterious DNA double-strand breaks. Difficult-to-treat cancers, such as gynecologic cancers upregulating the chemoresistance P-glycoprotein (p-gp) and overexpressing the membrane protein mesothelin (MSLN), are promising targets for TATs. Here, based on the previous encouraging findings with monotherapy, we investigated the efficacy of the mesothelin-targeted thorium-227 conjugate (MSLN-TTC) both as monotherapy and in combination with chemotherapies and antiangiogenic compounds in ovarian and cervical cancer models expressing p-gp. MSLN-TTC monotherapy showed equal cytotoxicity in vitro in p-gp–positive and -negative cancer cells, while chemotherapeutics dramatically lost activity on p-gp–positive cancer cells. In vivo, MSLN-TTC exhibited dose-dependent tumor growth inhibition with treatment/control ratios of 0.03–0.44 in various xenograft models irrespective of p-gp expression status. Furthermore, MSLN-TTC was more efficacious in p-gp–expressing tumors than chemotherapeutics. In the MSLN-expressing ST206B ovarian cancer patient-derived xenograft model, MSLN-TTC accumulated specifically in the tumor, which combined with pegylated liposomal doxorubicin (Doxil), docetaxel, bevacizumab, or regorafenib treatment induced additive-to-synergistic antitumor efficacy and substantially increased response rates compared with respective monotherapies. The combination treatments were well tolerated and only transient decreases in white and red blood cells were observed. In summary, we demonstrate that MSLN-TTC treatment shows efficacy in p-gp–expressing models of chemoresistance and has combination potential with chemo- and antiangiogenic therapies.

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Reverse Transcription Polymerase Chain Reaction

Biotechnology

Concepts

Mesothelin Medicine Ovarian cancer Cancer research Bevacizumab In vivo Pharmacology Olaparib Carboplatin Paclitaxel Doxorubicin Cytotoxicity Cancer In vitro Chemotherapy Internal medicine Chemistry Cisplatin Biology Biochemistry Gene Polymerase Poly ADP ribose polymerase Biotechnology

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Type: article
Language: en
Landing Page: https://doi.org/10.1158/1535-7163.mct-22-0808
PDF: https://aacrjournals.org/mct/article-pdf/doi/10.1158/1535-7163.MCT-22-0808/3343751/mct-22-0808.pdf
OA Status: hybrid
Cited By: 4
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Title: A Targeted Thorium-227 Conjugate Demonstrates Efficacy in Preclinical Models of Acquired Drug Resistance and Combination Potential with Chemotherapeutics and Antiangiogenic Therapies

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Publication year: 2023

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Publication date: 2023-06-26

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Authors: Sabine Zitzmann-Kolbe, Alexander Kristian, Dieter Zopf, Claudia Kamfenkel, Oliver Politz, Christine Ellingsen, Jochen Hilbig, Mark U. Juul, Jesper Fonslet, Carsten H. Nielsen, Christoph A. Schatz, Roger M. Bjerke, Alan Cuthbertson, Dominik Mumberg, Urs B. Hagemann

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Landing page: https://doi.org/10.1158/1535-7163.mct-22-0808

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Concepts: Mesothelin, Medicine, Ovarian cancer, Cancer research, Bevacizumab, In vivo, Pharmacology, Olaparib, Carboplatin, Paclitaxel, Doxorubicin, Cytotoxicity, Cancer, In vitro, Chemotherapy, Internal medicine, Chemistry, Cisplatin, Biology, Biochemistry, Gene, Polymerase, Poly ADP ribose polymerase, Biotechnology

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Cited by: 4

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