The Peptide-Drug Conjugate TH1902: A New Sortilin Receptor-Mediated Cancer Therapeutic against Ovarian and Endometrial Cancers

Currie, Jean-Christophe; Demeule, Michel; Charfi, Cyndia; Zgheib, Alain; Larocque, Alain; Danalache, Bogdan; Ouanouki, Amira; Béliveau, Richard; Marsolais, Christian; Annabi, Borhane

doi:10.3390/cancers14081877

Cited by 17 publications

(9 citation statements)

References 46 publications

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“…In this research, after data mining based on the TCGA-LIHC dataset, it was uncovered that SORT1 expression was substantially As demonstrated in previous studies, SORT1 inhibition could slow down tumor growth and cancer progression. 28 To cite an instance, SORT1 depletion substantially impedes the proliferative, invasive, and migrative abilities of gastric cancer cells. 15 Besides, SORT1 interference also decreases cell adhesion and invasion in pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

Sortilin 1 regulates hepatocellular carcinoma progression by activating the PI3K/AKT signaling

Wang

Zhou

et al. 2022

Hum Exp Toxicol

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Background Sortilin 1 (SORT1) has been reported as an oncogene in several human tumors. Nonetheless, the biological functions of SORT1 in hepatocellular carcinoma (HCC) remain poorly understood. Methods Western blotting was employed for the determination of protein expression. Hepatocellular carcinoma cell viability, apoptosis, migration, and invasion were measured via CCK-8, flow cytometry, wound healing, and Transwell assays. Results Sortilin 1 was upregulated in HCC and closely associated with unsatisfactory outcomes of HCC patients. Furthermore, in vitro and in vivo assays revealed that SORT1 knockdown significantly diminished HCC cell proliferation and metastasis but accelerated HCC cell apoptosis; moreover, SORT1 depletion also restrained the growth of xenografted HCC tumors. Mechanistically, SORT1 activated PI3K/AKT signaling in HCC cells, thereby promoting the malignant behaviors of HCC cells. Conclusion This study demonstrated that SORT1 might promote HCC progression by activating PI3K/AKT signaling, indicating that SORT1 might be a promising target and biomarker for HCC treatment and prognosis.

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Section: Discussionmentioning

confidence: 99%

Sortilin 1 regulates hepatocellular carcinoma progression by activating the PI3K/AKT signaling

Wang

Zhou

et al. 2022

Hum Exp Toxicol

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“…Studies have confirmed that both TH1902 (a docetaxel-TH19P01 conjugate) and TH1904 (a doxorubicin-TH19P01 conjugate) require a SORT1-dependent mechanism of action to exert anticancer activities ( 4 , 5 ). In recent preclinical studies performed in immunocompromised animal models, which are unable to produce mature T-cells, TH1902 was effective against several human SORT1-positive xenograft models including triple-negative breast cancer (TNBC), ovarian cancer, and endometrial cancer ( 5 , 6 ).…”

Section: Introductionmentioning

confidence: 99%

Sudocetaxel Zendusortide (TH1902) triggers the cGAS/STING pathway and potentiates anti-PD-L1 immune-mediated tumor cell killing

Demeule,

Currie,

Charfi

et al. 2024

Front. Immunol.

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The anticancer efficacy of Sudocetaxel Zendusortide (TH1902), a peptide-drug conjugate internalized through a sortilin-mediated process, was assessed in a triple-negative breast cancer-derived MDA-MB-231 immunocompromised xenograft tumor model where complete tumor regression was observed for more than 40 days after the last treatment. Surprisingly, immunohistochemistry analysis revealed high staining of STING, a master regulator in the cancer-immunity cycle. A weekly administration of TH1902 as a single agent in a murine B16-F10 melanoma syngeneic tumor model demonstrated superior tumor growth inhibition than did docetaxel. A net increase in CD45 leukocyte infiltration within TH1902-treated tumors, especially for tumor-infiltrating lymphocytes and tumor-associated macrophages was observed. Increased staining of perforin, granzyme B, and caspase-3 was suggestive of elevated cytotoxic T and natural killer cell activities. Combined TH1902/anti-PD-L1 treatment led to increases in tumor growth inhibition and median animal survival. TH1902 inhibited cell proliferation and triggered apoptosis and senescence in B16-F10 cells in vitro, while inducing several downstream effectors of the cGAS/STING pathway and the expression of MHC-I and PD-L1. This is the first evidence that TH1902 exerts its antitumor activity, in part, through modulation of the immune tumor microenvironment and that the combination of TH1902 with checkpoint inhibitors (anti-PD-L1) could lead to improved clinical outcomes.

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“…An intriguing finding of this study was that CT can use SORT1 as a cell-entry receptor for intoxication. Fortuitously, SORT1 is being explored as a target for ovarian cancer 42 . SORT1 is also being explored as a receptor for protein and siRNA delivery, using galectin-1 43 .…”

Section: Discussionmentioning

confidence: 99%

Enhanced delivery of protein therapeutics with a diphtheria toxin-like platform that evades pre-existing neutralizing immunity

Gill,

Sugiman-Marangos,

Beilhartz

et al. 2024

Preprint

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Targeted intracellular delivery of therapeutic peptides and proteins remains an important but unresolved goal in biotechnology. A promising approach is to engineer bacterial exotoxins that deliver their cytotoxic enzymes into cells and can be engineered to target cancer cells as is the case with immunotoxins. The well-studied diphtheria toxin translocation domain is ideally suited as a delivery platform as it has been shown to be capable of delivering a wide range of macromolecular cargo. Widespread deployment of DT-based therapeutics in humans, however, is complicated by the prevalence of pre-existing anti-DT antibodies from childhood vaccinations that reduce the exposure, efficacy and safety of this important class of protein drugs. Thus, there is a great need for delivery platforms with no pre-existing immunity in humans. Here, we describe the discovery and characterization of a distant diphtheria toxin homolog from the ancient reptile pathogenAustwickia chelonaethat we have named Chelona Toxin (CT). We show that CT is comparable to DT structure and function in all respects except that it is not recognized by pre-existing anti-DT antibodies present in human sera. Moreover, we demonstrate that the CT translocase is superior to the DT translocase at delivering therapeutic protein cargo into target cells. These findings highlight CT as a potentially class-enabling new chassis for developing safer and more efficacious immunotoxins and intracellular protein delivery platforms for cancer therapy.

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The Peptide-Drug Conjugate TH1902: A New Sortilin Receptor-Mediated Cancer Therapeutic against Ovarian and Endometrial Cancers

Cited by 17 publications

References 46 publications

Sortilin 1 regulates hepatocellular carcinoma progression by activating the PI3K/AKT signaling

Sortilin 1 regulates hepatocellular carcinoma progression by activating the PI3K/AKT signaling

Sudocetaxel Zendusortide (TH1902) triggers the cGAS/STING pathway and potentiates anti-PD-L1 immune-mediated tumor cell killing

Enhanced delivery of protein therapeutics with a diphtheria toxin-like platform that evades pre-existing neutralizing immunity

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