TH1902, a new docetaxel‐peptide conjugate for the treatment of sortilin‐positive triple‐negative breast cancer

Demeule, Michel; Charfi, Cyndia; Currie, Jean-Christophe; Larocque, Alain; Zgheib, Alain; Kozelko, Sophie; Béliveau, Richard; Marsolais, Christian; Annabi, Borhane

doi:10.1111/cas.15086

Cited by 35 publications

(45 citation statements)

References 67 publications

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“…In addition, based on the specific binding of peptides to proteins, peptides represent the novel drug conjugates. For example, a peptide-docetaxel-conjugate (TH1902) targeting sortilin exerts anticancer effects in TNBC cells and tumor xenograft models [ 165 ]. A novel analog conjugate (CX-2009, praluzatamab ravtansine) was studied in 22 patients with advanced HR + /HER − BC with the probody drug conjugate (PDC), showing that 9% patients had partial responses and 45% of patients had stable disease [ 166 ].…”

Section: Immunotherapy For Tnbcmentioning

confidence: 99%

Recent advances in therapeutic strategies for triple-negative breast cancer

et al. 2022

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Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer (BC) with a poor prognosis. Current treatment options are limited to surgery, adjuvant chemotherapy and radiotherapy; however, a proportion of patients have missed the surgical window at the time of diagnosis. TNBC is a highly heterogeneous cancer with specific mutations and aberrant activation of signaling pathways. Hence, targeted therapies, such as those targeting DNA repair pathways, androgen receptor signaling pathways, and kinases, represent promising treatment options against TNBC. In addition, immunotherapy has also been demonstrated to improve overall survival and response in TNBC. In this review, we summarize recent key advances in therapeutic strategies based on molecular subtypes in TNBC.

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Section: Immunotherapy For Tnbcmentioning

confidence: 99%

Recent advances in therapeutic strategies for triple-negative breast cancer

et al. 2022

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“…Efficient inhibition of cells exhibiting VM is challenging given the combined lack of specific cell surface biomarkers and functional targeting. Recently, a novel targeted therapy strategy was developed against sortilin (SORT1)-positive ovarian and breast cancers ( 16 , 17 ). As such, tumor suppressive capacities of TH1902, a drug currently tested in a phase 1, open-label first-in-human study in solid cancer (ClinicalTrials.gov Identifier: NCT04706962), were demonstrated against SORT1-positive TNBC xenograft models ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, a novel targeted therapy strategy was developed against sortilin (SORT1)-positive ovarian and breast cancers ( 16 , 17 ). As such, tumor suppressive capacities of TH1902, a drug currently tested in a phase 1, open-label first-in-human study in solid cancer (ClinicalTrials.gov Identifier: NCT04706962), were demonstrated against SORT1-positive TNBC xenograft models ( 17 ). SORT1 is a key scavenging receptor discovered two decades ago as the first member of the small family of vacuolar protein sorting 10 protein domain (Vps10p) ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

New Peptide-Drug Conjugates for Precise Targeting of SORT1-Mediated Vasculogenic Mimicry in the Tumor Microenvironment of TNBC-Derived MDA-MB-231 Breast and Ovarian ES-2 Clear Cell Carcinoma Cells

et al. 2021

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Vasculogenic mimicry (VM) is defined as the formation of microvascular channels by genetically deregulated cancer cells and is often associated with high tumor grade and cancer therapy resistance. This microcirculation system, independent of endothelial cells, provides oxygen and nutrients to tumors, and contributes also in part to metastasis. VM has been observed in ovarian cancer and in triple negative breast cancer (TNBC) and shown to correlate with decreased overall cancer patient survival. Thus, strategies designed to inhibit VM may improve cancer patient treatments. In this study, sortilin (SORT1) receptor was detected in in vitro 3D capillary-like structures formed by ES-2 ovarian cancer and MDA-MB-231 TNBC-derived cells when grown on Matrigel. SORT1 gene silencing or antibodies directed against its extracellular domain inhibited capillary-like structure formation. In vitro, VM also correlated with increased gene expression of matrix metalloproteinase-9 (MMP-9) and of the cancer stem cell marker CD133. In vivo ES-2 xenograft model showed PAS+/CD31- VM structures (staining positive for both SORT1 and CD133). TH1904, a Doxorubicin-peptide conjugate that is internalized by SORT1, significantly decreased in vitro VM at low nM concentrations. In contrast, VM was unaffected by unconjugated Doxorubicin or Doxil (liposomal Doxorubicin) up to μM concentrations. TH1902, a Docetaxel-peptide conjugate, altered even more efficiently in vitro VM at pM concentrations. Overall, current data evidence for the first time that 1) SORT1 itself exerts a crucial role in both ES-2 and MDA-MB-231 VM, and that 2) VM in these cancer cell models can be efficiently inhibited by the peptide-drug conjugates TH1902/TH1904. These new findings also indicate that both peptide-drug conjugates, in addition to their reported cytotoxicity, could possibly inhibit VM in SORT1-positive TNBC and ovarian cancer patients.

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“…Recently, scientists exploited peptides conjugated with anticancer drugs to eradicate tumor cells. In a study carried out by Annabi et al , it was shown that a novel curcumin-peptide conjugate called TH1901 inhibited cancer cell proliferation in sortilin-positive cancers including ovary (ES2), breast (MD-MB231, HCC-1569, and HCC-1954), skin (SK-MEL-28 and A-375), and colorectal (HT-29) cancers 29 . Two other peptides conjugated to docetaxel (TH1902) and doxorubicin (TH1904) are specifically designed to target sortilin receptor (SORT1).…”

Section: Discussionmentioning

confidence: 99%

Monoclonal Antibody Against Sortilin Induces Apoptosis in Human Breast Cancer Cells

Simonian¹,

Ghaffari²,

Salimi³

et al. 2022

AJMB

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Background: Sortilin has an important role in various malignances and can be used as a promising target to eradicate cancer cells. Methods: In this study, the expression of sortilin in 4T1 and MDA-MB231 cell lines was evaluated by flow cytometry and immunocytochemistry. Apoptosis assay was also applied to evaluate apoptosis induction in 4T1 and MDA-MB231 cell lines. Results: Based on cell surface flow cytometry results, anti-sortilin (2D8-E3) mAb could recognize sortilin molecules in 79.2% and 90.3% of 4T1 and MDA-MB231 cell-lines, respectively. The immunocytochemistry staining results confirmed sortilin surface expression. Apoptosis assay indicated that anti-sortilin mAb could induce apoptosis in 4T1 and MDA-MB231 cell lines. Conclusion: Our study revealed the important role of surface sortilin in breast carcinoma cell survival and its possible application as a therapeutic agent in cancer targeted therapies.

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TH1902, a new docetaxel‐peptide conjugate for the treatment of sortilin‐positive triple‐negative breast cancer

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 35 publications

References 67 publications

Recent advances in therapeutic strategies for triple-negative breast cancer

Recent advances in therapeutic strategies for triple-negative breast cancer

New Peptide-Drug Conjugates for Precise Targeting of SORT1-Mediated Vasculogenic Mimicry in the Tumor Microenvironment of TNBC-Derived MDA-MB-231 Breast and Ovarian ES-2 Clear Cell Carcinoma Cells

Monoclonal Antibody Against Sortilin Induces Apoptosis in Human Breast Cancer Cells

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