Abstract P3-10-07: Receptor-mediated chemotherapy using a new Docetaxel-peptide conjugate for Sortilin-positive triple-negative breast cancer
Bibliographic record
Abstract
Abstract Background: Triple-negative breast cancer (TNBC) still lacks defined molecular biomarkers. Thus, targeting of specific gene/protein molecular signature of tumors emerged among the best anticancer strategies. Recently, increased expression of the cell surface receptor Sortilin was reported in tumors from patients with TNBC. Given Sortilin’s functions in protein internalization and trafficking; we developed a new Sortilin-targeted peptide-anticancer drug conjugate to treat Sortilin-positive breast cancer. The conjugate consists of 2 molecules of Docetaxel linked to a 17 amino acids peptide (TH-1902) which enables specific binding to Sortilin and subsequent internalization of TH-1902. Methods: MDA-MB-231 breast cancer cells were used as a TNBC model for in vitro and in vivo xenograft assays. Female CD-1 nude mice (Crl:NU-Foxn1nu) were used for xenograft tumor models, female athymic nude mice (Crl:NU(NCr)-Foxn1nu) were used in hematotoxicology and female Crl: CD-1 mice were used for pharmacokinetic evaluation. In vitro cell migration was assessed using the xCELLigence real-time system, whereas MTT assay was used for cell proliferation analysis. Apoptosis biomarkers expression was assessed by immunoblotting. The microtubule polymerization and depolymerization assay was performed by spectrofluorimetry, whereas fluorescent TH-peptide uptake was assessed by flow cytometry. Tissue microarrays included 9 normal adjacent tissues, 35 infiltrating ductal carcinomas (IDC), and 10 lymph nodes metastatic (LNM) carcinomas. Hematotoxicity assay allowed for blood neutrophil counts analysis in plasma samples. Results: Fluorescent Alexa488-labeled TH-peptide was found to be internalized in MDA-MB-231 cells and reduced by 72% upon transient SORT1 gene silencing. Alexa488-labeled TH-peptide uptake was inhibited by 65% in the presence of an excess of unlabeled TH-peptide and by the Sortilin ligands Neurotensin and Progranulin. TH-1902 exerted potent anti-proliferative and anti-migratory activities in vitro. TH-1902, like Docetaxel alone, triggered cell death mechanisms. The apoptotic and anti-migratory effects were reversed upon siRNA-mediated gene silencing of SORT1. Conjugation of Docetaxel to TH-peptide did not affect its capacity to alter microtubule stabilization, once internalized and cleaved from the TH-peptide within the cells. This further triggered the down-regulation of IL-6, Bcl-xL and mutant p53 pro-survival biomarkers. Sortilin immunolabeling showed very low levels in normal adjacent tissues, whereas high levels of Sortilin labeling were scored in IDC and LNM. In vivo, TH-1902 exhibited a greater tumor regression capacity with a prolonged survival in a murine MDA-MB-231 xenograft tumor model than did Docetaxel. Hematotoxic assays revealed that neutrophils count decreased significantly in Docetaxel-treated mice at MTD after 3 cycles, whereas they remained within normal limits in TH-1902-treated mice at an equivalent dose of Docetaxel even after six injections of TH-1902. Preliminary assessment of TH-1902 in normal CD-1 mice revealed that most Docetaxel remained associated with the peptide over the time course analyzed after a single IV bolus injection at 50 mg/kg. Absence of neutropenia in the presence of TH-1902 may be explained by the low levels of free Docetaxel in mouse plasma. Conclusions: The results demonstrate that Sortilin can be used as a target for treatment of TNBC. In addition, TH-1902 specifically internalized Docetaxel through a receptor-mediated mechanism exploiting Sortilin’s functions and significantly decreased the concentration of Docetaxel in normal cells. Overall, TH-1902 improved the efficacy and safety profiles compared to Docetaxel, which makes it a promising novel therapy for the treatment of TNBC. Citation Format: Michel Demeule, Cyndia Charfi, Jean-Christophe C Currie, Alain Larocque, Alain Zgheib, Christian Marsolais, Richard Béliveau, Borhane Annabi. Receptor-mediated chemotherapy using a new Docetaxel-peptide conjugate for Sortilin-positive triple-negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-07.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".