Abstract 2071: Pre-clinical evidence for new camptothecin-peptide conjugates in the treatment of sortilin-positive colorectal cancers
Bibliographic record
Abstract
Abstract Limitations in current colorectal cancer (CRC) camptothecin (CPT)-based chemotherapy have mostly been attributed to low specificity and high systemic cytotoxic side effects. More effective therapies are therefore required to improve the clinical outcomes of patients with CRC. Here, we developed a selective and better anticancer drug delivery of CPT through conjugation to a peptide (TH19P01) that targets Sortilin (SORT1), a scavenging receptor expressed in various tumor tissues including CRC. In the current study, significant SORT1 expression was detected in various CRC cell lines as well as that of irinotecan analogs efflux pump (ABCG2) in LoVo and HT-29 cells. Considering this result, we used our proprietary peptide conjugation SORT1 technology to increase cell targeting selectivity and cell delivery efficacy of CPT analogs. Different peptide drug conjugates (PDCs) were generated linking the TH19P01 peptide to SN-38 (an irinotecan metabolite) or exatecan, which are two main CPT derivatives used in recent antibody drug conjugates (ADC) as payloads. In vitro, immunonofluorescent microscopy revealed that TH19P01 was rapidly internalized (<15 min) in a SORT1-positive human HT-29 CRC cell model. These PDCs also inhibited CRC cell proliferation at low nM concentrations (3-90 nM). In vivo, weekly administration of TH2101 (SN-38) and of TH2303 (exatecan) conjugates were well tolerated as they had little impact on mouse body weight but caused a more potent growth inhibition of the HT-29 CRC tumor xenograft model than did either unconjugated irinotecan or exatecan molecules. In fact, at their maximum tolerable dose, irinotecan and exatecan caused a tumor growth inhibition of only 48% and 45% whereas TH2101 and TH2303 inhibited the growth of HT-29 tumors by 83% and 91%, respectively. These results provide strong pre-clinical evidence for the future development of novel CPT PDCs therapeutics with targeting of SORT1-positive CRC cells. Citation Format: Sanjoy Das, Jean-Christophe Currie, Michel Demeule, Cyndia Charfi, Alain Zgheib, Amit Nayyar, Anh Minh Thao Nguyen, Bogdan Alexandru Danalache, Richard Beliveau, Christian Marsolais, Borhane Annabi. Pre-clinical evidence for new camptothecin-peptide conjugates in the treatment of sortilin-positive colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2071.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".