Abstract 675: Targeting Bcl-2/Bcl-xl for small cell lung cancer treatment with LP-118
Notice bibliographique
Résumé
Abstract Small cell lung cancer (SCLC) is an aggressive form neuroendocrine carcinoma with limited treatment options and poor prognosis, and novel approaches are urgently needed for the treatment of this disease. Bcl-2 and Bcl-xl are aberrantly expressed in 60-70% SCLC and have been considered as promising therapeutic targets for SCLC. However, navitoclax (ABT-263), a Bcl-2/Bcl-xl dual inhibitor, demonstrated limited efficacy in SCLC while induced sever adverse events, such as thrombocytopenia due to the platelet toxicity mediated by Bcl-xl inhibition. Therefore, agents with novel mechanisms of action and safety profile are to be developed for the treatment of SCLC with Bcl-2/Bcl-xl dependency. LP-118 is a new generation and super potent Bcl-2 inhibitor with moderate Bcl-xl activity, and it is being evaluated in Phase1 clinical trials in solid tumors and hematological cancers (NCT05025358, NCT04771572). In this preclinical study, we aimed to evaluate the single agent activity of LP-118 in a panel of 9 SCLC cell lines and to further determine if LP-118 can enhance the efficacies of Standard of Cares (SOC) in vitro and in vivo. The results show that LP-118 has high in vitro activity in a subset of SCLC cell lines, and it is particularly potent in Bcl-2-depended cell lines, such as NCI-H889, with the IC50 of 0.15 nM. LP-118 is also very potent in NCI-H1963, a Bcl-xl dependent cell line (IC50: 5nM), and NCI-H526, a Bcl-2/Bcl-xl co-dependent cell line (IC50: 4-5.1 nM). Overall, LP-118 is more potent than ABT-263 in Bcl-2 or Bcl-2/Bcl-xl co-dependent cell lines, and it is relatively less active in Bcl-2/Bcl-xl/Mcl-1 co-dependent cell lines, such as NCI-H69 (IC50: 169.7 nM). In addition, combinations of LP-118 and SN-38 (the active metabolite of irinotecan), topotecan, or etoposide, induced strong synergist effects in both NCI-H69 and NCI-H146 cell lines, suggesting that LP-118 could enhance the cytotoxicity of these drugs. Consistent with the in vitro data, treatment with LP-118 alone induced complete tumor remissions in NCI-H889-derived xenograft models (10/10), whereas no complete tumor remission was observed in the ABT-263-treated group. Moreover, LP-118 plus carboplatin or topotecan dramatically inhibited tumor growth of NCI-H526 xenograft models and has significantly better efficacy than either carboplatin or topotecan alone. Importantly, no significant body weight loss was observed in mice treated with LP-118 single agent or the combinations, indicating such regimens were well tolerated. In summary, LP-118, a new generation Bcl-2/Bcl-xl dual inhibitor, is highly active, as single agent or in combination with SOCs, in a large subset of SCLC cell lines. Clinical trials are ongoing to further evaluate the safety and efficacy of LP-118 in hematological cancers and solid tumors, including SCLC. Additional studies are also underway to develop predictive biomarkers for facilitating patient stratification in the clinic. Citation Format: Ling-Ling Lee, Huan Chen, Cong Zhu, Yao Chen, Brianna Feldmeier, Yue Shen, Yu Chen, Stephen P. Anthony, Fenlai Tan, Yi Chen, Bing Dai. Targeting Bcl-2/Bcl-xl for small cell lung cancer treatment with LP-118 [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 675.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».