A novel small molecule targeting protein translation for pancreatic cancer treatment

一种用于胰腺癌治疗的新型靶向蛋白质翻译的小分子

• 批准号: 10508642
• 负责人: RUIWU LIU
• 金额: $ 18.64万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-04 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10508642
• 关键词: Affect; Architecture; Area; Biogenesis; Biological Process; Body Weight; Cancer Cell Growth; Cancer Etiology; Cancer cell line; Cell Proliferation; Cells; Chemotherapy and/or radiation; Clinical; Clinical Trials; Complex; Diagnosis; Disease; Disease Progression; Drug Combinations; Drug Kinetics; Eukaryota; Evaluation; Evolution; Excision; Exhibits; Exploratory/Developmental Grant; Goals; Hepatotoxicity; Human; KPC model; KRASG12D; Lead; Malignant Neoplasms; Malignant neoplasm of pancreas; Molecular; Mus; New Agents; Oncogenes; Operative Surgical Procedures; Organoids; Paclitaxel; Pancreatic Ductal Adenocarcinoma; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pre-Clinical Model; Protein Biosynthesis; Proteins; Radiation therapy; Regimen; Research; Ribosomes; Role; Safety; Structure; Testing; Therapeutic; Therapeutic Effect; Time; Transgenic Organisms; Translations; Tumor Suppressor Genes; United States; Unresectable; Work; anti-cancer; cancer initiation; cancer therapy; cell growth; chemotherapy; clinically relevant; clinically translatable; design; gemcitabine; human subject; improved outcome; in vivo; in vivo evaluation; mortality; mouse model; novel; novel drug combination; pancreatic cancer cells; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; pharmacokinetics and pharmacodynamics; programs; response; small molecule; small molecule inhibitor; targeted cancer therapy; transcriptome sequencing; treatment strategy; tumor growth; tumor progression

Summary Pancreatic cancer, a leading cause of cancer mortality in the US with a five-year survival of around 10%, is one of the most lethal cancers. Surgery, which offers the only realistic hope, has a limited role, with only about 20% of patients undergoing resection of any variety. Current chemotherapy or radiation therapy regimens offer minimal or no help. Thus, there is a dire need for new agents against pancreatic cancer. Recently, we designed and synthesized multiple promising small molecule inhibitors with strong in vivo anticancer efficacy. Our novel lead agent LLS132 shows high potency in reducing pancreatic cancer cell growth and significantly reducing in vivo growth of these tumors. In preliminary studies, LLS132 (30 mg/kg; i.p 5x/week) reduced pancreatic tumor growth by 78%, compared to controls, and this effect was superior to that of gemcitabine (100 mg/kg; i.p 2x/week), which reduced tumor growth by only 48%. Of note, LLS132 was safe with mice showing no liver toxicity or changes in body weight. In addition, using a RNA-seq analysis of human pancreatic cancer Panc-1 cells treated with LLS132, we identified ribosomal biogenesis as a key biological process affected by LLS132. Furthermore, LLS132 synergized with nab-paclitaxel in both Panc-1 and MIA PaCa-2 pancreatic cancer cell lines. These preliminary results strongly indicate that LLS132 is safe and effective in multiple preclinical models of PDA, and provides synergistic therapeutic effects with nab-paclitaxel therapy, warranting further evaluation. The objective of this R21 project is to develop an effective new drug combination for PDA. Particular emphasis will be given to the involvement of ribosomal biogenesis as the primary biological process affected by LLS132. Our hypothesis is that the LLS132/nab-paclitaxel drug combination will show synergistic effect in vivo against PDA. In Aim 1, we propose to evaluate the safety, pharmacokinetics and pharmacodynamics of LLS132 alone and in combination with nab-paclitaxel, whereas in aim 2, we propose to determine the efficacy and key molecular drivers of the LLS132/nab-paclitaxel drug combination in preclinical models of PDA. To achieve these goals, we will use multiple distinct, yet complementary, clinically relevant preclinical models of PDA. These include organoid-grafted organoids (OGOs) and a transgenic PDA mouse model (LSL-KrasG12D, LSL- Trp53R172H/+, Pdx1-Cre; KPC). At the completion of these studies, we expect to have determined key pharmacological parameters of this promising novel drug combination for PDA treatment, and setting the stage for further research on human subjects. Given the importance of PDA and the lack of effective agents against it, we believe that the proposed work holds the promise of a significant advance in this area.

概括 胰腺癌是美国癌症死亡的主要原因之一，其五年生存率约为 10% 最致命的癌症之一。手术作为唯一现实的希望，其作用有限，只有约 20% 接受任何类型切除术的患者。目前的化疗或放射治疗方案提供 很少或没有帮助。因此，迫切需要抗胰腺癌的新药物。最近，我们设计了 并合成了多种具有强大体内抗癌功效的有前景的小分子抑制剂。我们的小说 主要药物 LLS132 在减少胰腺癌细胞生长方面表现出高效能，并显着减少 这些肿瘤的体内生长。在初步研究中，LLS132（30 mg/kg；腹膜内注射 5 次/周）可减少胰腺肿瘤 与对照相比，生长增加了 78%，并且这种效果优于吉西他滨（100 mg/kg；腹膜内注射 2 次/周），仅使肿瘤生长减少了 48%。值得注意的是，LLS132 对于小鼠来说是安全的，没有表现出肝毒性 或体重的变化。此外，使用人类胰腺癌 Panc-1 细胞的 RNA-seq 分析 经过 LLS132 处理后，我们发现核糖体生物合成是受 LLS132 影响的一个关键生物过程。 此外，LLS132 与白蛋白结合型紫杉醇在 Panc-1 和 MIA PaCa-2 胰腺癌细胞中具有协同作用 线。这些初步结果有力地表明 LLS132 在多种临床前模型中是安全有效的 PDA，并与白蛋白结合型紫杉醇疗法提供协同治疗效果，值得进一步评估。 R21项目的目标是开发一种有效的PDA新药组合。特别强调 将考虑核糖体生物合成作为受 LLS132 影响的主要生物过程。 我们的假设是，LLS132/nab-紫杉醇药物组合将在体内表现出协同作用 掌上电脑。在目标 1 中，我们建议单独评估 LLS132 的安全性、药代动力学和药效学 并与白蛋白结合型紫杉醇联合使用，而在目标 2 中，我们建议确定疗效和关键 PDA 临床前模型中 LLS132/nab-紫杉醇药物组合的分子驱动因素。为了实现这些 为了实现目标，我们将使用多个不同但互补的、临床相关的 PDA 临床前模型。这些 包括类器官移植类器官（OGO）和转基因 PDA 小鼠模型（LSL-KrasG12D、LSL- Trp53R172H/+、Pdx1-Cre；科威特石油公司）。完成这些研究后，我们希望确定关键的 这种有前景的新型药物组合用于 PDA 治疗的药理学参数，并奠定基础 以便对人类受试者进行进一步的研究。鉴于 PDA 的重要性以及缺乏有效的对抗药物， 我们相信，拟议的工作有望在这一领域取得重大进展。