A novel small molecule targeting protein translation for pancreatic cancer treatment

总结 胰腺癌是美国癌症死亡率的主要原因，五年生存率约为10%， 最致命的癌症。手术，这提供了唯一现实的希望，有一个有限的作用，只有约20% 接受各种切除术的患者。目前的化疗或放疗方案提供了 很少或没有帮助。因此，迫切需要针对胰腺癌的新药剂。最近，我们设计了 并合成了多种有前景的体内抗癌效果强的小分子抑制剂。我们的新型 先导剂LLS 132在减少胰腺癌细胞生长方面显示出高效力， 这些肿瘤的体内生长。在初步研究中，LLS 132（30 mg/kg; i.p 5x/周）减少胰腺肿瘤 与对照组相比，生长减少了78%，并且该效果上级于吉西他滨（100 mg/kg; i.p 2x/周），其仅使肿瘤生长减少48%。值得注意的是，LLS 132对小鼠是安全的，没有显示出肝毒性。 或体重的变化。此外，使用人胰腺癌Panc-1细胞的RNA-seq分析， 用LLS 132处理后，我们确定核糖体生物发生是受LLS 132影响的关键生物过程。 此外，LLS 132与白蛋白结合型紫杉醇在Panc-1和MIA PaCa-2胰腺癌细胞中均具有协同作用， 线这些初步结果强烈表明，LLS 132在多种临床前模型中是安全有效的 的PDA，并提供与白蛋白结合型紫杉醇治疗的协同治疗效果，进一步评价。 该R21项目的目标是开发一种有效的PDA新药组合。特别强调 将给予参与核糖体生物合成作为受LLS 132影响的主要生物过程。 我们的假设是LLS 132/nab-紫杉醇药物组合将在体内显示协同作用， PDA。在目标1中，我们建议评估单独使用LLS 132的安全性、药代动力学和药效学 与白蛋白结合型紫杉醇联合，而在目的2中，我们提出确定疗效和关键 在PDA的临床前模型中LLS 132/nab-紫杉醇药物组合的分子驱动。实现这些 我们将使用多种不同但互补的临床相关PDA临床前模型。这些 包括类器官移植类器官（OALG）和转基因PDA小鼠模型（LSL-KrasG 12 D，LSL-KrasG 12 D）， Trp53R172H/+，Pdx 1-Cre; KPC）。在这些研究完成后，我们预计将确定关键的 这种有前途的新型药物组合治疗PDA的药理学参数，并设置阶段 对人体进行进一步研究鉴于PDA的重要性和缺乏有效的代理人， 我们认为，拟议的工作有望在这一领域取得重大进展。

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.