Therapeutic potential of Palmatine in pancreatic cancer

目前的预测预测胰腺导管腺癌（PDAC）将成为第二大原因 到2030年，癌症相关死亡人数将超过乳腺癌、前列腺癌和结肠直肠癌。缺乏治疗 能够降低几乎相等的发病率和死亡率的策略是这种疾病的障碍。一个关键 PDAC的特征是结缔组织增生，其特征在于增加的纤维化和炎症。结缔 不仅在胰腺的发病机制中起关键作用，而且在肿瘤的维持和限制治疗中也起关键作用。 通过减少药物进入肿瘤来提高疗效。肿瘤中存在的胰腺星状细胞（PSC） 微环境（TME）是结缔组织增生的主要贡献者。因此，靶向肿瘤间质 通过重新编程PSC激活的相互作用已经成为一种新的治疗策略，并导致药物 例如Nab-紫杉醇与吉西他滨的组合。然而，它们的效用有限。所以我们 提出除了“重编程PSC激活”之外，破坏PSC与胰腺的相互作用， 癌细胞（PCC）对于有效的PDAC抑制至关重要。我们鉴定了一种新化合物（Palmatine; PMT），显示了符合这一范式的初步证据。我们假设“PMT介导的 抑制PCCs中介导PSC中GLI/COL 1A 1轴活化的音刺猬（Shh）， 将COL 1A 1释放到TME中将破坏PSC的活化以及其与PCC的相互作用， 纤维化相关结缔组织增生”。将使用相关细胞培养和临床前试验来检验这一假设。 三个具体目标的动物模型。目的1研究将检验从PCC激活Shh的假设， 导致PSC中GLI/COL 1A 1轴的激活和随后COL 1A 1释放到细胞外 促进与PCC和PMT相互作用的空间将抑制这种旁分泌相互作用。药理学， 遗传抑制和拯救方法将与生物化学和功能测定相结合， 这些研究在共培养和条件培养基培养条件下进行。目标2研究将检验这一假设 PMT在体内破坏PCC-PSC之间的旁分泌相互作用，从而使用 临床前LSL K-ras G12 D +; LSL-Trp 53 R172 H/+; Pdx-1Cre转基因模型（KPC小鼠）。组织病理 胰腺的评估，包括肿瘤分级和转移、分子标志物的组织水平、组织和 将评估PMT的血清水平和血清代谢物改变。目的3研究测试假设 PMT将在源自患者的胰腺组织的短期离体培养物中抑制GLI、COL 1A 1。 研究的影响：这项改变范式的研究将确立这样一个概念，即靶向激活 需要PSC并抑制其与PCC的相互作用以提供PDAC的治疗功效。胰腺 癌症患者组织将提供PMT对抗人类PDAC的有用性的证据; 临床翻译。此外，这项研究还将确定可以作为标记物开发的分子， 预测治疗抗性/敏感性，这也将具有显著的转化潜力。

Current projections predict pancreatic ductal adenocarcinoma (PDAC) will become the second leading cause of cancer-related deaths surpassing breast, prostate and colorectal cancers by 2030. Lack of treatment strategies that can reduce the near equal incidence and mortality rate is a barrier for this disease. A key feature of PDAC is desmoplasia, which is characterized by increased fibrosis and inflammation. Desmoplasia plays a critical role not only in pancreas pathogenesis but also in tumor maintenance and limiting therapeutic efficacy by decreasing drug access to the tumor. Pancreatic stellate cells (PSCs) present in the tumor microenvironment (TME) are major contributors to desmoplasia. Accordingly, targeting tumor-stromal interactions by reprogramming PSC activation has emerged as a new therapeutic strategy and led to drugs such as Nab-Paclitaxel in combination with Gemcitabine. However their utility have been limited. Therefore, we propose that in addition to “reprogramming PSC activation” disruption of PSC interaction with pancreatic cancer cells (PCCs) is critical for effective PDAC inhibition. We have identified a new compound (Palmatine; PMT) that shows preliminary evidence of fitting this paradigm. We have hypothesized that “PMT-mediated inhibition of sonic hedgehog (Shh) from PCCs that mediates activation of GLI/COL1A1 axis in PSCs and releases COL1A1 into the TME will disrupt activation of PSC as well as its interaction with PCCs to inhibit fibrosis associated with desmoplasia”. This hypothesis will be tested using relevant cell culture and preclinical animal models in three specific aims. Aim 1 studies will test the hypothesis that activation of Shh from PCCs leads to activation of GLI/COL1A1 axis in PSCs and subsequent release of COL1A1 into the extracellular space to facilitate interaction with PCCs and PMT will inhibit this paracrine interaction. Pharmacological, genetic inhibition and rescue approaches will be combined with biochemical and functional assays to address these studies in co-culture and conditioned media culture conditions. Aim 2 studies will test the hypothesis that PMT disrupts paracrine interaction between PCC-PSC in vivo to suppress PDAC development using the pre-clinical LSL K-ras G12D+; LSL-Trp53R172H/+; Pdx-1Cre transgenic model (KPC mice). Histopathological evaluation of pancreas including tumor grade and metastasis, tissue levels of molecular markers, tissue and serum levels of PMT and serum metabolite alterations will be assessed. Aim 3 studies test the hypothesis that PMT will inhibit GLI, COL1A1, in short-term ex vivo cultures of patient-derived pancreatic tissues. Impact of the study: This paradigm changing study will establish the notion that targeting the activation of PSC and inhibiting its interaction with PCC is required to provide therapeutic efficacy for PDAC. Pancreatic cancer patient tissues will provide evidence of the usefulness of PMT against human PDAC; and set the stage for clinical translation. Further this study will also identify molecules that can be developed as markers to predict therapeutic resistance/sensitivity, which will also have significant translational potential.