Therapeutic potential of Palmatine in pancreatic cancer

目前的预测显示，胰腺导管腺癌将成为第二大病因。 到2030年，与癌症相关的死亡人数将超过乳腺癌、前列腺癌和结直肠癌。缺乏治疗 能够降低近乎相等的发病率和死亡率的策略是这种疾病的障碍。一把钥匙 PDAC的特点是促结缔组织增生，其特征是纤维化和炎症增加。结缔组织发育不全 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方面也起着关键作用。 通过减少药物进入肿瘤的途径来提高疗效。肿瘤中存在的胰腺星状细胞(PSCs) 微环境(TME)是促结缔组织发育的主要因素。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，并导致了药物的出现 如NAB-紫杉醇联合吉西他滨。然而，它们的效用一直受到限制。因此，我们 提出除了“重新编程PSC激活”外，还中断了PSC与胰腺的相互作用 癌细胞(PCCs)是有效抑制PDAC的关键。我们鉴定了一种新的化合物(巴马汀； (PMT)，这表明符合这一范式的初步证据。我们假设“PMT调停 抑制PCCs的Sonic Hedgehog(Shh)介导PSCs中GLI/COL1A1轴的激活 向TME释放COL1A1将扰乱PSC的激活以及它与PCCs的相互作用以抑制 纤维化与结缔组织增生症相关“。这一假设将通过相关的细胞培养和临床前试验进行验证。 动物模型的三个具体目标。Aim 1研究将验证从PCCs激活Shh的假设 导致PSCs中GLI/COL1A1轴的激活，随后COL1A1释放到细胞外 促进与PCCs和PMT相互作用的空间将抑制这种旁分泌相互作用。药理上的， 基因抑制和挽救方法将与生化和功能分析相结合，以解决 这些研究在共培养和条件培养条件下进行。Aim 2研究将检验这一假说 PMT在体内干扰PCC-PSC之间的旁分泌相互作用，从而抑制PDAC的发展 临床前LSL K-ras G12D+、LSL-Trp53R172H/+、PDX-1Cre转基因模型(KPC小鼠)。组织病理学 胰腺的评估包括肿瘤分级和转移，组织分子标志物水平，组织和 将评估血清PMT水平和血清代谢物变化。Aim 3研究验证了这一假说 PMT将在患者来源的胰腺组织的短期体外培养中抑制GLI，COL1A1。 研究的影响：这项改变范式的研究将建立这样一个概念，即以激活 PSC和抑制其与PCC的相互作用是提供PDAC疗效所必需的。胰腺 癌症患者组织将提供PMT对抗人类PDAC的有效性的证据；并为 用于临床翻译。此外，这项研究还将确定可以开发为标记的分子 预测治疗耐药性/敏感性，这也将具有显著的翻译潜力。

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.