Targeting ribosome biogenesis and desmoplastic tumor microenvironment for the treatment of advanced pancreatic cancer

胰腺癌(Panca)的治疗非常困难，因为对可用药的反应极差。 治疗选择。这种不良反应主要是由于核糖体生物发生和促结缔组织发育失调所致。 胰腺肿瘤微环境。这项SC1提案的主要目标是建立一个基于 治疗晚期胰腺癌的新治疗方案。这种新的疗法 将通过同时靶向核糖体来提供治疗益处和规避化疗耐药性 RNA聚合酶I抑制剂(BMH-21)的生物发生与透明质酸促结缔组织肿瘤微环境 抑制剂(4-甲基伞形酮)。核糖体的生物发生是复杂的、高度协调的细胞 导致核糖体产生的过程。这一过程在发展过程中被异常地操作 癌症，包括胰腺癌，也参与了对治疗药物的化疗耐药，例如 吉西他滨。透明质酸是分泌细胞外基质的主要成分之一 成纤维细胞和星状细胞参与胰腺肿瘤中促结缔组织增生的形成 阻止药物在肿瘤中的可获得性。因此，战略靶向核糖体生物发生和 透明质酸合成可有效抑制胰腺肿瘤的生长和转移。BMH-21是 最近开发的一种有效的RNA聚合酶选择性抑制剂，已显示出强大的抗癌效果 在临床前研究中。我们的初步结果显示了良好的抗癌和化学增敏作用。 在Panca模型中发现了BMH-21。4-甲基伞形酮(4-MU)是一种无毒的透明质酸合成抑制剂 具有一种从未与BMH-21结合用于潘卡治疗的抗癌特性。BMH- 21在小鼠原位移植瘤模型中表现出明显的肿瘤生长抑制作用 结合4-MU。基于这些令人信服的证据，我们假设BMH-21的组合 而4-MU提供了显著的抗癌效果，这是因为通过抑制 结缔组织增生症和核糖体生物发生过程。提出了三个具体目标。在目标1中，我们计划 研究BMH-21和4-MU抑制生长的潜在分子机制和功能影响。 转移表型，并克服化疗耐药。在目标2中，我们将调查BMH-21是否以及如何 联合应用4-MU可抑制小鼠胰腺癌原位移植模型的生长和转移。 在目标3下，我们将阐明BMH-21和4-MU的联合治疗和化疗增敏效果。 在panca转基因小鼠模型(KPC)中。我们还将确定这种组合对胰腺的影响。 肿瘤免疫监测。这项研究对临床有非常重要的翻译影响，因为它将建立 治疗人类晚期转移性胰腺癌的新理论基础。成功 完成这项SC1建议将为PI和他的研究团队进一步研究奠定坚实的基础 NIH竞争性拨款(即R01或R21)，用于未来的临床相关研究。

Pancreatic cancer (PanCa) treatment is exceptionally difficult due to the extremely poor response to available therapeutic options. This poor response is mainly due to dysregulation of ribosome biogenesis and desmoplastic pancreatic tumor microenvironment. The main objective of this SC1 proposal is to establish a rationale based novel therapeutic regimen for the treatment of advanced stage pancreatic cancer (PanCa). This novel therapy will provide therapeutic benefit and circumvent chemoresistance via simultaneous targeting of ribosome biogenesis by RNA polymerase I inhibitor (BMH-21) and desmoplastic tumor microenvironment with hyaluronan inhibitor (4-Methylumbelliferone). The ribosome biogenesis is the complex and highly coordinated cellular process leading to the production of ribosomes. This process is aberrantly operated during the development of cancer, including PanCa and also involved in chemoresistance to therapeutic drugs, such as including gemcitabine. Hyaluronan (Hyaluronic acid) is one of the major components of the extracellular matrix secreted by fibroblasts and pancreatic stellate cells which is involved in the formation of desmoplasia in pancreatic tumors that prevent drug accessibility in the tumors. Thus, strategically targeting of both ribosome biogenesis and hyaluronan synthesis will effectively suppress the growth and metastasis of pancreatic tumors. BMH-21 was recently developed as a potent selective inhibitor of RNA polymerase that has shown potent anti-cancer effect in pre-clinical studies. Our preliminary results have shown promising anti-cancer and chemosensitization effects of BMH-21 in PanCa models. 4-Methylumbelliferone (4-MU) is a non-toxic hyaluronic acid synthesis inhibitor with an anti-cancer property that has never been tested in combination with BMH-21 for PanCa treatment. BMH- 21 demonstrated remarkable tumor growth inhibition in the orthotopic tumor xenograft mouse model when combined with 4-MU. Based on these compelling evidences, we hypothesize that the combination of BMH-21 and 4-MU proffers a pronounced anti-cancer efficacy due to improved drug uptake into tumors via repression of desmoplasia and ribosome biogenesis processes. Three specific aims are proposed. In Aim 1, we plan to investigate underlying molecular mechanisms and functional impact of BMH-21 and 4-MU to inhibit the growth, metastatic phenotypes, and overcome chemoresistance. In Aim 2, we will investigate whether and how BMH-21 and 4-MU combination inhibits pancreatic tumor growth and metastasis in an orthotopic xenograft mouse model. Under Aim 3, we will elucidate the therapeutic and chemosensitization efficacy of BMH-21 and 4-MU combination in a transgenic mouse model (KPC) of PanCa. We will also determine how this combination influences pancreatic tumor immune surveillance. This study has a high significant translational impact on the clinic as it will establish a new rationale-based therapy for the treatment of advanced metastatic PanCa in humans. Successful completion of this SC1 proposal will set a strong foundation for the PI and his research team to further pursue an NIH competitive grant (i.e. R01 or R21) for future clinically related studies.