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

胰腺癌（PanCa）的治疗是非常困难的，因为对可用的药物的反应极差。 治疗选择这种不良反应主要是由于核糖体生物合成和促纤维增生的失调 胰腺肿瘤微环境SC 1提案的主要目标是建立一个基于 用于治疗晚期胰腺癌（PanCa）的新治疗方案。这种新疗法 将通过同时靶向核糖体提供治疗益处并避免化学抗性 RNA聚合酶I抑制剂（BMH-21）和透明质酸促结缔组织增生肿瘤微环境的生物发生 抑制剂（4-甲基伞形酮）。核糖体的生物发生是复杂的、高度协调的细胞内 导致核糖体产生的过程。这一过程在发育过程中异常运作， 癌症，包括PanCa，也涉及对治疗药物的化学耐药性，如包括 健择。透明质酸是细胞外基质分泌的主要成分之一 通过成纤维细胞和胰腺星状细胞参与胰腺肿瘤中结缔组织增生的形成 阻止药物进入肿瘤。因此，核糖体生物发生和 透明质酸的合成将有效地抑制胰腺肿瘤的生长和转移。BMH-21是 最近开发出一种有效的RNA聚合酶选择性抑制剂，已显示出有效的抗癌作用 在临床前研究中。我们的初步研究结果显示了有希望的抗癌和化疗增敏作用 BMH-21在PanCa模型中的含量4-甲基伞形酮（4-MU）是一种无毒的透明质酸合成抑制剂 具有从未与BMH-21组合用于PanCa治疗的抗癌特性。BMH- 21在原位肿瘤异种移植小鼠模型中表现出显著的肿瘤生长抑制， 与4-MU结合。基于这些令人信服的证据，我们假设BMH-21的组合 和4-MU提供了一个显着的抗癌功效，由于改善药物摄取到肿瘤通过抑制 结缔组织增生和核糖体生物发生过程。提出了三个具体目标。在目标1，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，并克服化疗耐药性。在目标2中，我们将研究BMH-21是否以及如何 和4-MU的组合抑制原位异种移植小鼠模型中的胰腺肿瘤生长和转移。 在目标3下，我们将阐明BMH-21和4-MU组合的治疗和化学增敏功效 在PanCa的转基因小鼠模型（KPC）中。我们还将确定这种组合如何影响胰腺 肿瘤免疫监视这项研究对临床具有高度重要的转化影响，因为它将建立 一种新的基于理论的治疗人类晚期转移性PanCa的疗法。成功 这份SC 1提案的完成将为PI及其研究团队的进一步研究奠定坚实的基础 NIH竞争性资助（即R 01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.