Overcoming pancreatic tumor resistance to gemcitabine

描述(申请人提供)：癌症是美国第二大死因。化疗仍然是一种关键的癌症治疗方法，但由于耐药性的产生，往往只能产生微乎其微的好处。我们的长期目标是开发一种有效的方法来改进癌症化疗并克服癌症的化疗耐药性。我们目前应用的总体目标是开发一种新的策略来增强吉西他滨对胰腺肿瘤的疗效，并通过将我们实验室先前开发的吉西他滨纳米粒与一种打破肿瘤促结缔组织间质的新方法相结合来克服胰腺肿瘤对吉西他滨的耐药性。吉西他滨作为单一药物是治疗晚期胰腺癌的一线药物。然而，随着时间的推移，肿瘤获得耐药性，这成为大多数吉西他滨相关治疗的主要问题。胰腺肿瘤对吉西他滨的耐药性源于生物和生理两方面的障碍。我们已经证明，我们的吉西他滨纳米粒可以克服生物障碍。然而，最近一些研究的数据表明，肿瘤促结缔组织间质作为生理屏障，阻止吉西他滨或其他药物到达肿瘤细胞，具有重要的作用。我们的中心假设是，结合使用我们的吉西他滨纳米粒传递吉西他滨和通过耗尽肿瘤相关巨噬细胞来破坏肿瘤间质，将有效地克服胰腺肿瘤对吉西他滨的耐药性。我们计划通过追求以下特定目标来检验这一假说：(1)阐明吉西他滨纳米颗粒克服吉西他滨耐药性的潜在机制；(2)在与人类胰腺癌非常相似的动物模型中评估吉西他滨纳米颗粒的抗肿瘤活性；(3)确定调节胰腺癌促纤维形成间质将在多大程度上影响吉西他滨纳米颗粒的抗肿瘤活性及其克服吉西他滨耐药性的能力。目前的提案结合了一位在药物输送方面经验丰富的药剂学家(CUI)和两位在胰腺癌模型(赫斯汀)和肿瘤组织学(Kiguchi)方面有专长的癌症生物学家的专业知识。这项工作的主要创新是有针对性地消耗肿瘤相关巨噬细胞，以突破肿瘤促结缔组织基质屏障，使我们的吉西他滨纳米颗粒能够有效地到达并杀死肿瘤细胞，甚至是对吉西他滨具有耐药性的细胞。这项非常有意义的工作解决了克服胰腺肿瘤对化疗的耐药性的迫切需要，特别是吉西他滨。研究结果将提供原则性证据，证明当我们的吉西他滨纳米粒与一种新的、临床上可行的方法相结合来打破肿瘤促结缔组织间质时，可以改善胰腺癌治疗的临床结果。因此，这些研究将为未来测试这一策略的临床试验提供初步基础，并将鼓励将类似策略与其他化疗药物一起测试，以及在其他肿瘤中更广泛地应用类似策略。

DESCRIPTION (provided by applicant): Cancer is the second leading cause of death in the United States. Chemotherapy remains a critical cancer treatment modality, but often produces only marginal benefits due to the development of resistance. Our long- term goal is to develop an efficacious approach to improve cancer chemotherapy and to overcome cancer chemoresistance. Our overall objective in the present application is to develop a novel strategy to enhance the efficacy of gemcitabine against pancreatic tumors and to overcome pancreatic tumor resistance to gemcitabine by combining the gemcitabine-nanoparticles previously developed in our lab with a novel method to breach the tumor desmoplastic stroma. Gemcitabine as a single agent is the first line treatment of advanced pancreatic cancers. However, tumors acquire resistance over time, which becomes a major issue for most gemcitabine- related therapies. Pancreatic tumor resistance to gemcitabine arises from both biological and physiological barriers. We have shown that our gemcitabine-nanoparticles can overcome the biological barrier. However, data from a number of recent studies demonstrate the essential role of tumor desmoplastic stroma as a physiological barrier, preventing gemcitabine or other drugs from reaching tumor cells. Our central hypothesis is that combining the delivery of gemcitabine using our gemcitabine-nanoparticles with the breaching of tumor stroma by depleting tumor-associated macrophages will effectively overcome pancreatic tumor resistance to gemcitabine. We plan to test the hypothesis by pursuing the following specific aims: (1) to elucidate the mechanisms underlying the gemcitabine-nanoparticle's ability to overcome gemcitabine resistance; (2) to evaluate the antitumor activity of the gemcitabine-nanoparticles in animal models that closely resemble human pancreatic cancers; (3) to identify the extent to which modulating pancreatic tumor desmoplastic stroma will affect the antitumor activity of the gemcitabine-nanoparticles and their ability to overcome gemcitabine resistance. The current proposal combines the expertise of a pharmaceutical scientist experienced in drug delivery (Cui) and two cancer biologists with expertise in pancreatic cancer models (Hursting) and tumor histology (Kiguchi). The primary innovation of this work is the targeted depletion of tumor-associated macrophages to breach the tumor desmoplastic stromal barrier, allowing our gemcitabine-nanoparticles to then efficiently reach and kill tumor cells, even cells that are resistant to gemcitabine. This highly significant work addresses the urgent need to overcome pancreatic tumor resistance to chemotherapy, particularly gemcitabine. Study findings will provide the proof of principle that when combined with a novel and clinically feasible method to breach tumor desmoplastic stroma, our gemcitabine-nanoparticles can improve the clinical outcomes of pancreatic cancer therapy. Consequently, these studies will provide the initial underpinnings for future clinical trials testing this strategy and will also encourage the testing f similar strategies with other chemotherapeutic agents, as well as the broader application of similar strategies in other tumors.