Overcoming pancreatic tumor resistance to gemcitabine

描述（由申请人提供）：癌症是美国第二大死亡原因。 化疗仍然是一种关键的癌症治疗方式，但由于耐药性的发展，往往只产生边际效益。我们的长期目标是开发一种有效的方法来改善癌症化疗和克服癌症化疗耐药性。我们在本申请中的总体目标是开发一种新的策略，以增强吉西他滨对胰腺肿瘤的功效，并通过将我们实验室先前开发的吉西他滨纳米颗粒与破坏肿瘤促纤维增生基质的新方法组合来克服胰腺肿瘤对吉西他滨的耐药性。吉西他滨作为单药是晚期胰腺癌的一线治疗。然而，肿瘤随着时间的推移获得耐药性，这成为大多数吉西他滨相关疗法的主要问题。胰腺肿瘤对吉西他滨的耐药性来自生物学和生理学屏障。我们已经证明我们的吉西他滨纳米颗粒可以克服生物屏障。然而，来自许多最近研究的数据表明肿瘤促结缔组织增生基质作为生理屏障的重要作用，阻止吉西他滨或其他药物到达肿瘤细胞。我们的中心假设是，将使用我们的吉西他滨纳米颗粒的吉西他滨递送与通过消耗肿瘤相关巨噬细胞破坏肿瘤基质相结合，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具体目标来检验该假设：（1）阐明吉西他滨纳米颗粒克服吉西他滨耐药性的能力的机制;（2）在与人类胰腺癌非常相似的动物模型中评价吉西他滨纳米颗粒的抗肿瘤活性;（3）鉴定调节胰腺肿瘤促结缔组织增生基质将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的程度。目前的提案结合了一位在药物输送方面经验丰富的制药科学家（Cui）和两位在胰腺癌模型（Hursting）和肿瘤组织学（Kiguchi）方面具有专业知识的癌症生物学家的专业知识。这项工作的主要创新是靶向清除肿瘤相关巨噬细胞，以突破肿瘤促结缔组织增生基质屏障，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，甚至是对吉西他滨耐药的细胞。这项非常重要的工作解决了迫切需要克服胰腺肿瘤对化疗，特别是吉西他滨的耐药性。研究结果将提供原理证明，当与一种新的和临床上可行的方法结合以破坏肿瘤促结缔组织增生基质时，我们的吉西他滨纳米颗粒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种策略的临床试验提供初步基础，也将鼓励测试其他化疗药物的类似策略，以及类似策略在其他肿瘤中的更广泛应用。

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.