Glutaminase Inhibitor Drug Discovery and Nanoparticle-Based Delivery for Pancreatic Cancer Therapy

谷氨酰胺酶抑制剂药物的发现和基于纳米颗粒的胰腺癌治疗递送

基本信息

批准号：
9028315
负责人：
Justin S. Hanes
金额：
$ 42.56万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9028315
关键词：
Abraxane Adjuvant Chemotherapy Albumins Amino Acids Ammonia Attenuated Binding Biological Assay Blood Circulation Cancer Etiology Cancer Model Cancer Patient Cells Cessation of life Characteristics Clinic Clinical Collaborations Cytidine Deaminase Detection Disease Dose Doxorubicin Hydrochloride Liposome Drug Delivery Systems Drug Exposure Drug Kinetics Effectiveness Energy-Generating Resources Enzymes Formulation Genes Glutamates Glutaminase Glutamine Glycolates Goals Growth Health Homologous Gene Human Immune system In Vitro KRAS2 gene Knowledge Laboratories Legal patent Malignant Neoplasms Malignant neoplasm of pancreas Metabolism Methods Modeling Molecular Mus Mutate Mutation Oncogenic Operative Surgical Procedures Paclitaxel Pancreas Pancreatic Ductal Adenocarcinoma Pathology Patients Penetration Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pre-Clinical Model Production Property Rattus Reactive Oxygen Species Reporting Structure Structure-Activity Relationship Sulfides Surface Testing Therapeutic Index Time Tissues Toxic effect Translating Tumor Tissue Viral Oncogene Xenograft procedure analog base cancer cell cancer therapy clinically relevant density deprivation design drug discovery drug efficacy ethylene glycol gemcitabine improved improved outcome in vivo inhibitor/antagonist intravenous injection meetings mouse model nanomedicine nanoparticle nanosized novel novel strategies oncology outcome forecast pancreatic cancer cells pancreatic neoplasm prototype sarcoma small molecule success tumor tumor metabolism

项目摘要

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal diseases despite continual improvements in therapy. Thus new approaches are sorely needed. Mutations in the oncogenic KRAS gene occur in over 90% of PDACs. KRAS is a known regulator of glutamine metabolism that renders cancer cells dependent on glutamine. Therefore, targeting glutamine metabolism may be particularly effective in treating a large portion of patients with pancreatic cancer. The first step of glutamie metabolism is the conversion of glutamine to glutamate via glutaminase. We have demonstrated that small molecule glutaminase inhibitors, such as BPTES (bis-2-[5-(phenylacetamido)-1,3,4-thiadiazol-2-yl]ethyl sulfide), block the production of glutamine in pancreatic cancer cells and attenuate growth rates in both in vitro and in vivo preclinical models. However, BPTES and other available glutaminase inhibitors are generally poorly soluble, metabolically unstable, nonselective, and/or require high doses, which reduce their efficacy and therapeutic index. Recently, nano-sized vehicles to enhance drug delivery in cancer have been approved (e.g. Doxil(r), Abraxane(r)) and have been rationalized as an approach to circumvent the stromal barrier which is a clinical challenge to drug delivery in pancreatic cancer. We recently demonstrated that nanoparticle delivery of BPTES can be safely administered and relative to free BPTES, provides dramatic improvement in tumor drug exposure and retention, resulting in greater efficacy. We have now identified several proprietary BPTES derivatives that are 10- to 100-fold more potent than BPTES and, at the same time, retain the key physicochemical properties (cLogP, PSA) required for nanoparticle encapsulation and delivery. We plan to further optimize the potency of the glutaminase inhibitors (Aim 1) and their compatibility to encapsulation (Aim 2) and evaluate their effectiveness in orthotopic xenografts from KRAS mutated patient-derived pancreatic tumors as well as KrasLSL.G12D/+; p53R172H/+; PdxCretg/+ (or KPC) mice that develop natural pancreatic tumors with characteristic stroma (Aim 3). Ultimately, we seek to translate these findings into the clinic and improve outcomes for pancreatic cancer patients. The proposal builds on the complementary strengths of the three collaborating laboratories - Slusher (small molecule drug discovery), Hanes (nanoparticle design), and Le (cancer metabolism).

描述（由适用提供）：胰腺导管腺癌（PDAC）仍然是治疗中最致命的疾病目的地连续性改善之一。迫切需要这种新方法。超过90％的PDAC中，致癌性KRAS基因的突变发生。 KRAS是谷氨酰胺代谢的已知调节剂，它使癌细胞依赖于谷氨酰胺。因此，靶向谷氨酰胺代谢可能在治疗大部分胰腺癌患者方面特别有效。谷氨酰胺代谢的第一步是将谷氨酰胺通过谷氨酰胺转化为谷氨酸。我们已经证明，小分子谷氨酰胺抑制剂，例如BPTE（BIS-2- [5-（苯基乙酰胺）-1,1,3,4-硫二唑-2-基]乙基硫化物），阻止了胰腺癌细胞中胰腺癌细胞中谷氨酰胺的产生，并在Vivo Perfol Prastly Prastlanical In In Vivo Prastlanicalisicalisical中均可阻止。但是，BPTE和其他可用的谷氨酰胺酶抑制剂通常固体效果不佳，代谢不稳定，非选择性和/或需要高剂量，从而降低其有效性和治疗指数。最近，已批准了纳米大小的车辆来增强癌症的药物（例如Doxil（R），Abraxane（R）），并已合理化为避免基质屏障的方法，这是对胰腺癌药物递送的临床挑战。我们最近证明，BPTE的纳米颗粒递送可以安全地给药，并且相对于自由BPTE，可显着改善肿瘤药物暴露和保留，从而提高效率。现在，我们已经确定了几个专有BPTES衍生物，它们的潜力比BPTE高10至100倍，同时保留了纳米颗粒封装和交付所需的关键物理特性（ClOGP，PSA）。我们计划进一步优化谷氨酰胺酶抑制剂的效力（AIM 1）及其封装的兼容性（AIM 2），并评估它们在KRAS突变的患者衍生胰腺肿瘤的原位异种移植物中的有效性，以及Kraslsl.g12d/+; p53r172h/+; PDXCRETG/+（或KPC）小鼠会形成具有特征性基质的天然胰腺肿瘤（AIM 3）。最终，我们试图将这些发现转化为诊所，并改善胰腺癌患者的结局。该提案建立在三个合作实验室的互补优势的基础上 - Slusher（小分子药物发现），Hanes（纳米颗粒设计）和LE（癌症代谢）。