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

 描述(申请人提供)：胰腺导管腺癌(PDAC)仍然是最致命的疾病之一，尽管治疗方法不断改进。因此，迫切需要新的方法。致癌的KRAS基因突变发生在90%以上的PDAC中。KRAS是已知的谷氨酰胺代谢调节剂，使癌细胞依赖谷氨酰胺。因此，靶向谷氨酰胺代谢可能对治疗很大一部分胰腺癌患者特别有效。谷氨酰胺代谢的第一步是谷氨酰胺通过谷氨酰胺酶转化为谷氨酸。我们已经证明，小分子谷氨酰胺酶抑制剂，如(bis-2-[5-(phenylacetamido)-1，3，4-thiadiazol-2-yl]ethyl硫化物)，在体外和体内临床前模型中都能阻断胰腺癌细胞谷氨酰胺的产生，并减缓生长速度。然而，BPTES和其他现有的谷氨酰胺酶抑制剂通常难于溶解，代谢不稳定，无选择性，和/或需要高剂量，这降低了它们的疗效和治疗指数。最近，用于增强癌症药物输送的纳米载体已被批准(例如Doxil(R)，Abraxane(R))，并已被合理化，作为一种绕过胰腺癌药物输送的临床挑战的基质屏障的方法。我们最近证明，BPTES的纳米粒可以安全地给药，相对于游离的BPTES，可以显著改善肿瘤药物的暴露和滞留，从而产生更好的疗效。我们现在已经确定了几种专有的BPTES衍生物，它们的效力是BPTES的10到100倍，同时保留了纳米颗粒包裹和传递所需的关键物理化学性质(cLogP，PSA)。我们计划进一步优化谷氨酰胺酶抑制剂的效力(目标1)及其对包囊的兼容性(目标2)，并评估它们在KRAS突变患者来源的胰腺肿瘤以及KrasLSL.G12D/+；p53R172H/+；PdxCretg/+(或KPC)小鼠发展为具有特征间质的自然胰腺肿瘤(目标3)的异种移植中的有效性。最终，我们寻求将这些发现转化为临床并改善胰腺癌患者的预后。该提案建立在三个合作实验室的优势互补的基础上-Slusher(小分子药物发现)、Hanes(纳米颗粒设计)和Le(癌症新陈代谢)。

 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).