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

 描述（由申请人提供）：尽管治疗方法不断改进，但胰腺导管腺癌（PDAC）仍然是最致命的疾病之一。因此，迫切需要新的方法。致癌KRAS基因突变发生在超过90%的PDAC中。KRAS是一种已知的谷氨酰胺代谢调节剂，使癌细胞依赖于谷氨酰胺。因此，靶向谷氨酰胺代谢可能对治疗大部分胰腺癌患者特别有效。谷氨酰胺代谢的第一步是通过谷氨酰胺酶将谷氨酰胺转化为谷氨酸。我们已经证明，小分子谷氨酰胺酶抑制剂，如BPTES（双-2-[5-（苯乙酰氨基）-1，3，4-噻二唑-2-基]乙基硫醚），阻断胰腺癌细胞中谷氨酰胺的产生，并在体外和体内临床前模型中减弱生长速率。然而，BPTES和其他可用的转氨酶抑制剂通常溶解性差、代谢不稳定、非选择性和/或需要高剂量，这降低了它们的功效和治疗指数。最近，用于增强癌症中药物递送的纳米尺寸的载体已经被批准（例如Doxil（r）、Abraxane（r）），并且已经被合理化为绕过间质屏障的方法，所述间质屏障是胰腺癌中药物递送的临床挑战。我们最近证明，BPTES的纳米颗粒递送可以安全地施用，并且相对于游离BPTES，提供了肿瘤药物暴露和保留的显著改善，从而产生更大的功效。我们现在已经确定了几种专有的BPTES衍生物，其效力是BPTES的10至100倍，同时保留了纳米颗粒包封和递送所需的关键理化性质（cLogP，PSA）。我们计划进一步优化转氨酶抑制剂的效力（目标1）及其与包封的相容性（目标2），并评估其在来自KRAS突变的患者来源的胰腺肿瘤以及发展具有特征性基质的天然胰腺肿瘤的KrasLSL.G12D/+; p53 R172 H/+; Pdxlag/+（或KPC）小鼠的原位异种移植物中的有效性（目标3）。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互补优势之上- Slusher（小分子药物发现），Hanes（纳米颗粒设计）和Le（癌症代谢）。

 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).