Optimizing selective in vivo inhibition of pancreatic tumor JAK2/STAT3 signaling

优化胰腺肿瘤 JAK2/STAT3 信号传导的选择性体内抑制

• 批准号: 8431069
• 负责人: Mitch A Phelps
• 金额: $ 20.53万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-14 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8431069
• 关键词: Apoptosis; Biological Availability; Cancer Etiology; Cancer Model; Cancer cell line; Caspase; Cell Proliferation; Cell Survival; Cessation of life; Chronic; Cytotoxic Chemotherapy; DNA Binding; Data; Development; Disease; Dose; Drug Formulations; Drug Kinetics; Epidermal Growth Factor Receptor; Frequencies; Funding; Generations; Grant; Growth; Homeostasis; Homodimerization; Human; Immune; Immunologics; Immunosuppression; Immunosuppressive Agents; In Vitro; Intravenous; JAK2 gene; Knockout Mice; Knowledge; Lead; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediator of activation protein; Modeling; Modification; Movement; Mus; Nature; New Agents; Nude Mice; Oral Administration; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Pharmacodynamics; Phosphorylation; Plasma; Prodrugs; Protein Tyrosine Kinase; Proteins; Recovery; Regimen; Resistance; Role; Route; Scheme; Signal Pathway; Signal Transduction; Simulate; Site; Solubility; Specificity; Specimen; Stat3 protein; Stream; Survival Rate; Testing; Therapeutic; Time; Tissues; Toxic effect; Tumor Cell Line; Tumor Volume; United States; United States National Institutes of Health; Vascular Endothelial Growth Factor Receptor; Xenograft procedure; angiogenesis; base; clinically relevant; drug development; improved; in vivo; inhibitor/antagonist; inorganic phosphate; intraperitoneal; mouse model; neoplastic cell; novel; novel therapeutics; pancreatic cancer cells; pancreatic neoplasm; pharmacodynamic model; public health relevance; research clinical testing; simulation; src Homology Region 2 Domain; therapeutic target; treatment strategy; tumor

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer death in the United States with a grim 5-year survival rate of less than 5%. Pancreatic cancers are resistant to cytotoxic therapies, and their profound immunosuppressive nature renders patients unresponsive to immunologic therapies. These barriers highlight the urgent need for new therapeutic strategies for this disease. One principal mediator in pancreatic cancer is the Signal-Transducer and Activator of Transcription-3 (STAT3) protein. STAT3 is activated (phosphorylated to pSTAT3) in most human pancreatic cancer specimens and cooperates with activated K-Ras and Pdx to drive initiation and progression of pancreatic ductal adenocarcinoma, as has been demonstrated in mouse models.6 STAT3 signaling is therefore an attractive target due to its role in regulating cell proliferation, apoptosis, invasion, angiogeness and immune suppression. STAT3 inhibition is known to promote apoptosis of human pancreatic cancer cell lines in vitro and in mouse tumor models, and it serves as a convergence point for multiple upstream tyrosine kinases relevant to cell survival. STAT3 targeting may therefore be superior to other approaches for overcoming therapy resistance that is observed in most patients. Finally, STAT3 is inactive in normal pancreas or other differentiated tissues and is not required for pancreatic development or homeostasis as shown by conditional knockout mice. Based on this evidence, STAT3 is an important and clinically relevant target for pancreatic cancer. However, development of inhibitors to directly and specifically inhibit STAT3 protein has been challenging. This is due to the hydrophobic nature of the phospho-Tyr705 site within the STAT3 Src homology 2 domain required for STAT3-STAT3 homodimerization and its downstream effects. Our group previously described a novel lead compound, FLLL32, that directly interacts with the STAT3 SH2 domain, inhibits phosphorylation and DNA binding, and induces caspase-dependent apoptosis of pancreatic and other tumor cell lines. Although FLLL32 was potent and STAT3 specific, its hydrophobic nature was a detriment to bioavailability. We subsequently developed a second generation phosphate pro-drug, FLLL100P. Pharmacokinetic (PK) studies revealed FLLL100P has superior solubility, rapid de-phosphorylation to active FLLL100, and 10-fold higher systemic exposure compared to FLLL32. Importantly, the active FLLL100 metabolite retains STAT3 specificity and similar potency to FLLL32. In this proposal, we will systematically define the in vivo relationship between FLLL100P PK and modulation of STAT3 signaling (PD) in pancreatic tumors. These studies will enable development of dose regimens to achieve FLLL100P concentrations and durations of exposure within pancreatic tumors in vivo for optimal suppression of STAT3 signaling. This has not been accomplished previously, and is therefore essential for movement of these agents further in development. Resulting data will be valuable for guiding further structural or formulation modifications to further enhance their activities and ultimately move them into clinical evaluation in patients with pancreatic cancer.

描述（由申请人提供）：胰腺癌是美国癌症死亡的第四大原因，5年生存率低于5%。胰腺癌对细胞毒性疗法具有抗性，并且其深刻的免疫抑制性质使得患者对免疫疗法无反应。这些障碍突出了对这种疾病的新的治疗策略的迫切需要。胰腺癌中的一种主要介质是信号转导和转录激活因子-3（STAT 3）蛋白。STAT 3在大多数人胰腺癌标本中被激活（磷酸化为pSTAT 3），并与激活的K-Ras和Pdx合作驱动胰腺导管腺癌的发生和进展，如在小鼠模型中所证明的。6因此，STAT 3信号转导是一个有吸引力的靶点，因为它在调节细胞增殖、凋亡、侵袭、血管生成和免疫抑制中发挥作用。已知STAT 3抑制在体外和小鼠肿瘤模型中促进人胰腺癌细胞系的凋亡，并且其充当与细胞存活相关的多种上游酪氨酸激酶的汇聚点。因此，STAT 3靶向可能上级克服大多数患者中观察到的治疗抗性的其他方法。最后，STAT 3在正常胰腺或其他分化组织中是无活性的，并且如条件性敲除小鼠所示，对于胰腺发育或体内平衡不是必需的。基于这一证据，STAT 3是胰腺癌的重要且临床相关的靶点。然而，开发直接和特异性抑制STAT 3蛋白的抑制剂一直具有挑战性。这是由于STAT 3-STAT 3同源二聚化所需的STAT 3 Src同源2结构域内的磷酸-Tyr 705位点的疏水性质及其下游效应。我们的小组先前描述了一种新的先导化合物FLLL 32，它直接与STAT 3 SH 2结构域相互作用，抑制磷酸化和DNA结合，并诱导胰腺和其他肿瘤细胞系的半胱天冬酶依赖性凋亡。虽然FLLL 32是有效的和STAT 3特异性的，但其疏水性对生物利用度不利。我们随后开发了第二代磷酸盐前药FLLL 100 P。药代动力学（PK）研究显示，与FLLL 32相比，FLLL 100 P具有上级溶解性、快速去磷酸化活性FLLL 100以及高10倍的全身暴露。重要的是，活性FLLL 100代谢物保留了STAT 3特异性和与FLLL 32相似的效力。在这个提议中，我们将系统地定义胰腺肿瘤中FLLL 100 P PK和STAT 3信号传导（PD）调节之间的体内关系。这些研究将能够开发剂量方案，以实现体内胰腺肿瘤内FLLL 100 P的浓度和暴露持续时间，从而实现STAT 3信号的最佳抑制。这是以前没有完成的，因此对于这些试剂的进一步发展至关重要。所得到的数据将有价值的指导进一步的结构或配方修改，以进一步提高他们的活动，并最终将其转移到胰腺癌患者的临床评价。