TIC10 anti-tumor effect through regulation of Foxo3a and TRAIL

TIC10 通过调节 Foxo3a 和 TRAIL 发挥抗肿瘤作用

• 批准号: 9327902
• 负责人: WAFIK S. EL-DEIRY
• 金额: $ 37.81万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2019-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9327902
• 关键词: Address; Advanced Malignant Neoplasm; Apoptosis; Apoptotic; Binding; Biological; Biological Availability; Blood; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cancer Model; Cell Death; Cell Nucleus; Clinic; Clinical; Clinical Trials; Colon Carcinoma; Colorectal Cancer; Consensus Sequence; Cytoplasm; Data; Development; Disease Progression; Family; Family member; Future; Genes; Genetic Transcription; Half-Life; Human; Laboratory Study; Literature; Lymphoma; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Mediating; Molecular; Molecular Target; Normal Cell; Nuclear Translocation; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Phosphotransferases; Post-Translational Protein Processing; Primary Neoplasm; Production; Property; Proteins; Recombinant Proteins; Recombinants; Regulation; Role; Safety; Sampling; Serum; Signal Transduction; Signaling Molecule; Specificity; Specimen; TNF-related apoptosis-inducing ligand; TNFSF10 gene; Testing; Therapeutic Agents; Toxic effect; Transcriptional Activation; Transgenic Mice; Translating; Translational Research; Translations; Validation; Work; Xenograft procedure; aggressive therapy; anti-cancer therapeutic; antitumor agent; antitumor effect; base; cancer cell; clinical translation; cofactor; colon cancer cell line; cost; improved; in vivo; insight; killings; malignant breast neoplasm; member; neoplastic cell; novel; novel therapeutics; overexpression; pre-clinical; promoter; public health relevance; response; small molecule; therapy resistant; transcription factor; translational medicine; tumor; tumor progression; tumor xenograft

DESCRIPTION (provided by applicant): The potency and safety of TRAIL has prompted clinical trials with the recombinant protein as a novel treatment for human cancer. While TRAIL is very active in killing tumor cells, recombinant TRAIL possesses drug properties that limit its efficacy such as short serum half-life, instability, and the inability to cross the intact blood-brin barrier. To overcome these limitations we identified a small molecule inducer of the TRAIL gene, TIC10 that is superior to recombinant TRAIL in terms of stability, bioavailability, ability to cros the blood-brain barrier, cost of production, and spectrum of activity. Importantly, our data shows that TIC10 is highly active in several aggressive and therapy-resistant cancers. On a mechanistic level, TIC10 causes potent antitumor effects and TRAIL-induction that is mediated by the transcription factor Foxo3a, which directly regulates the TRAIL gene promoter. Furthermore, we found that TIC10 results in the dual inactivation of Akt and ERK, thereby inhibiting their constitutive phosphorylation of Fox3a and potentiating its translocation to the nucleus and binding to the TRAIL gene promoter (Allen et al, Science Translational Medicine, In Press, 2013). We hypothesize that TIC10 induces potent antitumor effects that require Akt- and ERK-mediated Foxo3a nuclear translocation and transcriptional activation of the TRAIL gene. To address the hypothesis we propose the following specific aims: Specific Aim #1: Identify TIC10-induced effects on Foxo3a expression, phosphorylation, and subcellular localization; Specific Aim #2: Elucidate the role of Akt and ERK kinases in the mechanism of action of TIC10; Specific Aim #3: Determine the differential regulation of TRAIL gene transcription by FOXO family members. These studies will create a comprehensive molecular understanding of how TIC10 harnesses Foxo3a to achieve its potent antitumor activity and also has the potential to undercover novel regulatory mechanisms of Foxo3a activity that are biologically significant. Preclinical cancer models including orthotopic xenografts and transgenic mice along with primary human tumor specimens will substantiate the efficacy and validate the mechanistic findings regarding TIC10 and Foxo3a. Together, these studies will elucidate key and novel regulatory mechanisms involving Foxo3a with the first-in-class molecule TIC10 to yield insight regarding its mechanism of action as well as in clinical samples in the context of colon cancer disease progression. Our studies will facilitate the clinical translation of a novel anti-cancer therapeutic agent through further development in preclinical laboratory studies.

描述（由申请人提供）：TRAIL的效力和安全性促使了将重组蛋白作为人类癌症的新型治疗方法的临床试验。虽然TRAIL在杀死肿瘤细胞方面非常活跃，但重组TRAIL具有限制其功效的药物性质，例如短血清半衰期、不稳定性和不能穿过完整的血液屏障。为了克服这些限制，我们鉴定了TRAIL基因的小分子诱导剂TIC 10，其在稳定性、生物利用度、穿过血脑屏障的能力、生产成本和活性谱方面上级重组TRAIL。重要的是，我们的数据显示TIC 10在几种侵袭性和耐药性癌症中具有高度活性。在机制水平上，TIC 10引起有效的抗肿瘤作用和由转录因子Foxo 3a介导的TRAIL诱导，所述转录因子Foxo 3a直接调节TRAIL基因启动子。此外，我们发现TIC 10导致Akt和ERK的双重失活，从而抑制它们对Fox 3a的组成性磷酸化并增强其易位至细胞核并结合至TRAIL基因启动子（艾伦等人，Science Translational Medicine，In Press，2013）。我们假设TIC 10诱导强效抗肿瘤作用，需要Akt和ERK介导的Foxo 3a核转位和TRAIL基因的转录激活。为了解决这一假设，我们提出了以下具体目标：具体目标#1：确定TIC 10诱导的对Foxo 3a表达、磷酸化和亚细胞定位的影响;具体目标#2：阐明Akt和ERK激酶在TIC 10作用机制中的作用;具体目标#3：确定FOXO家族成员对TRAIL基因转录的差异调节。这些研究将对TIC 10如何利用Foxo 3a来实现其有效的抗肿瘤活性产生全面的分子理解，并有可能揭示具有生物学意义的Foxo 3a活性的新调控机制。包括原位异种移植物和转基因小鼠沿着以及原发性人肿瘤标本的临床前癌症模型将证实疗效并验证关于TIC 10和Foxo 3a的机制发现。总之，这些研究将阐明涉及Foxo 3a与一流分子TIC 10的关键和新型调控机制，以了解其作用机制以及结肠癌疾病进展背景下的临床样本。我们的研究将通过临床前实验室研究的进一步发展促进新型抗癌治疗剂的临床转化。