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

基本信息

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
项目类别：
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

项目摘要

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重组蛋白作为人类癌症的新型治疗方法进行临床试验。虽然 TRAIL 在杀死肿瘤细胞方面非常活跃，但重组 TRAIL 的药物特性限制了其功效，例如血清半衰期短、不稳定以及无法穿过完整的血盐屏障。为了克服这些限制，我们鉴定了 TRAIL 基因的小分子诱导剂 TIC10，它在稳定性、生物利用度、穿过血脑屏障的能力、生产成本和活性谱方面优于重组 TRAIL。重要的是，我们的数据表明 TIC10 在几种侵袭性和难治性癌症中高度活跃。在机制水平上，TIC10 产生有效的抗肿瘤作用和由转录因子 Foxo3a 介导的 TRAIL 诱导作用，Foxo3a 直接调节 TRAIL 基因启动子。此外，我们发现 TIC10 导致 Akt 和 ERK 双重失活，从而抑制 Fox3a 的组成型磷酸化，并增强其转位至细胞核并与 TRAIL 基因启动子结合（Allen 等人，Science Translational Medicine，In Press，2013））。我们假设 TIC10 诱导有效的抗肿瘤作用，这需要 Akt 和 ERK 介导的 Foxo3a 核转位和 TRAIL 基因的转录激活。为了解决这一假设，我们提出以下具体目标：具体目标#1：识别 TIC10 诱导的对 Foxo3a 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 TIC10 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 TIC10 如何利用 Foxo3a 实现其有效的抗肿瘤活性产生全面的分子理解，并且还有可能发现具有生物学意义的 Foxo3a 活性的新调控机制。包括原位异种移植物和转基因小鼠以及原发性人类肿瘤标本在内的临床前癌症模型将证实 TIC10 和 Foxo3a 的功效并验证其机制发现。这些研究将共同阐明 Foxo3a 与一流分子 TIC10 的关键和新颖的调控机制，以深入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。