Network-Based Novel Therapeutics in Colorectal Cancers

基于网络的结直肠癌新疗法

基本信息

批准号：
10241395
负责人：
Soumita Das
金额：
$ 31.6万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-11 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241395
关键词：
ACVR1 gene Acute Promyelocytic Leukemia Adjuvant Adult Agonist Antineoplastic Agents Area Biological Markers Biological Models CDX2 gene Cancer Patient Cell Death Cell Survival Childhood Clinical Research Clinical Trials Colon Colorectal Colorectal Adenoma Colorectal Cancer Companions Complex Computational algorithm Data Set Diabetic Nephropathy Differentiation Therapy Disease Disease Resistance Drug usage Evolution Fetus Focus Groups Gene Expression Profile Genes Genetic Models Goals HCT116 Cells Hematopoietic Neoplasms Human Immunotherapy Inherited Interview Leadership Logistics MSH2 gene Malignant Neoplasms Methods Modality Modeling Molecular Monitor Mus Neoplasm Metastasis Network-based Normal tissue morphology Oral Organoids Pathway Analysis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Pharmacology Study Phase Phase 0 Trial Phase I/II Trial Phenotype Physiological Plasma Polyps Prevention Process Regulator Genes Role SET gene Signal Pathway Signal Transduction Source Stress Surveys Syndrome Therapeutic Time Tissues Toxic effect Transcend Treatment Efficacy Validation adenoma adenylate kinase anti-cancer antitumor effect cancer cell cancer initiation cancer type cell type colon cancer cell line design disease heterogeneity drug candidate drug repurposing efficacy testing fetal forging gastrointestinal epithelium high risk human disease human tissue in vivo insight interest leukemia mathematical algorithm neoplastic cell novel novel therapeutics pediatric patients phase I trial polyposis pre-clinical prediction algorithm programs recruit response stem stem cells stemness synergism therapy resistant transcriptome sequencing transcriptomics trial design tumor villin weapons

项目摘要

ABSTRACT Differentiation therapy is a non-conventional therapeutic modality aimed at re-activating endogenous differentiation programs in cancer cells with subsequent tumor cellular maturation and concurrent loss of the tumor phenotype. The ‘curative’ power of such therapy has been documented in acute promyelocytic leukemia (APML), but despite multiple attempts to harness the power of differentiation therapy and its popularity as an attractive theoretical option, such therapy has not emerged. Among the reasons cited are- 1) incomplete understanding of the normal stemness-differentiation pathways, and 2) our theoretical inability to pinpoint such a fundamental, actionable and effective target to drive a complex and nebulous process of cancer-to-normal tissue transitioning. Using publicly available transcriptomic datasets from adult and pediatric patients with sporadic and hereditary CRCs and those afflicted with polyposis syndromes and a set of unbiased novel computational approaches (Boolean analysis and Boolean Networks) an unexpected and novel target was identified. These computational approaches, which are designed to identify invariant genes that drive differentiation program in the colon crypts predicted that agonists of the target can trigger differentiation and halt the initiation and progression, and even induce regression of colorectal adenomas and cancers (CRCs), despite disease heterogeneity. Expression pharmacology studies using a companion biomarker in FFPE human tissues confirmed that the pro-differentiation pathway orchestrated by this target is silenced during CRC initiation and progression. Using a potent and highly specific drug that was previously developed for another indication and found to be safe in Phase I trials on healthy human adults, it was confirmed that activation of the target is necessary and sufficient for activation of a pro-differentiation signaling program and in inducing crypt-budding in colon-derived organoids. This proposal seeks to validate the repurposing of a potent and specific drug for activating a novel pro-differentiation target, the first of its kind, in the treatment of colorectal polyposis and cancers. Our specific Aims during the 3-y UG3 phase are all geared towards target validation: obtaining proof- of-mechanism in healthy murine and human colon-derived organoids (Aim 1); preclinical proof-of-principle studies using murine genetic models of CRCs (Aim 2); and expression pharmacology and proof-of-concept Phase ‘0’ trials in patient-derived organoids (pediatric and adults; Aim 3). Successful demonstration of efficacy in UG3 phase will trigger the UH3-phase (Clinical trial planning; Aim 4). Although the focus here is on pediatric and adult polyposis syndromes and CRCs, network analysis revealed the possibility that the proposed therapeutic/indication pairing may transcend other types of cancers. Much like immunotherapy acts by reinvigorating a physiologic response, the pro-differentiation therapy proposed here promises to reinvigorate yet another physiologic program; it fulfils a much-needed weapon in our anti-cancer armamentarium. Their combined synergy when used as adjuvants may elevate response to ‘cure’.

抽象的分化治疗是一种旨在重新激活内生的非常规治疗方式随后肿瘤细胞成熟和同时丧失的癌细胞中的分化程序肿瘤表型。这种疗法的“治愈性”能力已记录在急性前临床白血病中（APML），但渴望多次尝试利用分化疗法的力量及其作为一种有吸引力的理论选择，这种疗法尚未出现。在引用的原因之一为-1）不完整理解正常的干性分化途径，以及2）我们的理论无能为力。一个基本，可行且有效的目标，用于驱动复杂而模糊的癌症与正常的过程组织过渡。使用成人和儿科患者的公开转录组数据集零星和遗传性CRC以及患有多念珠综合征和一组公正的小说的CRC 计算方法（布尔分析和布尔网络）一个出乎意料且新颖的目标是确定。这些计算方法旨在识别驱动的不变基因结肠隐窝中的分化程序预测，目标的激动剂会触发分化和停止主动性和进步，甚至影响彩色腺瘤和癌症（CRC）的回归，疾病异质性。在FFPE人体组织中使用伴随生物标志物的表达药理学研究确认在CRC启动期间，该目标精心策划的差异途径和进展。使用以前用于另一种指示的潜在和高度特异性药物发现在健康人类成年人的I期试验中是安全的，可以证实目标的激活是必要且足够激活前分化信号传导程序以及在诱导的加密budding中结肠衍生的类器官。该提案旨在验证重新利用潜在药物和特定药物激活一个新型的促分化目标，即同类的第一个，用于治疗结直肠息肉和癌症。我们在3-Y UG3阶段的具体目标均针对目标验证：获得证明 - 健康的鼠和人类结肠衍生的器官中的机制（AIM 1）；临床前原则证明使用CRC的鼠遗传模型的研究（AIM 2）；和表达药理学和概念证明患者衍生的类器官（儿科和成人； AIM 3）的“ 0”试验。成功的效率证明在UG3阶段，将触发UH3相（临床试验计划； AIM 4）。尽管这里的重点是小儿和成人多息护素综合征和CRC，但网络分析揭示了拟议的治疗/指示配对可能超越其他类型的癌症的可能性。就像免疫疗法通过重振生理反应而采取的行动一样这里有望振兴另一个生理计划。它在我们的反癌中履行了急需的武器武术。当用作调节器时，它们的结合协同作用可能会提升对“治愈”的反应。