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’.

抽象的分化疗法是一种非常规治疗方式，旨在重新激活内源性癌细胞的分化程序，随后肿瘤细胞成熟并同时丧失这种疗法的“疗效”已在急性早幼粒细胞白血病中得到证实。（APML），但尽管多次尝试利用分化疗法的力量及其作为一种流行的治疗方法有吸引力的理论选择，但这种疗法尚未出现，其原因包括： 1）不完整。对正常干性分化途径的理解，以及2）我们理论上无法查明这种一个基本的、可操作的和有效的目标，以推动癌症正常化的复杂而模糊的过程使用来自成人和儿童患者的公开转录组数据集。散发性和遗传性 CRC 以及患有息肉病综合征的患者和一组公正的新颖计算方法（布尔分析和布尔网络）是一个意想不到的新颖目标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靶标的激动剂可以触发分化并停止结直肠腺瘤和癌症（CRC）的发生和进展，甚至诱导消退，尽管使用 FFPE 人体组织中的伴随生物标志物进行表达药理学研究。证实由该靶标精心策划的促分化途径在 CRC 启动过程中被沉默，并且使用先前为另一种适应症开发的有效且高度特异性的药物进展，在对健康成年人进行的第一阶段试验中发现是安全的，并证实目标的激活是对于激活促分化信号程序和诱导隐窝出芽是必要和充分的该提案旨在验证一种有效且特定的药物的重新利用。在结直肠息肉病的治疗中激活第一个新型促分化靶点我们在 3 年 UG3 阶段的具体目标都是针对目标验证：获得证据- 健康小鼠和人类结肠源性类器官的机制（目标 1）；使用 CRC 的小鼠遗传模型进行研究（目标 2）以及表达药理学和概念验证；患者来源类器官的“0”期试验（儿童和成人；目标 3）成功证明疗效。 UG3 阶段将触发 UH3 阶段（临床试验计划；目标 4）。尽管这里的重点是儿童和成人息肉病综合征和 CRC，但网络分析揭示了所提出的治疗/适应症配对可能超越其他类型癌症的可能性。就像免疫疗法通过重振生理反应来发挥作用一样，促分化疗法提出了这里承诺重振另一个生理程序；它实现了我们抗癌中急需的武器；它们用作佐剂时的协同作用可能会提高“治愈”的反应。