Network-Based Novel Therapeutics in Colorectal Cancers

摘要 分化治疗是一种非传统的治疗方式，旨在重新激活内源性 在癌细胞中的分化程序，随后的肿瘤细胞成熟和同时的丧失， 肿瘤表型这种疗法的“治愈”能力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治疗方法的普及， 有吸引力的理论选择，这种疗法还没有出现。其中列举的原因有：（1）不完整 理解正常的干细胞分化途径，2）我们的理论上无法确定这种 一个基本的，可操作的和有效的目标，以推动一个复杂的和模糊的过程，癌症正常 组织转变。使用来自成人和儿科患者的公开可用的转录组数据集， 散发性和遗传性CRCs和那些患有息肉综合征患者，以及一组无偏见的新的 计算方法（布尔分析和布尔网络）一个意想不到的和新颖的目标， 鉴定这些计算方法，旨在确定不变的基因，驱动 结肠隐窝中的分化程序预测，靶点的激动剂可以触发分化并停止 结肠直肠腺瘤和癌症（CRC）的发生和进展，甚至诱导消退，尽管 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 证实由该靶点协调的促分化途径在CRC起始期间沉默， 进展使用一种以前为另一种适应症开发的强效且高度特异性的药物， 在健康成人的I期试验中发现是安全的，证实了靶点的激活是 这对于激活促分化信号程序和诱导细胞中的隐窝出芽是必要的和足够的。 结肠衍生的类器官。该提案旨在验证一种强效和特异性药物的再利用， 在结肠直肠息肉病的治疗中激活一种新的促分化靶点， 癌的我们在3年UG 3阶段的具体目标都是针对目标验证：获得证据- 在健康小鼠和人类结肠源性类器官中的机制（目的1）;临床前原理验证 使用CRC的鼠遗传模型的研究（目标2）;以及表达药理学和概念验证 患者源性类器官的“0”期试验（儿科和成人;目标3）。有效性的成功证明 UG 3阶段将触发UH 3阶段（临床试验计划;目标4）。 虽然这里的重点是儿童和成人息肉综合征和CRC，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新激活生理反应起作用一样， 它有望重振另一个生理学项目;它实现了我们抗癌中急需的武器 医疗设备当用作佐剂时，它们的组合协同作用可提高对“治愈”的反应。

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’.