Network-Based Novel Therapeutics in Colorectal Cancers

摘要 辨证治疗是一种旨在重新激活内源性的非常规治疗方式。 癌细胞的分化程序与随后的肿瘤细胞成熟和同时丢失的 肿瘤表型。这种疗法在急性早幼粒细胞白血病中的疗效已有文献记载。 (APML)，但尽管多次尝试利用分化疗法的力量及其作为一种 尽管理论上有吸引力的选择，但这种疗法尚未出现。其中提到的原因有不完整的 对正常茎分化途径的理解，以及2)我们在理论上无法准确定位 一个基本的、可操作的和有效的靶点，以推动复杂和模糊的癌症向正常的过程 组织转换。使用来自成人和儿童患者的公开可用的转录数据集 散发性和遗传性癌及患有息肉综合征的人和一套公正的小说 计算方法(布尔分析和布尔网络)一个意想不到的新目标是 已确认身份。这些计算方法被设计用来识别驱动 结肠隐窝中的分化程序预测，靶点的激动剂可以触发分化和停止 结直肠腺瘤和癌(CRC)的发生和发展，甚至诱导消退，尽管 疾病异质性。利用伴随生物标记物在FFPE人体组织中的表达药理学研究 确认由该靶点编排的促分化通路在CRC启动和 进步。使用一种有效且高度特异的药物，这种药物以前是为另一种适应症而开发的 在健康成人身上进行的I期试验中发现是安全的，证实了靶标的激活是 激活促分化信号程序和诱导隐窝萌发的必要条件和充分条件 结肠衍生的有机化合物。这项提案旨在验证一种有效和特定的药物的再用途 激活一种新的促分化靶点，这是此类靶点中的第一个，用于治疗大肠息肉病和 癌症。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衍生有机化合物的作用机制(目标1)；临床前原则证明 使用小鼠CRCs遗传模型的研究(目标2)；表达药理学和概念验证 病人来源的有机化合物的‘0’期试验(儿童和成人；目标3)。功效的成功示范 在UG3阶段将触发UH3阶段(临床试验规划；目标4)。 虽然这里的重点是儿童和成人息肉综合征和CRC，但网络分析 揭示了拟议的治疗/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，促进分化的疗法建议 这里承诺重振另一项生理学计划；它满足了我们抗癌方面亟需的武器 兵工厂。当它们作为佐剂使用时，它们的联合协同作用可能会提高对“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’.