Targeting Oncogenic Drivers in Cancer

针对癌症的致癌驱动因素

• 批准号: 10228096
• 负责人: Matthew W Boudreau
• 金额: $ 4.6万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-03-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228096
• 关键词: Accounting; Address; Alleles; Allelic Imbalance; Aromatase Inhibitors; Biological; Biological Availability; Biological Models; Brain; CTNNB1 gene; Cancer Biology; Cell Death; Cell Line; Cells; Clinic; Clinical; Clinical Oncology; Clinical Trials; Coin; Complex; Cytostatics; Cytotoxic agent; Data; Data Set; Development; Disease; Disease Management; Disease Resistance; Doxycycline; Drug Kinetics; Estrogen Receptor alpha; Estrogen Therapy; Estrogens; Evaluation; Generations; Growth; Incidence; Investigation; Lead; Link; Lung; Malignant Neoplasms; Malignant neoplasm of liver; Mammary Neoplasms; Measures; Mediating; Metabolism; Metastatic breast cancer; Metastatic malignant neoplasm to brain; Modality; Modeling; Mutation; Neoplasm Metastasis; Nitrogen; Normal Cell; Normal tissue morphology; Oncogenes; Oncogenic; Oral; Pathway interactions; Patients; Penetrance; Pharmaceutical Chemistry; Pharmacodynamics; Phase; Phase I Clinical Trials; Plant Roots; Positioning Attribute; Primary carcinoma of the liver cells; Property; Proteins; Proteomics; Resistance; Sampling; Selective Estrogen Receptor Modulators; Signal Transduction; Testing; Therapeutic; Toxic effect; Training; Work; addiction; anti-cancer; base; beta catenin; blood-brain barrier penetration; bone; cancer cell; cancer therapy; cancer type; career; clinical development; complex data; cytotoxic; driver mutation; drug discovery; experience; experimental study; gain of function; genomic data; in vivo; insight; malignant breast neoplasm; metabolic abnormality assessment; metabolomics; mortality; mouse model; mutant; neurotoxicity; novel; overexpression; resistance mechanism; response; skills; small molecule; success; targeted treatment; therapeutic target; therapy resistant; tumor; tumor eradication; tumor growth; tumor metabolism

Project Summary & Abstract Targeting estrogen receptor alpha (ERα) is a major anticancer strategy in the treatment of ERα-positive breast cancer. However, current targeted therapies for ERα have only cytostatic activity and do not induce rapid quantitative killing of cancer cells, ultimately leading to resistance. A major resistance mechanism is ERα mutation leading to constitutively activation that drives tumor growth and metastasis, with Y537S and D538G accounting for the majority of driver mutations. These resistant tumors maintain overexpression of ERα, suggesting an opportunity to develop novel small molecules that can leverage aberrant ERαWT/Mut expression. We have discovered one such compound, ErSO, that has profound cytotoxic activity against ERαWT/Mut positive cancer cells, via rapid activation of the ERαWT/Mut-dependent anticipatory unfolded protein response (aUPR). The power of this cytotoxic activity has been observed with multiple examples of complete eradications of ERαWT/Mut-positive breast tumors in orthotopic and metastatic murine models. While there is a high translational potential for ErSO with a Phase 1 clinical trial planned for 2020, herein we discuss features of ErSO that demonstrate ErSO may only be an ideal candidate treating brain metastases. There is ample need for a second- generation ErSO with better pharmacokinetic properties and safer toxicity profile for the treatment of ERα- positive cancer. Planned work (F99 phase) consists of synthesizing more polar derivatives of ErSO, which will be assessed in mechanistic studies, in vivo tolerability, blood-brain barrier penetration, and efficacy models. These second generation compounds will likely have increased bioavailability, minimal neurotoxicity, and a safer toxicity profile, enabling their translational potential for addressing the treatment of ERα-positive cancer. While targeted anticancer therapy has altered the clinical landscape for challenging cancers, hepatocellular carcinoma (HCC) remains highly lethal with a rising mortality and incidence rate. HCC is vastly heterogenous disease with the only conserved driver mutations found in TERT and CTNNB1, which currently lie in the ‘undruggable’ target space. Herein, I describe efforts study CTNNB1 mutant allele imbalance (MAI) as a measure of CTNNB1 oncogenic addiction and propose in-depth cellular studies to annotate the impact of CTNNB1 MAI on oncogenic metabolism (K00 Phase). This exploration will provide insights into potential therapeutic targets for the treatment of HCC. These F99/K00 proposals seek produce a well-rounded, in-depth skill set to prepare me for success as an independent PI. Specifically, the F99 proposed work will refine my work in drug discovery and small molecule development. Planned K00 work will expand my expertise with new experiences in managing complex data sets to elucidate conclusions about fundamental cancer biology. Completion of this training will produce a powerful basis for my career in developing novel translational solutions for clinical oncology.

项目总结及摘要 靶向雌激素受体α（ERα）是治疗 ERα 阳性的主要抗癌策略 乳腺癌。然而，目前针对 ERα 的靶向治疗仅具有细胞抑制活性，并不能诱导快速细胞增殖。 定量杀死癌细胞，最终导致耐药性。主要耐药机制是ERα Y537S 和 D538G 突变导致组成型激活，驱动肿瘤生长和转移 占驱动突变的大部分。这些耐药肿瘤维持 ERα 的过度表达， 这表明有机会开发能够利用异常 ERαWT/Mut 表达的新型小分子。 我们发现了一种这样的化合物，ErSO，它对 ERαWT/Mut 具有深远的细胞毒活性 阳性癌细胞，通过快速激活 ERαWT/Mut 依赖性预期未折叠蛋白反应 （aUPR）。通过多个完全根除的例子观察到了这种细胞毒活性的威力 原位和转移性小鼠模型中 ERαWT/Mut 阳性乳腺肿瘤的研究。虽然翻译率很高 计划于 2020 年进行一期临床试验，了解 ErSO 的潜力，在此我们讨论 ErSO 的特征 证明 ErSO 可能只是治疗脑转移的理想候选者。非常需要第二个 新一代 ErSO 具有更好的药代动力学特性和更安全的毒性特征，用于治疗 ERα- 阳性癌症。计划工作（F99 阶段）包括合成更多极性的 ErSO 衍生物，这将 通过机制研究、体内耐受性、血脑屏障渗透性和功效模型进行评估。 这些第二代化合物可能具有更高的生物利用度、最小的神经毒性和更安全的特性。 毒性特征，使其具有治疗 ERα 阳性癌症的转化潜力。 虽然靶向抗癌治疗改变了具有挑战性的癌症的临床格局，但肝细胞 癌症（HCC）仍然具有高度致命性，死亡率和发病率不断上升。 HCC 具有很大的异质性 该疾病在 TERT 和 CTNNB1 中发现了唯一保守的驱动突变，目前位于 “不可药物”的目标空间。在此，我描述了研究 CTNNB1 突变等位基因失衡 (MAI) 的努力作为一种衡量标准 CTNNB1 致癌成瘾的影响，并提出深入的细胞研究来注释 CTNNB1 MAI 的影响 致癌代谢（K00 相）。这项探索将提供对潜在治疗靶点的见解 用于治疗 HCC。 这些 F99/K00 提案旨在培养全面、深入的技能，为我作为一名成功的人做好准备 独立PI。具体来说，F99 提议的工作将完善我在药物发现和小分子方面的工作 发展。计划的 K00 工作将通过管理复杂数据集的新经验来扩展我的专业知识 阐明有关基本癌症生物学的结论。完成本次培训将产生强大的 为我开发临床肿瘤学新型转化解决方案的职业生涯奠定了基础。