Targeting Oncogenic Drivers in Cancer

针对癌症的致癌驱动因素

• 批准号: 10554643
• 负责人: Matthew W Boudreau
• 金额: $ 8.59万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-07 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554643
• 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; translational potential; 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.

项目摘要和摘要 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。但是，当前的ERα靶向疗法仅具有细胞抑制活性，并且不会诱导快速 癌细胞的定量杀死，最终导致抗药性。主要电阻机制是ERα 突变导致组成性激活，驱动肿瘤生长和转移，Y537和D538G 考虑大多数驾驶员突变。这些抗性肿瘤维持ERα的过表达， 提出有机会开发新型的小分子，这些分子可以利用异常的ERαWT/MUT表达。 我们发现了一种这样的化合物ERSO，具有对ERαWT/MUT的深刻细胞毒性活性 阳性癌细胞，通过快速激活ERαWT/Mut依赖性预期展开的蛋白质反应 （AUPR）。已经观察到这种细胞毒性活性的功能，有多个完全放射的示例 原位和转移性鼠模型中的ERαWT/MUT阳性乳腺肿瘤。虽然有很高的翻译 ERSO的潜力进行了计划于2020年的1阶段临床试验，在此，我们讨论了ERSO的特征 证明ERSO可能仅是治疗脑转移的理想候选者。非常需要第二次 具有更好的药代动力学特性和安全毒性特征的生成ERSO，用于治疗ERα- 阳性癌症。计划的工作（F99阶段）包括综合ERSO的更多极性衍生物，这将 在机械研究，体内耐受性，血脑屏障渗透和有效模型中进行评估。 这些第二代化合物可能会增加生物利用度，最小的神经毒性和更安全的 毒性特征，使其翻译的潜力用于解决ERα阳性癌症的治疗。 虽然有针对性的抗癌治疗改变了挑战者的临床景观，但肝细胞癌 癌（HCC）仍然具有高度致命性，死亡率和发病率上升。 HCC非常异质 目前位于TERT和CTNNB1中发现的唯一配置的驱动器突变的疾病，目前位于 目标空间“不良”。在本文中，我将努力研究CTNNB1突变等位基因不平衡（MAI）作为一种度量 CTNNB1致癌成瘾和提议深入细胞研究，以注释CTNNB1 MAI的影响 在致癌代谢（K00期）上。这种探索将为潜在的治疗靶标提供见解 用于治疗HCC。 这些F99/K00的建议寻求生产一项全面的，深入的技能，以准备我为成功做好准备 独立pi。具体而言，F99提出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。这项培训的完成将产生强大的 我在开发临床肿瘤学新颖的翻译解决方案方面的职业生涯。