Targeting Oncogenic Drivers in Cancer

针对癌症的致癌驱动因素

• 批准号: 10581701
• 负责人: Matthew W Boudreau
• 金额: $ 8.87万
• 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/10581701
• 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; Classification; 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; Estrogens; Evaluation; Generations; Growth; Heterozygote; Incidence; Investigation; Licensing; 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; Pharmacotherapy; Phase; Phase I Clinical Trials; 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; 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; metabolomics; mortality; mouse model; mutant; neurotoxicity; novel; overexpression; resistance mechanism; response; skills; small molecule; success; targeted treatment; therapeutic target; therapy resistant; translational potential; trial planning; 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(&A) 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的靶向治疗只具有细胞抑制活性，并不能快速诱导 量化杀死癌细胞，最终导致抗药性。一种主要的耐药机制是ERα Y537S和D538G突变导致结构性激活，推动肿瘤生长和转移 导致了大部分的驱动基因突变。这些耐药肿瘤维持ERα的过度表达， 这意味着有机会开发能够利用ERαWT/Mut异常表达的新型小分子。 我们已经发现了一种这样的化合物，ERSO，它对ERαWT/Mut具有深刻的细胞毒活性 阳性癌细胞，通过快速激活ERαWT/MUT依赖的预期未折叠蛋白反应 (9月)。这种细胞毒活性的威力已经通过多个完全根除的例子得到了观察。 ERαWT/MUT阳性乳腺肿瘤在原位和转移性小鼠模型中的表达。虽然有很高的翻译率 ERSO的潜力与计划于2020年进行的第一阶段临床试验，在此我们讨论ERSO的特征， 证明ERSO可能只是治疗脑转移瘤的理想候选者。我们有足够的需求来第二次- 具有更好药代动力学特性和更安全毒性的ERSO治疗ER-α- 癌症呈阳性。计划的工作(F99阶段)包括合成更多ERSO的极性衍生物，这将 在机理研究、体内耐受性、血脑屏障穿透和疗效模型中进行评估。 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 毒性描述，使它们的翻译潜力能够解决ERα阳性癌症的治疗。 虽然靶向抗癌治疗已经改变了挑战癌症的临床格局，但肝细胞癌 癌症仍然具有很高的致命性，死亡率和发病率呈上升趋势。肝细胞癌的异质性很大 在TERT和CTNNB1中发现唯一保守的驱动程序突变的疾病，目前位于 “无法下药”的目标空间。在这里，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 对CTNNB1致癌成瘾的研究，并建议进行深入的细胞研究来诠释CTNNB1 MAI的影响 致癌代谢(K00期)。这一探索将为潜在的治疗靶点提供洞察。 用于治疗肝细胞癌。 这些F99/K00建议书寻求提供全面、深入的技能集，为我作为一名 独立PI。具体地说，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。计划中的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 阐明关于基础癌症生物学的结论。完成这项培训将产生强大的 为我的临床肿瘤学开发新型翻译解决方案奠定了基础。