Targeting Oncogenic Drivers in Cancer

项目概要和摘要 靶向雌激素受体α（ERα）是治疗ERα阳性的肿瘤的主要抗癌策略， 乳腺癌然而，目前针对ERα的靶向治疗仅具有细胞抑制活性，并且不诱导快速的细胞凋亡。 定量杀死癌细胞，最终导致耐药性。一种主要的耐药机制是ERα 突变导致组成性激活，驱动肿瘤生长和转移，Y 537 S和D538 G 占驱动突变的大多数。这些耐药肿瘤维持ERα的过表达， 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依赖性预期未折叠蛋白反应 （aUPR）。这种细胞毒活性的力量已经在多个完全根除的例子中观察到 原位和转移性小鼠模型中ERαWT/Mut阳性乳腺肿瘤的表达。虽然有很高的翻译 ErSO的潜力，计划于2020年进行1期临床试验，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物。我们需要第二个- 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- 阳性癌症计划的工作（F99阶段）包括合成更多极性的ErSO衍生物， 在机制研究、体内耐受性、血脑屏障渗透和疗效模型中进行评估。 这些第二代化合物将可能具有增加的生物利用度、最小的神经毒性和更安全的生物利用度。 毒性特征，使其能够用于治疗ERα阳性癌症的转化潜力。 虽然靶向抗癌治疗已经改变了具有挑战性的癌症的临床前景，但肝细胞癌 肝癌（HCC）仍然是高致死性的，死亡率和发病率不断上升。HCC具有很大的异质性 在TERT和CTNNB 1中发现的唯一保守的驱动突变的疾病，目前位于 “无法抵抗”的目标空间。在此，我描述了CTNNB 1突变等位基因失衡（MAI）作为衡量 CTNNB 1致癌成瘾，并提出深入的细胞研究，以注释CTNNB 1 MAI的影响 致癌代谢（K 00期）。这一探索将为潜在的治疗靶点提供见解 用于治疗HCC。 这些F99/K 00的建议寻求产生一个全面的，深入的技能，以准备我作为一个成功的 独立PI具体来说，F99计划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K 00工作将通过管理复杂数据集的新经验扩展我的专业知识 来阐明基本癌症生物学的结论。完成这项培训将产生一个强大的 这是我为临床肿瘤学开发新型转化解决方案的职业生涯的基础。

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.