Developmental therapy for selectively targeting MEK-ERK pathway in cancer cells and tumor stromal compartment

选择性靶向癌细胞和肿瘤基质室中 MEK-ERK 通路的发育疗法

• 批准号: 10589930
• 负责人: Shihui Liu
• 金额: $ 44.32万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-07 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589930
• 关键词: Address; Antigens; Antitumor Response; B-Lymphocytes; BRAF gene; Binding; Biodistribution; Blood capillaries; Brain; Cell Proliferation; Cell Survival; Cells; Cytosol; Data; Development; Developmental Therapeutics Program; Endothelial Cells; Engineering; Ensure; FDA approved; Fibroblasts; Future; Genetic; Goals; Human; KRAS2 gene; Link; MAP Kinase Gene; MAP2K1 gene; MAPK8 gene; MEK inhibition; MEKs; Malignant Neoplasms; Matrix Metalloproteinases; Metastatic Melanoma; Modeling; Molecular; Morphogenesis; Mus; Mutation; Names; Normal Cell; Oncogenic; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Physiological; Proteins; Ras/Raf; Regulatory T-Lymphocyte; Role; Signal Transduction; Solid Neoplasm; Specificity; Stromal Cells; Stromal Neoplasm; System; Targeted Toxins; Therapeutic; Therapeutic Index; Tissues; Toxic effect; Toxin; Tumor-associated macrophages; Urokinase; Variant; anthrax lethal factor; anthrax toxin; anthrax toxin receptors; cancer cell; carcinogenicity; cell type; clinical development; clinical efficacy; driver mutation; gain of function; genetic manipulation; in vivo; inhibitor; insight; lethal factor; loss of function; microbial; neoplastic cell; novel; p38 Mitogen Activated Protein Kinase; pathogenic bacteria; pre-clinical; receptor; side effect; small molecule; small molecule inhibitor; small molecule therapeutics; targeted treatment; therapeutic development; tumor; tumor microenvironment; tumor specificity; tumorigenesis

Project Summary/Abstract Carcinogenic mutations in the RAS-RAF-MEK-ERK pathway are present in 46% of all human cancers. This has inspired the successful development of many small molecule BRAF and MEK pathway inhibitors. These agents are currently FDA approved for the treatment of metastatic melanomas containing BRAF mutations. Although BRAF and MEK inhibitors have shown some benefits to patients, these “targeted” therapeutics have a very low therapeutic index, since these small molecules also target normal cells, causing undesirable, even fatal, side effects. Moreover, whether the clinical efficacy of these inhibitors is via direct effects on the tumor or through modulation of the tumor stromal compartment remains elusive. In this application, we address the above critical unmet needs and will develop a potent and highly tumor-selective MEK inactivator by engineering an anthrax toxin-based protein delivery system. Through manipulating the expression of the toxin receptor on specific tumor stromal cell types, we will also delineate how stromal MEK inhibition regulates tumor development. We propose two parallel, but independent Specific Aims to achieve these goals. In Aim 1, we will generate an anthrax toxin-based, highly tumor-selective MEK inactivator and evaluate its anti-tumor activity in a variety of tumor models. This MEK inactivator specifically binds to the major toxin receptor CMG2 (capillary morphogenesis protein-2) on tumor cells and tumor stromal cells. Specificity is ensured through strict reliance on the simultaneous presence of two distinct tumor-associated proteases, MMPs and urokinase, to gain entry into tumor cells and tumor stromal cells. Once inside, it inactivates MEK-ERK signaling, achieving potent selective targeting. In Aim 2, we will employ our unique tumor-host-toxin system to determine the roles of MEK-ERK signaling in tumor stromal cells in tumor development and in the toxin’s tumor targeting. We have previously established a genetic system allowing CMG2 gain-of-function or loss-of-function in various specific cell types in the tumor microenvironment. Thus, we hypothesize that a genetic manipulation of CMG2 expression on cancer cells and various tumor stromal cells in the whole body of CMG2-/- mice will provide the first tractable genetic system to delineate the role of specific cell types in the tumor microenvironment. Therefore, in this Aim 2, we will determine the roles of selected tumor stromal cell types including tumor endothelial cells (EC), tumor-associated macrophages (TAM), cancer-associated fibroblasts (CAF), B cells, and regulatory T cells (Treg), and the molecular mechanisms of MEK-ERK inhibition in these cells in tumor development. Upon completion of these studies, we expect to have developed a highly potent, tumor-selective MEK inactivator as a novel tumor-targeted therapeutic. These studies will also unambiguously determine the role of MEK-ERK signaling in both the tumor and the stroma, thereby validating and identifying specific tumor stromal cell types as targets for future therapeutics development.

项目概要/摘要 46% 的人类癌症中存在 RAS-RAF-MEK-ERK 通路的致癌突变。这有 启发了许多小分子 BRAF 和 MEK 通路抑制剂的成功开发。这些代理 目前 FDA 批准用于治疗含有 BRAF 突变的转移性黑色素瘤。虽然 BRAF 和 MEK 抑制剂已显示出对患者的一些益处，这些“靶向”疗法的副作用非常低 治疗指数，因为这些小分子也针对正常细胞，导致不良甚至致命的副作用 影响。此外，这些抑制剂的临床功效是通过直接作用于肿瘤还是通过 肿瘤基质区室的调节仍然难以捉摸。在此应用中，我们解决了上述关键问题 未满足的需求，并将通过设计炭疽来开发一种有效的、高度肿瘤选择性的 MEK 灭活剂 基于毒素的蛋白质递送系统。通过操纵特定肿瘤上毒素受体的表达 基质细胞类型，我们还将描述基质 MEK 抑制如何调节肿瘤发展。 我们提出两个平行但独立的具体目标来实现这些目标。在目标 1 中，我们将生成一个 基于炭疽毒素的高度肿瘤选择性 MEK 灭活剂，并评估其在多种肿瘤中的抗肿瘤活性 肿瘤模型。这种 MEK 灭活剂特异性结合主要毒素受体 CMG2（毛细血管形态发生） 蛋白-2)对肿瘤细胞和肿瘤基质细胞的影响。通过严格依赖来确保特异性 同时存在两种不同的肿瘤相关蛋白酶：MMP 和尿激酶，以进入肿瘤 细胞和肿瘤基质细胞。一旦进入，它就会使 MEK-ERK 信号失活，从而实现有效的选择性靶向。 在目标 2 中，我们将利用我们独特的肿瘤-宿主-毒素系统来确定 MEK-ERK 信号在 肿瘤基质细胞在肿瘤发展和毒素肿瘤靶向中的作用。我们之前已经建立了一个 允许 CMG2 在肿瘤中各种特定细胞类型中获得功能或丧失功能的遗传系统 微环境。因此，我们假设癌细胞上 CMG2 表达的基因操作和 CMG2-/-小鼠全身的各种肿瘤基质细胞将提供第一个易于处理的遗传系统 描述特定细胞类型在肿瘤微环境中的作用。因此，在这个目标 2 中，我们将确定 选定肿瘤基质细胞类型的作用，包括肿瘤内皮细胞 (EC)、肿瘤相关细胞 巨噬细胞 (TAM)、癌症相关成纤维细胞 (CAF)、B 细胞和调节性 T 细胞 (Treg) 以及 MEK-ERK 在肿瘤发展过程中抑制这些细胞的分子机制。完成这些后 通过研究，我们期望开发出一种高效的肿瘤选择性 MEK 灭活剂，作为一种新型肿瘤靶向药物 治疗性的。这些研究还将明确确定 MEK-ERK 信号在肿瘤中的作用 和基质，从而验证和识别特定的肿瘤基质细胞类型作为未来的目标 治疗学的发展。