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

基本信息

批准号：
10092258
负责人：
Shihui Liu
金额：
$ 42.9万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/10092258
关键词：
ANTXR2 gene 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 Pathway interactions Patients Peptide Hydrolases Physiological Proteins Ras/Raf Regulatory T-Lymphocyte Role Side Signal Transduction Solid Neoplasm Specificity Stromal Cells Stromal Neoplasm Structure System Targeted Toxins Therapeutic Therapeutic Index Tissues Toxic effect Toxin Tumor-associated macrophages Urokinase Variant anthrax lethal factor anthrax toxin anthrax toxin receptors base cancer cell carcinogenicity cell type clinical development clinical efficacy driver mutation gain of function genetic manipulation in vivo inhibitor/antagonist insight 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 tumorigenesis

项目摘要

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.

项目摘要/摘要 RAS-RAF-MEK-ERK途径中的致癌突变列出了46％的所有人类癌症。这就是启发了许多小分子BRAF和MEK途径抑制剂的成功发展。这些代理目前已批准用于治疗含有BRAF突变的转移性黑色素瘤。虽然 BRAF和MEK抑制剂对患者表现出了一些好处，这些“靶向”疗法非常低治疗指数，因为这些小分子也靶向正常细胞，导致不良，甚至致命的侧面效果。此外，这些抑制剂的临床有效性是通过对肿瘤的直接影响还是通过肿瘤基质室的调节仍然难以捉摸。在此应用程序中，我们解决以上关键未满足的需求，并将通过工程炭疽而产生潜在的肿瘤选择性MEK灭活剂基于毒素的蛋白质递送系统。通过操纵毒素受体在特定肿瘤上的表达基质细胞类型，我们还将描绘基质MEK抑制如何调节肿瘤的发育。我们提出了两个平行的，但独立的特定目的旨在实现这些目标。在AIM 1中，我们将产生一个基于炭疽毒素的高度肿瘤选择MEK灭活剂，并评估其在各种抗肿瘤活性肿瘤模型。这种MEK灭活剂特异性结合了主要的毒素受体CMG2（毛细管形态发生）蛋白-2）在肿瘤细胞和肿瘤基质细胞上。通过严格保留对同时存在两个不同肿瘤相关的蛋白酶MMP和尿激酶，以进入肿瘤细胞和肿瘤基质细胞。进入内部后，它会使MEK-ERK信号传导失活，从而实现潜在的选择性靶向。在AIM 2中，我们将采用我们独特的肿瘤宿主 - 毒素系统来确定MEK-ERK信号的作用肿瘤间基质细胞在肿瘤发育和毒素的肿瘤靶向中。我们以前已经建立了在肿瘤中各种特定细胞类型中允许CMG2功能获得或功能丧失的遗传系统微环境。这是，我们假设在癌细胞和 CMG2 - / - 小鼠整个体内的各种肿瘤基质细胞将提供第一个可探讨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，我们将确定选定的肿瘤基质细胞类型（包括肿瘤内皮细胞（EC））的作用，肿瘤相关巨噬细胞（TAM），癌症相关的成纤维细胞（CAF），B细胞和调节性T细胞（Treg）和这些细胞中MEK-ERK抑制在肿瘤发育中的分子机制。这些完成后研究，我们希望作为一种新型肿瘤靶向的高潜力，肿瘤选择性MEK灭活剂治疗性。这些研究还将明确确定MEK-ERK信号在两个肿瘤中的作用以及基质，从而验证和识别特定的肿瘤基质细胞类型作为未来的靶标治疗性开发。