MBQ-167 derivatives as antimetastatic cancer agents.

MBQ-167 衍生物作为抗转移癌药物。

基本信息

批准号：
10628411
负责人：
SURANGANIE DHARMAWARDHANE
金额：
$ 8.94万
依托单位：
UNIVERSITY OF PUERTO RICO MED SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-02 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10628411
关键词：
Address Affect Animal Model Antibodies Antineoplastic Agents Authorship Award Biological Biological Assay Biological Availability Biopsy Biotechnology Body Weight Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Cancer Etiology Canis familiaris Carcinoma Cell Line Cell Proliferation Cell Surface Receptors Cell model Cells Cessation of life Colon Complex Data Development Diagnostic Disease Disseminated Malignant Neoplasm Distant Metastasis Doctor of Philosophy Drops Drug Kinetics Environment Evaluation Family Goals Guanine Nucleotide Exchange Factors Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Image Immune Immunofluorescence Immunologic Immunohistochemistry In Situ Injections Invaded Lead Legal patent Luciferases MDA MB 231 MDA-MB-468 Malignant Neoplasms Malignant neoplasm of pancreas Medical Students Mentors Metastatic breast cancer Mus Mutate Neoplasm Metastasis Oncogenic Operative Surgical Procedures Outcome Outcome Study Parents Patients Pharmacodynamics Physiological Plasma Productivity Prognosis Publications Puerto Rico Rattus Research Research Design Resistance Rodent Safety Signal Pathway Students Survival Rate Tail Techniques Testing Therapeutic Tissues Toxic effect Training Tumor Tissue Tumor-infiltrating immune cells Underrepresented Minority Universities Validation Veins biomarker selection breast cancer progression cancer cell cancer stem cell cancer subtypes cell growth cell motility commercialization comparative efficacy design doctoral student drug development drug efficacy drug testing effective therapy graduate student immune cell infiltrate in vivo inhibitor innovation malignant breast neoplasm medical schools metastasis prevention mortality mouse model new therapeutic target novel therapeutics overexpression p21 activated kinase pancreatic cancer cells pancreatic cancer patients pancreatic neoplasm pharmacodynamic biomarker phase I trial pre-clinical prevent programs rac GTP-Binding Proteins rho skill acquisition stem student training subcutaneous targeted treatment therapy resistant triple-negative invasive breast carcinoma tumor growth tumor microenvironment undergraduate student

项目摘要

Metastatic disease is the primary cause of cancer mortality, but effective treatments remain elusive. Therefore, our LONG-TERM GOAL is to address the CRITICAL NEED for more targeted strategies to treat metastatic disease. The Rho family GTPases Rac and Cdc42 and their downstream effector p21-activated kinase (PAK) are pivotal regulators of metastatic cancer cell migration and invasion; and thus, represent ideal targets for prevention of metastasis. Rac and Cdc42 do not have to be overexpressed in cancer to drive metastasis, because they can be over activated by oncogenic cell surface receptor signaling pathways. Therefore, we developed MBQ-167, which inhibits Rac and Cdc42 activation by blocking GTP exchange without affecting expression. MBQ-167 is superior to other known Rac/Cdc42 inhibitors, and inhibits cell and tumor growth, metastasis and survival of metastases in breast and pancreatic cancer cell and mouse models at low physiological concentrations. Moreover, MBQ-167 has an excellent safety profile in both rodents and dogs (both non-GLP and GLP studies completed) up to 1000 mg/kg body weight and has acceptable bioavailability in rodent and dog plasma and tumor tissue (IND submitted to the US FDA). The rationale for this application stems from the PI’s SC3 GM084824 award (2008-2022), which resulted in ~25 publications, 3 patents, graduated 8 Ph.D. students, and trained numerous graduate and undergraduate students, all of whom are underrepresented minorities. During the present cycle of the SC3 award, we identified two new Rac/Cdc42 inhibitors, MBQ-168 and EHop-097, with enhanced efficacy compared to their respective parent molecules MBQ-167 and EHop-016. This SuRE proposal will test the HYPOTHSIS that Rac/Cdc42 inhibitors are viable antimetastatic cancer therapeutics in breast and pancreatic cancer. Aim 1 will demonstrate the efficacy, safety, and bioavailability of Rac/Cdc42 inhibitors MBQ-168 and EHop-097 in pre-clinical mouse models using chemiluminescence imaging of luciferase tagged breast and pancreatic cancer cells in mice from spontaneous and experimental metastasis assays. Aim 2 will demonstrate the efficacy of Rac/Cdc42 inhibitors in ex vivo cultures of patient tissues. Our innovative research design will use fresh breast and pancreatic cancer patient tissue (from biopsies and surgery), in ex vivo cultures, to test for changes in cancer cell proliferation, immune cell infiltration, and inhibitor efficacy following short-term vehicle, MBQ-167, MBQ-168, or EHop-097 treatment. Drug efficacy in cancer cells and the immune cells infiltrating the tumor microenvironment (TME) will be assessed in situ via immunohistochemistry, using specific antibodies to pharmacodynamic markers of Rac/Cdc42 efficacy, as well as immune cells in the TME. The OUTCOME of this study will delineate the complex action of Rac/Cdc42 inhibitors in experimental mouse models and patient tissues and forward the translational development of Rac/Cdc42 inhibitors in pancreatic and breast cancer. Moreover, graduate, undergraduate, and medical students will be trained in cutting edge techniques and concepts of cancer drug development.

转移性疾病是癌症死亡的主要原因，但有效的治疗方法仍然难以捉摸。我们的长期目标是满足对更有针对性的转移性治疗策略的迫切需求 Rho 家族 GTPases Rac 和 Cdc42 及其下游效应器 p21 激活激酶 (PAK)。是转移性癌细胞迁移和侵袭的关键调节因子；因此，代表了治疗的理想靶点；预防转移 Rac 和 Cdc42 不必在癌症中过度表达即可驱动转移，因为它们可以被致癌细胞表面受体信号通路过度激活。开发了MBQ-167，通过阻断GTP交换来抑制Rac和Cdc42激活而不影响 MBQ-167 优于其他已知的 Rac/Cdc42 抑制剂，并抑制细胞和肿瘤生长，低水平乳腺癌和胰腺癌细胞和小鼠模型中的转移和转移存活此外，MBQ-167 在啮齿动物和狗（两者）中都具有出色的安全性。非 GLP 和已完成的 GLP 研究）高达 1000 mg/kg 体重，并且在啮齿动物中具有可接受的生物利用度以及狗血浆和肿瘤组织（向美国FDA提交的IND）。 PI 的 SC3 GM084824 奖（2008-2022），该奖项产生了约 25 篇出版物，3 项专利，毕业了 8 名博士学位。学生，并培养了众多研究生和本科生，但这些学生的代表性不足在当前的 SC3 奖励周期中，我们确定了两种新的 Rac/Cdc42 抑制剂 MBQ-168。和EHop-097，与它们各自的母体分子MBQ-167和EHop-016相比，具有增强的功效。这项 SuRE 提案将测试 Rac/Cdc42 抑制剂是可行的抗转移癌症的假设目标 1 将证明乳腺癌和胰腺癌的治疗方法的有效性、安全性和生物利用度。使用化学发光在临床前小鼠模型中研究 Rac/Cdc42 抑制剂 MBQ-168 和 EHop-097 小鼠自发性和实验性荧光素酶标记乳腺癌和胰腺癌细胞的成像目标 2 将证明 Rac/Cdc42 抑制剂在离体培养物中的功效。我们的创新研究设计将使用新鲜的乳腺癌和胰腺癌患者组织（来自活组织检查和手术），在离体培养物中，测试癌细胞增殖、免疫细胞浸润的变化，以及短期载体、MBQ-167、MBQ-168 或 EHop-097 治疗后的抑制剂疗效。浸润肿瘤微环境（TME）的癌细胞和免疫细胞将通过以下方式进行原位评估免疫组织化学，使用针对 Rac/Cdc42 功效的药效标记物的特异性抗体，以及作为 TME 中的免疫细胞，本研究的结果将描述 Rac/Cdc42 的复杂作用。实验小鼠模型和患者组织中的抑制剂并推动其转化发展 Rac/Cdc42 抑制剂在胰腺癌和乳腺癌中的应用，适用于研究生、本科生和医学生。将接受癌症药物开发尖端技术和概念的培训。