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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，但有效的治疗仍然难以捉摸。因此，我们认为，我们的长期目标是解决对更有针对性的治疗转移性肿瘤的策略的关键需求。疾病Rho家族GTP酶Rac和Cdc 42及其下游效应子p21激活激酶（PAK）是转移性癌细胞迁移和侵袭的关键调节剂;因此，代表了预防转移。Rac和Cdc 42不必在癌症中过表达以驱动转移，因为它们可以被致癌细胞表面受体信号通路过度激活。所以我们开发了MBQ-167，它通过阻断GTP交换抑制Rac和Cdc 42的激活，而不影响表情MBQ-167上级于其它已知的Rac/Cdc 42抑制剂，并抑制细胞和肿瘤生长，乳腺癌和胰腺癌细胞和小鼠模型中的转移和存活生理浓度。此外，MBQ-167在啮齿类动物和犬中均具有优异的安全性（两者均为非GLP和已完成的GLP研究）高达1000 mg/kg体重，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（IND提交给US FDA）。该应用程序的基本原理源于 PI的SC 3 GM 084824奖（2008-2022），导致约25篇出版物，3项专利，8名博士毕业。学生，并培养了许多研究生和本科生，所有这些都是代表性不足少数群体在SC 3奖项的当前周期中，我们鉴定了两种新的Rac/Cdc 42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。该SuRE提案将测试Rac/Cdc 42抑制剂是可行的抗转移癌症的假设乳腺癌和胰腺癌的治疗。目的1将证明其有效性、安全性和生物利用度 Rac/Cdc 42抑制剂MBQ-168和EHop-097在临床前小鼠模型中的化学发光荧光素酶标记的乳腺癌和胰腺癌细胞在小鼠中的自发和实验成像转移测定。目的2将证明Rac/Cdc 42抑制剂在大肠杆菌的离体培养物中的功效。患者组织。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，以测试癌细胞增殖，免疫细胞浸润，和短期媒介物、MBQ-167、MBQ-168或EHop-097处理后的抑制剂功效。药物疗效将通过以下方法原位评估癌细胞和浸润肿瘤微环境（TME）的免疫细胞：免疫组织化学，使用Rac/Cdc 42功效的药效学标志物的特异性抗体，以及作为TME中的免疫细胞。本研究的结果将描述Rac/Cdc 42的复杂作用抑制剂在实验小鼠模型和患者组织中的表达，并促进胰腺癌和乳腺癌中的Rac/Cdc 42抑制剂此外，研究生、本科生和医学生将接受尖端技术和癌症药物开发概念的培训。