MBQ-167 derivatives as antimetastatic cancer agents.

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。因此， 我们的长期目标是满足治疗转移性肿瘤的更有针对性的战略的迫切需要。 疾病。Rho家族GTP酶Rac和CDc42及其下游效应蛋白p21激活的蛋白激酶(PAK) 是转移性癌细胞迁移和侵袭的关键调节因子；因此，它们是理想的靶点 防止转移。Rac和CDC42在癌症中不一定要过表达才能促进转移， 因为它们可能被致癌细胞表面受体信号通路过度激活。因此，我们 开发了MBq-167，它通过阻断GTP交换而抑制RAC和CDC42的激活，而不影响 表情。MBQ-167优于其他已知的RAC/CDC42抑制剂，并抑制细胞和肿瘤生长， 低氧条件下乳腺癌、胰腺癌细胞和小鼠转移模型的转移和存活 生理浓度。此外，MBQ-167在啮齿动物和狗(两者)中都具有极好的安全性 非GLP和GLP研究完成)高达1000毫克/公斤体重，在啮齿类动物中具有可接受的生物利用度 以及犬血浆和肿瘤组织(IND提交给美国FDA)。这个应用程序的基本原理源于 Pi的SC3 GM084824奖(2008-2022年)，发表了约25篇论文，获得了3项专利，8名博士毕业。 学生，培养了许多研究生和本科生，他们都没有得到充分的代表 少数族裔。在SC3奖的当前周期中，我们发现了两种新的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相比具有更强的疗效。 这项肯定的提案将检验RAC/Cdc42抑制剂是可行的抗转移癌症的下一步 乳腺癌和胰腺癌的治疗。目标1将展示其有效性、安全性和生物利用度 用化学发光法研究RAC/CDC42抑制剂MBq-168和EHop-097在临床前期小鼠模型中的作用 荧光素酶标记的自发和实验性小鼠乳腺和胰腺癌细胞的显像 转移试验。目的2证实RAC/Cdc42抑制剂在体外培养的人卵巢癌细胞中的作用。 病人的组织。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)，以在体外培养中测试癌细胞增殖、免疫细胞渗透、 以及短期赋形剂、MBq-167、MBq-168或EHop-097处理后的抑制效果。中国的药物疗效 癌细胞和渗入肿瘤微环境的免疫细胞(TME)将通过以下方式进行原位评估 免疫组织化学，也使用RAC/CDC42疗效的药效学标志物的特异性抗体 作为TME中的免疫细胞。这项研究的结果将描绘RAC/CDC42的复杂作用 抑制物在实验小鼠模型和患者组织中的作用，并推动其翻译开发 胰腺癌和乳腺癌中的RAC/CDC42抑制剂。此外，研究生、本科生和医学生 将接受抗癌药物开发的尖端技术和概念方面的培训。

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.