MBQ-167 derivatives as antimetastatic cancer agents. - MBQ-167 derivatives as antimetastatic cancer agents 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. Therefore, we developed MBQ-167, which inhibits Rac and Cdc42 activation and consequently inhibits cancer cell and tumor growth, metastasis and survival of metastases in breast and pancreatic cancer cell and mouse models at low physiological concentrations. This proposal will investigate two new Rac/Cdc42 inhibitors with enhanced efficacy compared to MBQ-167. We will test the HYPOTHSIS that Rac/Cdc42 inhibitors are viable antimetastatic therapeutics in pancreatic cancer. Aim 1 will demonstrate the efficacy, safety, and bioavailability of Rac/Cdc42 inhibitors in pre-clinical mouse models. Aim 2 will demonstrate the efficacy of Rac/Cdc42 inhibitors in ex vivo cultures of patient tissues. Our innovative research design will use fresh pancreatic cancer patient tissue (from biopsies and surgery) to test for changes in cancer cell proliferation, immune cell infiltration, and inhibitor efficacy following short-term vehicle, or Rac/Cdc42 inhibitor treatment. Drug efficacy in cancer cells and the immune cells infiltrating the tumor microenvironment will be assessed via immunohistochemistry, using specific antibodies to pharmacodynamic markers of Rac/Cdc42 efficacy, as well as immune cells in the tumor tissue. The OUTCOME of this study will forward the translational development of Rac/Cdc42 inhibitors in pancreatic cancer, for which there are no effective targeted therapies. Moreover, graduate, undergraduate, and medical students will be trained in cutting edge techniques and concepts of cancer drug development.
