Experimental Models for Testing Novel Targets for Pancreatic Cancer Cell Invasion

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DESCRIPTION (provided by applicant): Pancreatic cancer has the poorest survival of any intra-abdominal malignancy. Because of the inability to detect it at an early stage, the disease is often far advanced by the time the diagnosis is made. Better understanding of the cellular and molecular mechanisms involved in pancreatic tumor growth and metastasis is urgently needed to promote treatment of this disease. Malignancy is associated with a hypercoagulable state and high risk for thromboembolic complications. Activation of blood coagulation in cancer is a complex phenomenon, involving many different pathways of the hemostatic system. In this Exploratory Grant we will study the process of pancreatic tumor metastasis using a novel in vitro human vessel segment perfusion model developed in our laboratory to test compounds for efficacy in preventing the initial steps of tumor cell invasion into the vascular wall. Human umbilical vein segments will be perfused with autologous platelet-rich plasma containing pancreatic cancer cells. Attachment or invasion into the vessel segments will be quantified by microscopic observation. To validate the findings from the in vitro vessel segment model we will utilize an in vivo mouse model of spontaneous pancreatic metastasis. Test agents to be investigated are low molecular weight heparin compounds (LMWH), utilized in the presence or absence of chemotherapeutic agent Gemcitabine, to determine if they can enhance the anti-metastatic activities of this agent. Specifically, agents to be tested are commercially available LMWH Tinzaparin and non-anticoagulant LMWH (NACH). This NACH has limited to no systemic anticoagulant effects and limited effects on hemostasis. Correlations between the efficacies of agents in the vessel segments model to limit tumor cell invasion with subsequent protection against metastasis in the in vivo model would confirm the value of this model for predicting metastatic behavior of tumor cells and for screening compounds to prevent tumor cell invasion as a pre-requisite for tumor metastasis. There is crucial need for an improved management of both cancer and thrombosis in cancer patients. This exploratory grant utilizes innovative approaches that will be applicable to various tumor types by focusing on the screening and the evaluation of an effective treatment with LMWHs, alone or in combination with chemotherapeutic agents in the treatment of metastatic pancreatic cancer. Cancer patients often show abnormalities in processes associated with blood clotting that can worsen tumor growth and lead to metastatic spread of the cancer. Treatment with low molecular weight heparin compounds (LMWH) is associated with significant survival advantage in some patients but sometimes causes increases in bleeding times. This exploratory grant utilizes innovative approaches by focusing on the screening and the evaluation of an effective treatment with LMWHs (one, with limited effects on bleeding), alone or in combination with chemotherapeutic agents for the treatment of metastatic pancreatic cancer.