Ex vivo slice cultures of mouse pancreatic tumors to test novel regimens

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While chemotherapy remains the standard treatment, there is an increasing interest in developing novel regimens for pancreatic ductal adenocarcinoma (PDAC). Novel regimens, such as the combination of BET and HDAC inhibitors targeting epigenetic changes, are often tested initially in mouse models. However, mouse models have several limitations. With an ever-increasing number of drugs being developed for cancer, how best to evaluate these drugs in mouse models, either alone or in combination regimens, can also be quite daunting. Recently, ex vivo tissue slices of human tumors have been utilized for therapeutic studies, but one of the significant challenges of slice cultures with human PDAC tumors is the limited availability of fresh human PDAC tumors for research studies. As there is an urgent need to identify effective regimens for PDAC patients, slice cultures from PDAC tumors developing in transgenic mouse models may overcome the limitations of both mouse models and ex vivo slice cultures of human PDAC tumors. The main objective in this application is to validate slice cultures from PDAC tumors developing in transgenic mouse models as a means of testing novel regimens for pancreatic cancer. The central hypothesis is that slice cultures established from mouse PDAC tumors will readily allow the testing of novel regimens for pancreatic cancer. The rationale for the proposed research is that validating slice cultures from mouse PDAC tumors will accelerate the screening and identification of novel regimens for PDAC patients. Two specific aims are proposed: 1) Validate ex vivo slice cultures established from mouse PDAC tumors by testing approved chemotherapies. 2) Validate ex vivo slice cultures established from mouse PDAC tumors by testing the combination of BET and HDAC inhibitors. Under the first aim, chemotherapy regimens that have previously been shown to be effective in vivo in mouse models and human PDAC tumors will be tested in ex vivo slice cultures of tumors established from three different transgenic mouse models of PDAC. In addition, we will evaluate the effectiveness of adding targeted inhibitors to chemotherapy in ex vivo slice cultures of PDAC tumors from transgenic mice. In the second aim, the combination of BET and HDAC inhibitors will be tested in ex vivo slice cultures of tumors established from three different transgenic mouse models of PDAC. In addition, we will evaluate the relative efficacy of combining BET inhibitors with chemotherapy in the ex vivo tumor slice cultures. There are several innovative elements in this proposal, including the novel concept of using ex vivo slice cultures of mouse tumors to test various combination therapies for PDAC. This proposed research is significant because validating ex vivo slice cultures of mouse tumors to identify novel regimens will have important clinical-translational implications for PDAC patients.