Surrogate imaging biomarkers for tracking anti-stromal therapy

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Pancreatic ductal adenocarcinoma (PDA) is a common and lethal disease, with a 5-year survival rate of less than 6%. The unique tumor microenvironment prevents the disease from being eradicated, even when surgery is combined with chemotherapy. Specifically, the absence of a functional vasculature and the build-up of dense stromal regions impede drug delivery. Consequently, several researchers are actively developing therapies to improve drug delivery. Besides improving drug delivery, we should also track cancer cell growth and other features of the tumor microenvironment. We hypothesize that information about changes in stromal stiffness, cancer cell growth, and drug delivery will help clinical researchers evaluate novel therapies that improves drug delivery, such as radiotherapy and immunotherapy or hyaluronic acid ablation. Since vascular imaging techniques (e.g., MRI and CT) cannot provide this data, we will develop an integrated system of shear wave ultrasound elastography (USE) and optical fluorescence tomography (OFT). We will conduct this work in two phases. In the first phase, we will develop the integrated USE/OFT system (Aim 1). This hybrid system will provide co-registered images of shear modulus, which is related to total tissue pressure and drug delivery. We will use three models (an orthotopic pancreas xenograft model, a transgenic spontaneous tumor model, and a murine pancreatic cancer model) to characterize and optimize the system's performance in vivo. The xenograft AsPC-1 model is well-controlled with 5-25% stromal content and low vascular space (< 0.5%) when grown in the pancreas. We will also use the transgenic murine model, which more closely recapitulates the molecular phenotype of human PDA to validate performance (Aim 2). The murine pancreatic model will be used to study the efficacy of different therapeutic approaches for improving drug delivery. In these studies, we will assess the sensitivity of the proposed system to changes in mechanical properties and vascular permeability during the growth phase of PDA, as well as during hyaluronidase enzymatic treatment of the extracellular matrix and combinational therapy (immuno-enhanced radiotherapy). In the second phase (Aim 3), we will (a) translate the USE and OFT technology to an endoscopic platform; and (b) conduct preliminary safety and efficacy evaluation in a rabbit model of pancreatic cancer to prepare for human use. This last aim will provide data required to file an Investigational New Drug (IND) application with the Food and Drug Administration (FDA), and for human use with the local Institutional Review Board (IRB) to monitor changes in tumor microenvironment during combinational therapies as assessed here pre-clinically. The proposed team includes expertise in elastography, ultrasound transducer design, OFT, PDA models, and human pancreatic cancer. Together this is an ideal group to translate the technology through the research phase and into an alpha commercial prototype for clinical trials.