Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy and the fourth leading cause of cancer deaths in the United States. Surgical resection is the only known curative treatment for pancreatic cancer. However, only 15-20% of patients present with operable disease;all others have locally advanced or metastatic disease. Additionally, recurrence post-surgery is frequently observed, most often in the liver. We and others have shown that tumor-initiated myeloid cell recruitment from the bone marrow to the tumor site results in promotion of tumor growth and dissemination, as well as suppression of anti-tumor immune responses. We now have data showing inflammatory monocyte (IM) and macrophage prevalence in the blood and tumor, respectively, is predictive of survival. Our studies show that blockade of bone-marrow mobilization or peripheral depletion of IM can slow tumor growth and prolong survival in murine pancreas cancer models. Thus, our central hypothesis is that selective targeting of key regulators involved in the mobilization and traffickig of IM holds significant promise for the treatment of pancreas cancer. The CCL2/CCR2 chemokine/receptor pathway appears critical for IM mobilization and recruitment to the tumor. Recruitment of IM to the tumor and tumor growth is significantly reduced in mice lacking CCR2 as well as in mice treated with an orally active CCR2 antagonist. Based on these compelling data we initiated a phase I clinical trial in patients with locally-advanced, unresectable pancreas cancer.
In Aim 1 we propose to determine if targeting CCR2 signaling through the CCR2 antagonist enhances the efficacy of chemotherapy in patients with locally- advanced, unresectable pancreas cancer. We will explore whether CCR2 blockade reduces recruitment and function of myeloid cells in the bone marrow, periphery and tumor;whether the immune suppressor/effector ratio is altered in the tumor microenvironment, and whether any of these changes correlate with survival. In addition to the clinical trial we propose several pre-clinical studies in an orthotopic mouse model of pancreatic cancer to elucidate the mechanism and determine the optimal clinical setting for targeting CCR2/CCL2 in pancreatic cancer.
In Aim 2 we will determine if CCR2/CCL2 inhibition blocks mobilization of IM from the bone marrow to the primary tumor site in an orthotopic murine model of pancreas cancer. Using flow cytometry, immune cell depletion and gene expression analysis, we will determine which immune cell subset(s) is responsible for the antitumor effect of CCR2 inhibition. To define the role of IM in initiation and propagation of metastasis we will determine in Aim 3 if CCR2/CCL2 inhibition decreases tumor growth and distant spread in an orthotopic, metastatic model of pancreas cancer. Finally, optimal integration of CCR2 blockade with chemotherapy will be assessed in Aim 4 to allow for the rational design of combination therapy in subsequent clinical trials.
Pancreatic cancer is a deadly disease for which there is currently no effective treatment other than surgery. We propose to test a novel drug that effectively reduces tumor growth in preclinical animal studies. This drug will be tested in a phase I clinical trial in combination with chemotherapy in patients with locally advanced, unresectable patients. Additionally, we propose pre-clinical studies in mice to determine the optimal clinical setting for the drug.
|Nywening, Timothy M; Wang-Gillam, Andrea; Sanford, Dominic E et al. (2016) Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol 17:651-62|
|Connolly, Kelli A; Belt, Brian A; Figueroa, Nathania M et al. (2016) Increasing the efficacy of radiotherapy by modulating the CCR2/CCR5 chemokine axes. Oncotarget 7:86522-86535|
|Zhu, Yu; Knolhoff, Brett L; Meyer, Melissa A et al. (2014) CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res 74:5057-69|
|Panni, Roheena Z; Linehan, David C; DeNardo, David G (2013) Targeting tumor-infiltrating macrophages to combat cancer. Immunotherapy 5:1075-87|