Simultaneous targeting stroma and tumor cell compartments alleviates hypoxia, reduces inflammatory response, and enhances anti-PDAC therapy in KPC mice
Jun Zhao1, Huamin Wang2, Cheng-Hui Hsiao3, Diana Chow3, Yaan Kang4, Anirban Maitra2, David Piwnica-Worms1, Jason Fleming4, Chun Li1*
Departments of 1Cancer Systems Imaging, 2Pathology, and 3Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
3Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas 77030
Patients with pancreatic ductal adenocarcinoma (PDAC) currently face a dismal prognosis. Chemotherapy and radiotherapy for PDAC is not very effective in large part because the desmoplastic microenvironment of PDAC tumors limits the blood supply to tumor cells, thereby limiting drug delivery to tumors. Recent efforts have been focused on modulating cancer associated fibroblasts to remodel stroma and to enhance chemotherapy and radiotherapy. We have exploited the use of nanoparticles to enable simultaneous delivery of 2 drugs directed at stroma component and tumor cells in PDAC. We found that in a GEMM model of PDAC (KPC mice), treatment with our nano drug significantly reduced hyaluronic acid deposition in the tumor microenvironment, reduced inflammatory response, increased tumor microvessel density and alleviated hypoxia, and increased tumor infiltration of T cells. The treatment also significantly prolonged the survival of KPC mice with an early treatment protocol and a late treatment protocol compared to gemcitabine or abraxane treatments. Our data suggest that multifunctional nanoparticles directed at multiple cellular targets could enhance the efficacy of systemic treatments for PDAC and therefore is a potentially viable therapeutic strategy. This approach potentially may be used in combination with checkpoint inhibitors to enhance therapeutic effect against PDAC.
Acknowledgement: Supported in part by John S. Dunn Foundation and Gillson Longenbaugh Foundation