Sensitization of Therapeutic-Resistant Pancreatic Cancer by Cancer Cell-Specific Drug Delivery
Abstract
The proposed research project addresses the Topic Area of pancreatic cancer and the Military Relevance Focus Area of “gaps in cancer prevention, early detection/diagnosis, prognosis, treatment, and/or survivorship that may affect the general population but have a particular profound impact on the health and well-being of active duty Service members, Veterans, and their beneficiaries.” Pancreatic ductal adenocarcinoma (PDAC) is the deadliest cancer in humans, with a mere 7% 5-year survival rate. Unlike other solid tumors, since Nixon declared the war against cancer in 1971, the prognosis of PDAC has not shown much change (The Economist, Technology Quarterly, Targeting Tumors, September 16, 2017), suggesting new dramatic and innovative approaches are needed to make a difference of this cancer in men and women in active Service members, Veterans, and their beneficiaries since they are at an increased risk of the disease. The dismal prognosis of PDAC reveals the challenging features of this disease including the acquired stemness and resistance to conventional therapies, reciprocal interactions between tumor and host microenvironment, increased intra-tumoral pressure that impedes drug uptake and retention, and the lack of early diagnostic biomarkers that can diagnose PDAC early and accurately. In this proposal, we are addressing all these challenges by proposing a novel sensitization protocol of PDAC cells to conventional therapy, by probing the mechanisms of sensitization and cell death involving mitochondrial and lysosomal organelles, and developing a companion peptide diagnostic/monitoring biomarker, to detect PDAC earlier and accurately, and tracking therapeutic responsiveness using newly developed PDAC cell model systems that closely mimic PDAC patients. This Translational Team Science Award application is prepared by investigators from our current PDAC working group consisting of Drs. Leland W. K. Chung, Stephen Pandol from Cedars-Sinai Medical Center/UCLA and James Tomlinson from the VA Greater Los Angeles Health Care System/UCLA. Unique attributes of this research include: (1) developing new PDAC cell lines and xenograft models that closely mimic the patients; (2) testing sensitization mechanisms of a new cholesterol lowering simvastatin (SIM), delivered as a conjugate with a near-infrared dye, HMCD, that delivers SIM exclusively into cancer cells bypassing its action on host liver; (3) analyzing mitochondrial and lysosomal involvement and sonic hedgehog (Shh)-mediated paracrine communication between tumor-stroma as promising new targets, previously unexamined, for cancer therapy; and (4) validating a new peptide-based serum biomarker, GASP-1, as a companion diagnostic and monitoring tool for therapeutic responsiveness of the PDAC. The overall objectives of this proposal are: (1) Assess HMCD-SIM re-sensitization of PDAC tumors shown to become resistant to gemcitabine (GEM), paclitaxel (PTX), cisplatin (CDDP), or tyrosine kinase inhibitors (TKIs) in PDAC cells and xenograft tumors in mouse models. (2) Determine whether the main HMCD-SIM sensitizing mechanism acts by compromising mitochondria and lysosome function, or through cholesterol-mediated intracellular hedgehog signal transduction and cancer-stromal interaction or both. The above objectives will be accomplished by two aims: (1) To validate HMCD-SIM as a promising new drug for PDAC targeting and therapeutic sensitization. We will determine the therapeutic efficacy of HMCD-SIM on newly established PDAC cell lines and xenograft models that mimic closely the tumors in patients. We will examine re-sensitization of GEM, PTX, CDDP, and TKIs-resistant PDAC cells by HMCD-SIM, and we will validate the effectiveness of sera GASP-1 peptide as a companion diagnosis and therapeutic responsiveness biomarker in clinically relevant PDAC models. (2) To determine the mechanisms of HMCD-SIM-mediated cancer cell kill and therapeutic sensitization. We will focus o
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810446
Entities
People
- Leland Chung
Organizations
- Cedars-Sinai Medical Center
- United States Army