Precision medicine for pancreatic cancer. Biomarker-guided drug delivery of platinum to tumors

This project proposes to study the effects of new platinum anticancer drugs in pancreatic cancer. We suggest that the unique combination of two research areas - the implication of the glycocalyx in modification of the tumor extracellular matrix and the correlation of sensitivity of certain platinum agents with the glycosaminoglycan (GAG) status of the tumor – creates a unique profile amongst not just platinum agents but all currently used clinical anticancer drugs. The critical unmet need in the treatment of pancreatic cancer is two-fold: 1) therapeutics to effectively treat drug resistant disease and 2) predictive biomarkers to identify which patients will benefit most from the available therapies. Among chemotherapeutic drugs, platinum derivatives have a major importance in the therapeutic arsenal and oxaliplatin is a critical component of the FOLFIRINOX regimen for treatment of pancreatic cancer. Our studies show that tumors expressing high levels of chondroitin-4-sulfate (C4S) can be exploited for enhanced cellular accumulation and tumor delivery of the Phase II polynuclear platinum complex (PPC, specifically Triplatin) in breast and ovarian cancer PDX models because of the high affinity of the highly cationic drug to the highly negative GAGs, a property not shared by mononuclear oxaliplatin. Biomarkers to predict durable response to this drug were not available then, and further development of Triplatin was suspended. Recently, we have demonstrated that Triplatin could be superior to the main line platinums against tumors expressing high levels of chondroitin-4-sulfate (C4S). C4S is a tumor-specific glycosaminoglycan (GAG) attached to proteoglycans such as CD44, glypicans and syndecans, expressed on the cell surface and in tumor stroma. The positive charge of Triplatin increases its affinity to the negatively charged GAG, which facilitates the drug accumulation in the tumor cells and increases the level of Pt-DNA adducts. Interestingly, we noted that carboplatin follows an opposite trend. Together, our studies support the premise that GAG levels can predict carboplatin resistance and Triplatin sensitivity. Our central hypothesis is that high GAG levels in pancreatic cancer can be exploited to increase Triplatin uptake and improve the efficacy of current treatment regimens. A large research effort is ongoing to understand factors that influence the tumor response to therapy and to evaluate strategies to overcome the treatment failure caused by intrinsic or acquired resistance. Studies aimed at identification of the treatment targets for pancreatic cancer have mainly focused on mRNAs, miRNAs, and proteins, while carbohydrates, such as GAGs, remain relatively unexplored. The non-template driven nature of GAG biosynthesis involves a concerted action of multiple enzymes, complicating the analysis of expression at the genomic/proteomic level and their role in clinical oncology. New technologies, such as glycan reductive isotope labeling mass spectrometry (GRIL-MS), allow for quantitative and compositional analysis of GAGs in tumor samples. Proof of this concept will pave the way for repurposing Triplatin for companion biomarker- informed clinical trials.