Abstract 3890: Pharmacodynamic and proteomic analysis of combined gemcitabine/nab-paclitaxel in patient-derived pancreatic cancer xenograft models

Abstract

Abstract Gemcitabine (GEM) combined with albumin-bound paclitaxel nanoparticles (nab-PTX) is the first-line therapy for patients with metastatic pancreatic adenocarcinoma (PDAC). However, the in vivo mechanisms of drug action and interaction have not been investigated quantitatively for this combination. We evaluated the effects of GEM (100 mg/kg iv weekly) and nab-PTX (equivalent to 30 mg/kg PTX iv weekly), alone or combined, on tumor volume progression in 3 patient-derived xenograft (PDX) PDAC models in SCID mice. The MS1-based quantitative proteomic analysis (IonStar), which offers highly reproducible and accurate quantification with extremely low missing data (<0.5%), was conducted on Days 1, 4, and 8 after dosing to evaluate tumor pharmacodynamic responses in protein expression. Proteins were quantified based on species-specific peptides in order to identify responses of the PDAC cells (human) and tumor-associated stromal cells (murine). A population pharmacokinetic/pharmacodynamic model was developed to quantify tumor growth inhibition by the individual and combined drugs. Tumor growth kinetics were described by a composite function of exponential growth transitioning to linear growth. Treatment effects were represented by a 2nd-order, concentration-dependent parameter k that leads to cell death following delays arising from signal transduction. All 3 PDX models responded to the combination therapy, but with different sensitivities. PDX#14312 showed the least inhibition by the drugs alone (k[GEM]=13.6, k[PTX]=37.0 /day/mM), compared to the other PDXs (#18254: k[GEM]=68.1, k[PTX]=125; 18269: k[GEM]=112, k[PTX]=51.2 /day/mM). Compared to the more potent single-drug treatment for each PDX, the combination resulted in 1.33-fold greater cell death in #14312, 1.39 fold in #18269 and 1.19 fold in #18254. Model simulations showed distinct temporal profiles of cytotoxic signals in the 3 PDXs. Pathway analysis showed that the top changes mediated by the drug combination in PDX#14312 PDAC cells included extracellular matrix organization (FDR-corrected p-value = 7E-5), synthesis of nucleotide di- and triphosphates (p = 0.012), and interferon signaling (p = 0.04), whereas top changes in stroma included increased platelet activation (p = 3.8E-4) and extracellular matrix organization (p = 0.046). These processes represent potential contributors to the resistance of PDX#14312 to the drug combination. Top changes in #18269 and #18254, which were sensitive to the combination, included increased glycolysis (p = 0.038), decreased fatty acid beta-oxidation (p = 3E-5) and DNA replication (p = 0.0058) in PDAC cells, and increased complement activation (p < 1E-5) in stroma. Overall, inter-patient variability in PDAC responsiveness to GEM/nab-PTX therapy may be associated with tumor stress responses partially resembling wound healing processes. Citation Format: Jin Niu, Xue Wang, Shichen Shen, Ju Qu, Donald Mager, Robert M. Straubinger. Pharmacodynamic and proteomic analysis of combined gemcitabine/nab-paclitaxel in patient-derived pancreatic cancer xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3890.