lde225 and Carcinoma--Pancreatic-Ductal

Despite frequent overexpression of numerous growth factor receptors by pancreatic ductal adenocarcinomas (PDAC), such as EGFR, therapeutic antibodies have not proven effective. Desmoplasia, hypovascularity, and hypoperfusion create a functional drug delivery barrier that contributes to treatment resistance. Drug combinations that target tumor/stroma interactions could enhance tumor deposition of therapeutic antibodies, although clinical trials have yet to support this strategy. We hypothesize that macromolecular or nanoparticulate therapeutic agents may best exploit stroma-targeting "tumor priming" strategies, based on the fundamental principles of the Enhanced Permeability and Retention phenomenon. Therefore, we investigated the molecular and pharmacologic tumor responses to NVP-LDE225, an SMO inhibitor of sonic hedgehog signaling (sHHI), of patient-derived xenograft models that recapitulate the desmoplasia and drug delivery barrier properties of PDAC. Short-term sHHI exposure mediated dose- and time-dependent changes in tumor microvessel patency, extracellular matrix architecture, and interstitial pressure, which waned with prolonged sHHI exposure, and increased nanoparticulate permeability probe deposition in multiple PDAC patient-derived xenograft isolates. During sHHI-mediated priming, deposition and intratumor distribution of both a nontargeted mAb and a mAb targeting EGFR, cetuximab, were enhanced. Sequencing the sHH inhibitor with cetuximab administration resulted in marked tumor growth inhibition compared with cetuximab alone. These studies suggest that PDAC drug delivery barriers confound efforts to employ mAb against targets in PDAC, and that short-term, intermittent exposure to stromal modulators can increase tumor cell exposure to therapeutic antibodies, improving their efficacy, and potentially minimize adverse effects that may accompany longer-term, continuous sHHI treatment.

Topics: Animals; Biphenyl Compounds; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cetuximab; Dose-Response Relationship, Drug; Drug Delivery Systems; Hedgehog Proteins; Humans; Mice; Nanoparticles; Pancreatic Neoplasms; Pyridines; Signal Transduction; Time Factors; Xenograft Model Antitumor Assays

Pancreatic ductal adenocarcinoma (PDAC) is one of the most chemotherapy- and radiotherapy-resistant tumors. The c-Met and Hedgehog (Hh) pathways have been shown previously by our group to be key regulatory pathways in the primary tumor growth and metastases formation. Targeting both the HGF/c-Met and Hh pathways has shown promising results in preclinical studies; however, the benefits were not readily translated into clinical trials with PDAC patients. In this study, utilizing mouse models of PDAC, we showed that inhibition of either HGF/c-Met or Hh pathways sensitize the PDAC tumors to gemcitabine, resulting in decreased primary tumor volume as well as significant reduction of metastatic tumor burden. However, prolonged treatment of single HGF/c-Met or Hh inhibitor leads to resistance to these single inhibitors, likely because the single c-Met treatment leads to enhanced expression of Shh, and vice versa. Targeting both the HGF/c-Met and Hh pathways simultaneously overcame the resistance to the single-inhibitor treatment and led to a more potent antitumor effect in combination with the chemotherapy treatment.

Topics: Adenocarcinoma; Animals; Benzamides; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Disease Models, Animal; Drug Resistance, Neoplasm; Gemcitabine; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Hepatocyte Growth Factor; Humans; Imidazoles; Mice; Mice, Transgenic; Neoplasm Metastasis; Proto-Oncogene Proteins c-met; Pyridines; Triazines; Tumor Microenvironment