Developing drug combinations to co-target pancreatic cancer and its supporting stroma

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an intense desmoplastic stroma, due to the activation of pancreatic stellate cells (PSC). The activated PSC are characterized by a reduction of fat droplets, expression of α-smooth muscle actin (α-SMA), and an increased synthesis and secretion of several connective tissue components such as fibronectin (FN) and collagen type I. Aberrant stromal-epithelial interactions contribute to pancreatic cancer spread and metastasis raising the possibility that targeting the stroma may represent viable strategy for treating pancreatic cancer. Our group has shown that pancreatic cancer progression can be restrained via modulation of the stellate cells in the stroma. Methods: Organotypic cultures (OT) were constructed to mimic human PDAC. Treatment of OT was performed to mimic human chemotherapy regimen cycles with all-trans retinoic acid (ATRA), targeting PSC, and the chemotherapeutic agent Gemcitabine (GEM), targeting pancreatic cancer cells (PCC). Furthermore, KPC mice (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) were treated with the combination of GEM and ATRA. Appropriate controls were used for both in vivo and in vitro assays using either drug alone or vehicle alone to dissect effect of individual drug. Both in vivo and in vitro assays were studied for various surrogate endpoints for chemotherapy efficacy. Results:In the organotypic model, ATRA alone or in combination with GEM reduced cancer cell and stellate cell invasion. The same treatment also reduced cancer cell proliferation. Stellate cell activation, as measured by fibronectin production per stellate cell, was significantly reduced upon combination treatment with GEM/ATRA, in comparison to cultures treated with GEM or ATRA only. In the KPC mice model, ATRA alone or in combination with GEM caused stromal collapse. The same regimen treatment led to an increase in vascular density in the tumor area and a significant impairment of the tumor growth, when compared with mice treated with ATRA or GEM alone. The number of necrotic areas was also higher in tumors from mice treated with the combination treatment of GEM/ATRA. Further assessments are being carried out. Conclusions:The combination treatment of all-trans retinoic acid and Gemcitabine may have a synergistic detrimental effect upon pancreatic cancer progression