COLUMBUS, Ohio - Researchers at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James) have found a promising biological target for treating the most common form of pancreatic cancer. The discovery could lead to new targeted therapies for this often-fatal disease. Writing in the journal Signal Transduction and Targeted Therapy, the scientists – led by senior author Carlo Croce, MD, professor in the Department of Cancer Biology and Genetics at Ohio State – described pancreatic ductal adenocarcinoma (PDAC) as a lethal disease with an extraordinary ability to thrive and progress in a challenging tumor environment caused by the body’s strong reaction to the disease. That reaction is characterized by the growth of fibrous connective tissue around the tumor that compresses blood vessels and limits the supply of nutrients that the tumor needs for sustenance and growth. PDAC cells adapt to these unfavorable conditions, enabling the tumor to grow even when its nutrient supply is reduced. In this study, the OSUCCC – James scientists believe they have identified an adaptive mechanism. Their findings suggest that blocking molecules involved in the mechanism might offer a new way to improve outcomes for patients with PDAC, which is rising in incidence and is projected to become the second-leading cause of cancer-related mortality in the next few years.  The scientists state that studying how PDAC adapts to low nutrient conditions could enable them to identify critical vulnerabilities for these tumors and to find novel therapeutic approaches.  This basic-science study involved a genetic mouse model of PDAC and tumor samples from 38 patients who had undergone PDAC surgery without prior therapy. The adaptive mechanism involves dysregulation of a tumor-suppressor microRNA called miR-15 – a common occurrence in PDAC – and the consequences of its absence.    “We discovered that the loss of microRNA miR-15 in pancreatic cancer leads to the overproduction of a molecule called Fra-2. That molecule then helps pancreatic cancers adapt to nutrient deprivation,” Croce said. He explained that high levels of Fra-2 in turn result in high levels of insulin-like growth factor receptor (IGFIR), a signaling pathway that supports tumor growth amid nutrient deprivation. The IGFI signaling pathway regulates multiple cellular processes. To combat this, the scientists propose developing drugs that inhibit the IGFIR signaling pathway and sensitizing PDAC to those drugs through dietary restrictions for patients – restrictions that would make the drugs more effective. The scientists reported that this approach was effective in their preclinical genetic mouse models of PDAC.   “Nutrient restriction improves the efficacy of IGFIR inhibition in a Fra-2-dependent manner,” said Croce, who also is in the Cancer Biology Program at the OSUCCC – James. “Thus, we should consider IGFIR targeting in pancreatic cancers that have low expression of miR-15.” He added that future studies should be conducted to assess whether this regimen would be tolerated in patients, and whether miR-15 loss in PDAC could be used as a prognostic biomarker to identify tumors more likely to respond to this therapeutic approach. Media Contact: Mary Ellen Fiorino, Mary.Fiorino@osumc.edu