Sorah Yoon
Beckman Research Institute of City of Hope, USA
Title: Targeted therapeutics in pancreatic cancer for precision medicine
Biography
Biography: Sorah Yoon
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies and the 4th leading cause of cancer-related deaths in North America. The survival rate remains less than 5% at 5 years taking into account all stages of the disease. In contrast to other cancer types, the mortality rate of PDAC is increasing, with PDAC being predicted to become the second leading cause of cancer-related mortality by 2020. Despite great efforts to improve the treatment and outcome of patients with PDAC, limited progress has been made. Still, current therapeutic options are very disappointing. Genetic mutaions of tumor supperssor genes have been well characterized in pancreatic cancer. However, the pathophysical progression of PDAC doese not always correlate with these genetic changes, suggesting the possibility that unidentified genetic alterations or epigenetic factors might be involved in the progression of pancreatic maligancy. The loss of heteozygosity of lysine demethylase (KDM6B) encoding histone demethylase makes pancreatic cancer epigenetically silenced in the downstream target of CCAAT/enhancer binding protein alpha (C/EBPα), strong anti-proliferator by affecting p21, a cyclin-dependent kinase (CDK) inhibitor. The decreased expression of KDM6B and C/EBPα is well-correlated through the malignant progression of PDAC. For the precision medicine in pancreatic cancer, to activate the silened gene of C/EBPα for the therapeutics, small activating RNA(saNRA) to C/EBPα is developed. For targeted delivery of C/EBPα, RNA aptamers have been isolated via cell-SELEX, that showed the pancratic cancer cell specificity. The isolated RNA aptamers have been conjugated with C/EBPα-saRNA as targeting modalities. The targeted delivery of the C/EBPα-saRNA conjugates showed the increased expressionof C/EBPα in vitro with translational and transcriptional level. In vivo assay, the targeted delivery of C/EBPα-saRNA conjugates significantly inhibited the tumor growth without toxicity. Using pancreatic cancer specific aptamers, to reduce the non-specific absorption of cytotxic drugs in normal cells, aptamer-drug conjugates (ApDCs) were constructed with active metabolites of prodrugs, gemcitabine and 5FU, and chemotoxins, MMAE and DM1. The ApDCs with gemcitabine and 5FU showed the significant anti-prolieraction effects by inducing double-strand breask in nuclear without affecting non-targeting cells. Also, The ApDCs with MMAE and DM1 showed the stong anti-prolieraction effects by arresting the cycle without the cytotoxicity in non-targeting cells. Taken together, our studies prove the therapeutic strategies for precision medicine in pancrearic cancer by following firstly, targeting somatic mutaions for therapeutics and secondly, aptamer mediated targeted delivery of theapeutics with minimizing the side effects in normal cells.