Being one of the major cancers with the highest mortality rate and lowest 5-year survival rate, pancreatic cancer is growingly concerned world-wide. Recurrence rate after surgery is still high. Therefore, safe, affordable, and effective therapies are increasingly needed for a better outcome. The main objective of this project is to engineer an oncolytic adenovirus with modified genome that harbors an oncogene silencing factor to sensitize pancreatic tumor to oncolysis and chemotherapy. Our study specifically targets the oncogenic HMGA1 protein, with an aim to suppress the elevated expression of HMGA1 in pancreatic cancer cells. To achieve this goal, our approach was to utilize an adenovirus-mediated RNA antisense against HMGA1 to not only stringently attack cancer cells but also to recover anti-tumor activity. Specifically, we generated and amplified a DNA sequence coding for HMGA1-antisense RNA via PCR, then performed molecular cloning to insert the sequence into adenoviral genome backbone. Following successful generation of the HMGA1-antisense sequence and insertion of this sequence into the adenoviral genome, an oncolytic virus carrying the HMGA1-silencing factor, named HMGA-AS-RC, was successfully produced via transfection. The HMGA1-antisense engineered in HMGA-AS-RC is expected to significantly reduce HMGA1 level in different pancreatic cancer cell lines. With this adenoviral construct, the inhibition of HMGA1 synthesis by HMGA1-antisense can be further explored for in-depth understanding of the HMGA1-silencing effects on reverting cancer progression. The combined therapy served as a basis for developing new promising and influential treatments for pancreatic cancer. In addition, this research experience has provided me precious knowledge in cancer, virology, and gene regulation as well as experimental skill sets that are applicable for future cancer genetics studies.
Authors: Trang Dinh, Minh Thai, Shijia Cao
Advisor: Michael Kennedy, Chemistry and Biochemistry
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