Arun Srivastava, PhD
George H. Kitzman Professor of Genetics
Research Project Description
Two of the most common liver cancers include hepatoblastoma (HB) in children, and hepatocellular carcinoma (HCC) in adults. HB is the most frequent pediatric liver cancer in the United States. HCC is one of the five most common cancers involving solid tumors, and is highly fatal. HCC is rapidly emerging as a clinically important disease in developed countries and of grave concern is its increasing incidence to epidemic proportions in certain areas of the world. An alarming trend in its increase has been recently observed: 18,000 new cases of HCC are expected every year. Projected new cases in the coming years are likely to rise even more dramatically, based on the increasing number of hepatitis-C infected Americans (~4 million). Furthermore, the increasing incidence in the United States of obesity and diabetes, which have also been linked to the development of chronic liver disease and HCC, is likely to further augment the number of Americans afflicted with HCC. Thus, a novel therapeutic approach for the treatment of HB and HCC is warranted, which may involve the use of target-specific genes. We have had a long-term interest in a non-pathogenic human parvovirus, the adeno-associated virus (AAV), which has gained attention as a potentially safe vector for gene therapy, and has recently shown efficacy in Phase I clinical trials in patients with Leber’s congenital amaurosis and hemophilia B. We have observed that of the 10 AAV serotypes, AAV3 vectors transduce human HB and HCC cell lines and primary human hepatocytes extremely well, and also target human liver tumors in mouse xenograft models extremely efficiently. Medical students will be involved in using these optimized AAV3 vectors carrying therapeutic genes to potentially eradicate human liver tumors in mouse xenograft models. Funding for the project is provided by the National Institutes of Health and the George H. Kitzman Endowment.
- Ling, Y. Lu, B. Cheng, K.E. McGoogan, S.W.Y. Gee, W. Ma, B. Li, G.V. Aslanidi, and A. Srivastava. High-efficiency transduction of liver cancer cells by recombinant adeno-associated virus serotype 3 vectors. J. Vis. Exp., 49. Pii: 2538, doi: 10.3791/2538, 2011.
- B. Cheng, C. Ling, Y. Dai, L.G. Glushakova, Y. Lu, S.W.Y. Gee, K.E. McGoogan, G.V. Aslanidi, M. Park, P.W. Stacpoole, D. Siemann, C. Liu, Srivastava, and C. Ling. Development of optimized AAV3 serotype vectors: Mechanism of high-efficiency transduction of human liver cancer cells. Gene Therapy, 19: 375-384, 2012.
- Ling, Y. Wang, Y. Zhang, A. Ejjigani, Z. Yin, Y. Lu, L. Wang, M. Wang, J. Li, Z. Hu, G.V. Aslanidi, L. Zhong, G. Gao, A. Srivastava, and C. Ling. Selective in vivo targeting of human liver tumors by optimized recombinant AAV3 vectors in a murine xenograft model. Human Gene Therapy, 25: 1023-1034, 2014.
- Zhang, L, Wang, Y. Lu, G.V. Aslanidi, A. Srivastava, C. Ling, and C. Ling. Cytotoxic genes from traditional Chinese medicine inhibit tumor growth both in vitro and in vivo. J. Int. Medicine, 12: 483-494, 2014.
- Yin, G.D. Keeler, Y. Zhang, B.E. Hoffman, C. Ling, K. Qing, and A. Srivastava. AAV3-miRNA vectors for growth suppression of human hepatocellular carcinoma cells in vitro and human liver tumors in a murine xenograft model in vivo. Gene Therapy, in press, 2020.