M.D., Ph.D., The Fourth Military Medical University, Xi’an, China, 1992
4002 Haworth; Phone: (785) 864-5849, e-mail:
Molecular therapy targeting cancer and cancer stem cells
1. Novel nanovector delivery systems targeting cancer and cancer stem
My lab works on the tumor-targeted delivery of molecular cancer therapeutics using novel nanotechnology. A self-assembled, virus-mimicking, non-viral nanovector for systemic p53 gene therapy has shown promise in chemo- and radiosensitization of breast, prostate, head and neck cancer, is now in a first-in human Phase I clinical trial of non-viral tumor-targeted p53 gene therapy. Multiple US and International Patents are issued or pending. Currently, we are using this patented nanovector for tumor-targeted delivery of siRNA-based therapeutics and novel small-molecule therapeutics. Currently, we are working on the next generation nanovectors for targeting cancer stem cells.
2. Novel small-molecule cancer therapeutics—Drug discovery and molecular cancer therapy
My lab has been working on drug discovery for novel small molecule cancer therapeutics targeting cell death pathways, especially for cancer cell radiosensitization and chemosensitization by molecular modulation of apoptosis and autophagy. One of the first lead compounds tested in vitro and in vivo in my lab has entered Phase I-IIb clinical trials as the World’s first small-molecule inhibitor of Bcl-2/Bcl-xL/Mcl-1 approved by FDA and entered clinic trials. Currently, we are working on molecular cancer radio-sensitization with novel Mcl-1 inhibitors and with lead compounds inducing autophagy.
- Xu, L., Pirollo, K.F., and Chang, E.H., Transferrin-Liposome-Mediated p53 Sensitization of Squamous Cell Carcinoma of the Head and Neck to Radiation In Vitro. Hum Gene Ther 1997; 8:467-475.
- Xu L, Pirollo KF, Tang WH, Rait A and Chang EH. Transferrin-liposome-mediated Systemic p53 Gene Therapy in Combination with Radiation Results in Regression of Human Head and Neck Cancer Xenografts. Hum Gene Ther 1999; 10:2941-2952.
- Xu, L., Pirollo, K.F., and Chang, E.H. Tumor-Targeted p53-Gene Therapy Enhances the Efficacy of Conventional Chemo/Radiotherapy. J Controlled Release 2001; 74:115-128.
- Xu L, Frederik P, Pirollo KF, Tang WH, Rait A, Xiang LM, Huang W, Cruz I, Yin Y and Chang EH. Self-assembly of a virus-mimicking nanostructure system for efficient tumor-targeted gene delivery. Hum Gene Ther 2002; 13(3):469-481.
- Nikolovska-Coleska Z, Xu L, Hu Z, Tomita Y, Li P, Roller PP, Wang R, Fang X, Guo R, Zhang M, Lippman, ME, Yang D and Wang S, Discovery of Embelin as A Cell-Permeable, Small-Molecular Weight Inhibitor of XIAP through Structure-Based Computational Screening of Traditional Herbal Medicine Three-Dimensional Structural Database. J Med Chem 2004; 47(10):2430-2440.
- Sun H, Nikolovska-Coleska Z, Yang CY, Xu L, Liu M, Tomita Y, Pan H, Yoshioka Y, Krajewski K, Roller PP and Wang S. Structure-based design of potent, conformationally constrained Smac mimetics. J Am Chem Soc 2004; 126(51):16686-7.
- Xu L, Yang D, Wang S, Tang W, Liu M, Davis M, Chen J, Rae JM, Lawrence TS and Lippman ME. (-)-Gossypol enhances response to radiation therapy and results in tumor regression of human prostate cancer. Mol Cancer Ther 2005; 4(2):197-205. (PMID: 15713891)
- Meng Y, Tang W, Dai Y, Wu X, Liu M, Ji Q, Ji M, Pienta K, Lawrence TS and Xu L. Natural BH3-mimetic (-)-gossypol chemosensitizes human prostate cancer via Bcl-xL inhibition accompanied by increase of Puma and Noxa. Mol Cancer Ther 2008; 7(7):2192-2202. (PMID: 18645028)
- Abela RA, Qian J, Xu L, Lawrence TS and Zhang M. Radiation improves gene delivery by a novel transferrin-lipoplex nanoparticle selectively in cancer cells. Cancer Gene Ther 2008; 15(8):496-507. (PMID: 18483503)
- Ji Q, Hao X, Meng Y, Zhang M, DeSano J, Fan D and Xu L. Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres. BMC Cancer 2008; 8(1):266. (Highly accessed) (PMID: 18803879)
- Dai Y, Liu M, Tang W, DeSano TJ, Burstein E, Pienta K, Lawrence TS and Xu L. Molecularly targeted radiosensitization of human prostate cancer by modulating IAP. Clin Cancer Res 2008; 14(23):7701-10. (PMID: 19047096)
- Dai Y, DeSano TJ, Meng Y, Ji Q, Ljungman M, Lawrence TS and Xu L. Celastrol potentiates radiation therapy via impairment of DNA damage processing in human prostate cancer. Int J Radiat Oncol Biol Phys 2009; 74(4):1217-1225. (PMID: 19545787)
- Ji Q, Hao X, Zhang M, Tang W, Meng Y, Li L, Xiang D, DeSano TJ, Bommer GT, Fan D, Fearon ER, Lawrence TS and Xu L. MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS One 2009; 4(8): e6816. (PMID: 19714243)
- Dai Y, Liu M, Tang W, Li Y, Lian J, Lawrence TS and Xu L. A Smac-mimetic sensitizes prostate cancer cells to TRAIL-induced apoptosis via modulating both IAPs and NF-kB. BMC Cancer 2009; 9:392. (Highly accessed) (PMID: 19895686)
- DeSano TJ and Xu L. MicroRNA regulation of cancer stem cells and therapeutic implications. AAPS J 2009; 11(4):682-692. (PMID: 19842044)
- Ji Q, Karnak D, Hao P, Wang R and Xu L. No small matter: microRNAs -- key regulators of cancer stem cells. Int J Clin Exp Med 2010; 3(1):84-87. (PMCID: 2848309)
- Karnak D and Xu L. Chemosensitization of prostate cancer by modulating Bcl-2 family proteins. Current Drug Targets 2010; 11(6):699-707. (PMC - In Process)
- Wu X, Li M, Qu Y, Tang W, Zheng Y, Lian J, Ji M and Xu L. Design and synthesis of novel Gefitinib analogues with improved anti-tumor activity. Bioorg Med Chem 2010; 18(11):3812-3822. (PMC - In Process)
- Lian J, Wu X, He F, Karnak D, Tang W, Meng Y, Xiang D, Ji M, Lawrence TS and Xu L. A natural BH3-mimetic induces autophagy in apoptosis-resistant prostate cancer via modulating Bcl-2—Beclin1 interaction at endoplasmic reticulum. Cell Death Diff 2010 (in press).
- Chang, E.H., Xu, L. and Pirollo, K.F. Targeted liposome gene delivery. International Patent Application No. PCT/US98/24657, filed on 11/19/1998. United States Patent No. 6,749,863, issued on June 15, 2004.
- Xu L., Huang CC, Alexander W, Tang WH and Chang EH. Antibody fragment-targeted immunoliposomes for systemic gene delivery. European Patent No. EP 1,154,756, issued on Jan.3, 2007.
- Wang S, Yang D and Xu L. Small molecule antagonists of Bcl-2 family proteins. International Patent PCT filed on 12/05/2004. United States Patent No. US 7,432,304, issued on Oct.7, 2008.
- Xu L., Huang CC, Alexander W, Tang WH and Chang EH. Antibody fragment-targeted immunoliposomes for systemic gene delivery. United States Patent No. 7,479,276, issued on Jan. 20, 2009.
- Wang S, Sun H, Nikolovska-Coleska Z, Yang CY, Xu L, Saito N, Chen J. Conformationally Constrained SMAC Mimetics and The Uses Thereof. United States Patent No. US 7,674,787, issued on Mar.9, 2010.
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