Molecular therapy targeting cancer and cancer stem cells, via novel nanovectors and rational drug design.
1) 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 signaling pathways, especially for cancer cell chemo/radiosensitization by molecular modulation of apoptosis/autophagy/necroptosis. One of the first lead compounds tested in vitro and in vivo in my lab has completed Phase I-IIb clinical trials, as the World’s first pan-Bcl-2/Bcl-xL/Mcl-1 inhibitor entered clinic trials. Another XIAP inhibitor is also in clinical trials.
Currently, I am working on molecular cancer drug discovery, using structure-based rational drug design for novel small molecule inhibitors targeting Musashi-1/2 and HuR, the RNA-binding proteins so far believed “undruggable”. Through high-throughput screening and lead optimization, we obtained nanomolar to submicromolar lead compounds, and two provisional patents were filed in 2014. One new R01 was funded in 2014; one R01 scored 20, percentile 3%, started in 2015. Our long-term goal is for further lead optimization to obtain more potent and specific, drug like leads for development as first-in-class Musashi-1/2 or HuR inhibitors as whole new therapy for cancer.
2) Novel nanovector delivery systems targeting cancer and cancer stem cells - Drug/gene delivery.
Funded by multiple NIH and DOD grants, my lab works on the tumor-targeted delivery of molecular cancer therapeutics using novel nanotechnology. A self-assembled, virus-mimicking, non-viral nanovector for non-viral tumor-targeted, systemic p53 gene therapy has shown promise in chemo/radiosensitization of breast, prostate, head and neck cancer, just completed a first-in-human Phase I clinical trial, now in multi-center Phase II Trials. Multiple US and International Patents are issued or pending.
Currently, I am exploring next generation nanovectors for tumor-targeted delivery of siRNA/miRNA/CRISPR-based therapeutics for targeting cancer and cancer stem cells. In 2014, I have 7 papers published on nanoparticles for cancer targeting and molecular imaging. Imaging-based nano-drug delivery for cancer targeted therapy will be my focus.
Selected Publications —
- Lan L, Appelman C, Smith AR, Yu J, Larsen S, Marquez RT, Wu X, Gao P, Roy A, Anbanandam A, Gowthaman R, Karanicolas J, De Guzman RN, Rogers SA, Aube J, Ji M, Cohen RS, Neufeld KL, and Xu L. Natural product (–)-gossypol inhibits colon cancer cell growth by targeting RNA-binding protein Musashi-1. Molecular Oncology 2015 (in press)
- Wu X, Lan L, Wilson DM, Marquez RT, Tsao W-C, Gao P, Roy A, Turner B, McDonald P, Tunge JA, Rogers SA, Dixon DA, Aube J, and Xu L. Identification and validation of novel small molecule disruptors of HuR-mRNA interaction. ACS Chem Biol 2015 (in press)
- Smith AR, Marquez RT, Tsao W-C, Pathak S, Roy A, Ping J, Wilkerson B, Lan L, Meng W, Neufeld KL, Sun X-F, and Xu L. Tumor Suppressive microRNA-137 Negatively Regulates Musashi-1 in Colorectal Cancer. Oncotarget 2015 (in press).
- Carlson EA, Marquez RT, Wang Y, Xu L, Yan SD. Overexpression of 17β-hydroxysteroid dehydrogenase type 10 increases pheochromocytoma cell growth and resistance to cell death. BMC Cancer 2015 (in press).
- Li K, Liu H, Gao W, Chen M, Zeng Y, Liu J, Xu L, and Wu D, Mulberry-like dual-drug complicated nanocarriers assembled with apogossypolone amphiphilic starch micelles and doxorubicin hyaluronic acid nanoparticles for tumor combination and targeted therapy. Biomaterials 2015; 39(1):131-144.
- Liu H, Li K, Xu L, and Wu D, Bilayered near-infrared fluorescent nanoparticles based on low molecular weight PEI for tumor-targeted in vivo imaging. Journal of Nanoparticle Research, 2014; 16(12):2784.
- Lu J, Zhao W, Liu H, Marquez R, Huang Y, Zhang Y, Li J, Xie W, Venkataramanan R, Xu L, and Li S, An Improved D-α-Tocopherol-Based Nanocarrier for Targeted Delivery of Doxorubicin with Reversal of Multidrug Resistance. Journal of Controlled Release, 2014; 196:272-286. PMC4267990
- Deng L, Shang L, Bai S, Chen J, He X, Trevino RM, Chen S, Li X, Meng X, Yu B, Wang X, Liu Y, McDermott SP, Ariazi AE, Ginestier C, Ibarra I, Ke J, Luther TK, Clouthier SG, Xu L, Shan G, Song E, Yao H, Hannon GJ, Weiss SJ, Wicha MS, and Liu S, microRNA100 inhibits self-renewal of breast cancer stem-like cells and breast tumor development. Cancer Research 2014; 74(22):6648-6660.
- H Liu, K Li, L Lan, J Ma, Y Zeng, L Xu, and D Wu. Double-layered hyaluronic acid/stearic acid-modified polyethyleneimine nanoparticles encapsulating (−)-gossypol: a nanocarrier for chiral anticancer drugs. Journal of Materials Chemistry B 2014; 2(32):5238-5248.
- Lu J, Zhao W, Huang Y, Liu H, Marquez R, Gibbs RB, Li J, Venkataramanan R, Xu L, and Li S, Targeted Delivery of Doxorubicin by Folic Acid-Decorated Dual Functional Nanocarrier. Molecular Pharmaceutics 2014; 11(11):4164-4178.
- Wang B, Ni Z, Dai X, Qin L, Li X, Xu L, Lian J, and He F. The Bcl-2/xL inhibitor ABT-263 increases the stability of Mcl-1 mRNA and protein in hepatocellular carcinoma cells. Molecular Cancer 2014. 13(1):98. PMC4021276
- Zhang P, Huang Y, Liu H, Marquez RT, Lu J, Zhao W, Zhang X, Gao X, Li J, Venkataramanan R, Xu L, and Li S. A PEG-Fmoc conjugate as a nanocarrier for paclitaxel. Biomaterials 2014; 35(25):7146-7156. PMC4102141
- Ni Z, Wang B, Dai X, Ding W, Yang T, Li X, Jason S, Xu L, Lian J, and He F. HCC cells with high levels of Bcl-2 are resistant to ABT-737 via activation of the ROS-JNK-autophagy pathway. Free Radic Biol Med 2014, 70:194-203. PMID:24576507
- Qin J, Yang B, Xu B-Q, Smithc A, Xu L, Yuan J-L, and Li L, Concurrent CD44s and STAT3 expression in human clear cell renal cellular carcinoma and its impact on survival. International Journal of Clinical and Experimental Pathology 2014; 7(6):3235.
- Li L, Hao X, Qin J, Tang W, He F, Smith A, Zhang M, Simeone DM, Qiao X, Chen ZN, Lawrence TS, and Xu L. Antibody against CD44s Inhibits Pancreatic Tumor Initiation and Post-Radiation Recurrence in Mice. Gastroenterology 2014, 146(4):1108-1118. Highlighted in Nature Reviews Gastroenterol Hepatol 2014, 11(2). PMC3982149
- Wang L, Yang H, Palmbos PL, Ney G, Detzler TA, Coleman D, Leflein J, Davis M, Zhang M, Tang W, Hicks JK, Helchowski CM, Prasad J, Lawrence TS, Xu L, Yu X, Canman CE, Ljungman M, and Simeone DM. ATDC/TRIM29 Phosphorylation by ATM/MAPKAP Kinase 2 Mediates Radioresistance in Pancreatic Cancer Cells. Cancer Res 2014, 74(6):1778-1788. PMID:24469230
- Wang B, Chen L, Ni Z, Dai X, Qin L, Wu Y, Li X, Xu L, Lian J, and He F, Hsp90 inhibitor 17-AAG sensitizes Bcl-2 inhibitor (-)-gossypol by suppressing ERK-mediated protective autophagy and Mcl-1 accumulation in hepatocellular carcinoma cells. Experimental Cell Research 2014. 328(2):379-387. PMID:25196280
- Li L, Tang W, Wu X, Karnak D, Meng X, Thompson R, Hao X, Li Y, Qiao X, Lin J, Fuchs J, Simeone DM, Chen ZN, Lawrence TS, and Xu L. HAb18G/CD147 Promotes pSTAT3-Mediated Pancreatic Cancer Development via CD44s. Clin Cancer Res 2013, 19(24):6703-6715. PMID:24132924.
- Ni Z, Dai X, Wang B, Ding W, Cheng P, Xu L, Lian J, and He F. Natural Bcl-2 inhibitor (-)-gossypol induces protective autophagy via ROS-HMGB1 pathway in Burkitt lymphoma. Leuk Lymphoma 2013. Feb 12. PMID:23398207
- Cheng P, Ni Z, Dai X, Wang B, Ding W, Smith AR, Xu L, Wu D, and He F, Lian J. The novel BH-3 mimetic apogossypolone induces Beclin-1- and ROS-mediated autophagy in human hepatocellular cells. Cell Death Dis. 2013 Feb 7. PMID:23392177
- Marquez RT, Tsao BW, Faust NF and Xu L. Drug resistance and molecular cancer therapy: Apoptosis vs. Autophagy. In: Justine Rudner, ed., Apoptosis. Chapter 8. InTech. 2013, p155-196.
- Niu X, Li S, Wei F, Huang J, Wu G, Xu L, Xu D, and Wang S. Apogossypolone induces autophagy and apoptosis in breast cancer MCF-7 cells in vitro and in vivo. Breast Cancer 2012 Jun 19; PMID:22711315
- Marquez RT and Xu L. Bcl-2:Beclin 1 complex: multiple mechanisms regulating autophagy/apoptosis toggle switch. Am J Cancer Res 2012; 2(2):214-221.
- Lian J, Ni Z, Dai X, Su C, Smith AR, Xu L, and He F. Sorafenib sensitizes (-)-gossypol-induced growth suppression in androgen-independent prostate cancer cells via Mcl-1 inhibition and Bak activation. Mol Cancer Ther 2012; 11(2):416-426.
- Wu X, Li M, Tang W, Zheng Y, Lian J, Xu L, and Ji M. Design, Synthesis, and In vitro Antitumor Activity Evaluation of Novel 4-pyrrylamino Quinazoline Derivatives. Chem Biol Drug Des 2011; 78(6):932-940.
- Dai Y, Desano J, Qu Y, Tang W, Meng Y, Lawrence TS, and Xu L. Natural IAP inhibitor Embelin enhances therapeutic efficacy of ionizing radiation in prostate cancer. Am J Cancer Res 2011; 1(2):128-43. PMCID: 3144474.
- DeSano J, Lawrence TS and Xu L. MicroRNAs: Small but Critical Regulators of Cancer Stem Cells. In: Louise Laurent, ed., Cancer Stem Cells Theories and Practice. 2011. Chapter 15, p291-312. InTech.
- Pan X, Thompson R, Meng X, Wu D, and Xu L. Tumor-targeted RNA-interference: functional non-viral nanovectors. Am J Cancer Res 2011;1(1):32-49.
- 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 2011; 18(1):60-71. PMCID: 2950895
- Dai Y, DeSano J, Tang W, Meng X, Meng Y, Burstein E, Lawrence TS and Xu L. Natural Proteasome Inhibitor Celastrol Suppresses Androgen-Independent Prostate Cancer Progression by Modulating Apoptotic Proteins and NF-kappaB. PLoS One 2010; 5(12): e14153. PMCID: 3000808.
- Lian J, Karnak D and Xu L. The Bcl-2-Beclin 1 interaction in (-)-gossypol-induced autophagy versus apoptosis in prostate cancer cells. Autophagy 2010; 6(8):1201-3.
- 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.
- Karnak D and Xu L. Chemosensitization of prostate cancer by modulating Bcl-2 family proteins. Current Drug Targets 2010; 11(6):699-707.
- 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)
Complete List of Published Work in My Bibliography:
- Chang, E.H., Xu, L. and Pirollo, K.F. Targeted liposome gene delivery. United States Patent No. 6,749,863, issued on June 15, 2004. European Patent No. EP 1,032,369, issued on May 18, 2005.
- 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, Wang G, Tang G, Wang R, Nikolovska-coleska Z, Wang D, and Xu L. Small molecule inhibitors of anti-apoptotic BCL-2 family members and the uses thereof. European Patent No. EP 1,778,206, issued 2007.
- Wang S, Yang D and Xu L. Small molecule antagonists of Bcl-2 family proteins. United States Patent No. US 7,432,304, issued on Oct.7, 2008; and US 8,163,805, issued on Apr. 24, 2012.
- Xu L., Huang CC, Alexander W, Tang WH and Chang EH. Antibody fragment-targeted immunoliposomes for systemic gene delivery. United States Patent No. US 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.
- EH Chang, K Pirollo, L Xu, W Alexander. Systemic viral/ligand gene delivery system and gene therapy. European Patent No. EP 1,131,457, issued on Oct. 6, 2010.
- Chen J, Nikolovska-Coleska Z, Yang D, Wang S, Sun H, Xu L, Hu Z. Small molecule antagonists of XIAP family proteins. United States Patent No. US 7,910,621, issued on Mar. 22, 2011.
- Wang S, Sun H, Nikolovska-Coleska Z, Yang CY, Xu L. Conformationally Constrained SMAC Mimetics and The Uses Thereof. United States Patent No. US 7,932,382, issued on April 26, 2011.
- W Alexander, L Xu, C Huang, W Tang, EH Chang. Antibody fragment-targeted immunoliposomes for systemic gene delivery. European Patent No. EP 1,811,036, issued on Jun. 1, 2011.
- Simeone DM, Ljungman M, Xu L, Wang L, He F. Compositions and methods for treating cancer. US Patent No. US 8,088749, issued on Jan. 3, 2012.
- Wang S, Wang G, Tang G, Wang R, Nikolovska-Coleska Z, Yang D, and Xu L. Small molecule inhibitors of anti-apoptotic BCL-2 family members and the uses thereof. United States Patent No. US 8,557,812, issued on Oct. 15, 2013.