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Zhen Fan, M.D.

Present Title & Affiliation

Primary Appointment

Professor (with tenure), Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

Dual/Joint/Adjunct Appointment

Full Member, Graduate Faculty, The Graduate School of Biomedical Sciences (GSBS), The University of Texas Health Science Center at Houston, Houston, TX

Research Interests

The long-term goal of research in my laboratory is to explore innovative therapeutic strategies and to develop novel therapeutic agents for cancer treatment through applying and integrating emerging knowledge and new concepts in cancer biology and cancer immunology.

My laboratory has a long track record of investigating cell signaling aberrations (such as addiction to mutations, overlapping signaling pathways, and feedback regulation) downstream of EGFR and HER2 to develop targeted cancer therapy. Through our published work, we have made significant contributions toward elucidating the mechanisms by which two FDA-approved therapeutic antibodies, cetuximab (an EGFR-targeting antibody) and trastuzumab (a HER2-targeting antibody), inhibit cancer cell survival and proliferation and induce cancer cell death and the mechanisms by which cancer cells resist cetuximab or trastuzumab treatment.

Our current research focuses on three major areas that are connected through hypoxia-inducible factor-1 (HIF-1), a key transcription factor that is regulated by signaling pathways downstream of EGFR and HER2 and that plays a multifaceted role in cancer development: (1) HIF-1-mediated cancer metabolism, via stimulation of aerobic glycolysis (i.e., the Warburg effect), inhibition of oxidative phosphorylation in mitochondria, and disruption of redox homeostasis; (2) HIF-1-regulated cancer metastasis, via activation of metastasis-related genes and stimulation of angiogenesis and lymphangiogenesis; and (3) HIF-1-mediated cancer immune escape, via regulation of immune checkpoint pathways.

We have developed several antibody engineering platforms for developing novel therapeutic agents for cancer treatment. By utilizing cutting-edge recombinant antibody technology and innovative strategies to engineer new bispecific antibodies and antibody fusion proteins, we are striving to develop second-generation antibody-based drugs that have multiple functions and thus are expected to work better than the first-generation antibody drugs, such as cetuximab and trastuzumab, currently used to treat cancer patients.

Office Address

The University of Texas MD Anderson Cancer Center
1515 Holcombe Blvd
Unit Number: 1950
Houston, TX 77030

Education & Training

Degree-Granting Education

1988 Shanghai Medical University, School of Graduate Studies (now Fudan University Graduate School), Shanghai, China, MS, Histology/Embryology
1985 Shanghai Medical University (SMU), School of Medicine (now Fudan University Shanghai Medical College), Shanghai, China, MD, Clinical Medicine

Selected Publications

Peer-Reviewed Original Research Articles

1. Liang K, Qiu S, Lu Y, Fan Z. Autocrine/paracrine erythropoietin regulates migration and invasion potential and the stemness of human breast cancer cells. Cancer Biol Ther 15(1), news press at e-Pub 1/2014. PMID: 24100272.
2. Ai M, Qiu S, Lu Y, Fan Z. HER2 regulates Brk/PTK6 stability via upregulating calpastatin, an inhibitor of calpain. Cell Signal 25(9):1754-61, 9/2013. e-Pub 5/2013. PMCID: PMC3703634.
3. Lu H, Li X, Luo Z, Liu J, Fan Z. Cetuximab reverses the Warburg effect by inhibiting HIF-1-regulated LDH-A. Mol Cancer Ther. e-Pub 8/2013. PMID: 23920275.
4. Xu J, Lu Y, Qiu S, Chen ZN, Fan Z. A novel role of EMMPRIN/CD147 in transformation of quiescent fibroblasts to cancer-associated fibroblasts by breast cancer cells. Cancer Lett 335(2):380-6, 7/2013. e-Pub 3/2013. PMID: 23474495.
5. Ai M, Liang K, Lu Y, Qiu S, Fan Z. Brk/PTK6 cooperates with HER2 and Src in regulating breast cancer cell survival and epithelial-to-mesenchymal transition. Cancer Biol Ther 14(3):237-45, 3/2013. e-Pub 1/2013. PMCID: PMC3595306.
6. Lu H, Liang K, Lu Y, Fan Z. The anti-EGFR antibody cetuximab sensitizes human head and neck squamous cell carcinoma cells to radiation in part through inhibiting radiation-induced upregulation of HIF-1α. Cancer Lett 322(1):78-85, 9/2012. e-Pub 2/2012. PMCID: PMC3361552.
7. Bristol ML, Di X, Beckman MJ, Wilson EN, Henderson SC, Maiti A, Fan Z, Gewirtz DA. Dual functions of autophagy in the response of breast tumor cells to radiation: Cytoprotective autophagy with radiation alone and cytotoxic autophagy in radiosensitization by vitamin D3. Autophagy 8(5). e-Pub 5/2012. PMID: 22498493.
8. Li X, Lu Y, Liang K, Hsu J-M, Albarracin C, Mills G B, Hung M-C, Fan Z. Brk/PTK6 sustains activated EGFR signaling through inhibiting EGFR degradation and transactivating EGFR. Oncogene, 1/2012. e-Pub 1/2012. PMCID: PMCPMC3326223.
9. Luwor RB, Lu Y, Li X, Liang K, Fan Z. Constitutively active Harvey Ras confers resistance to epidermal growth factor receptor-targeted therapy with cetuximab and gefitinib. Cancer Letters 306(1):85-91, 7/2011. e-Pub 3/2011. PMCID: PMC3102794.
10. Guo W, Chen D, Fan Z, Epstein HF. Differential turnover of myosin chaperone UNC-45A isoforms increases in metastatic human breast cancer. J. Mol biol. 412(3):365-78, 7/2011. e-Pub 7/2011. PMID: 21802425.
11. Zhang G, Brewster A, Guan B, Fan Z, Brown PH, Xu XC. Tumor-suppressor activity of RRIG1 in breast cancer. BMC Cancer 11(32), 1/2011. PMCID: PMC3037341.
12. Lu Y, Li X, Lu H, Fan Z. 1, 9-Pyrazoloanthrones downregulate HIF-1α and sensitize cancer cells to cetuximab-mediated anti-EGFR therapy. PLoS One 5(12), 12/2010. PMCID: PMC3012113.
13. Liang K, Esteva FJ, Albarracin C, Stemke-Hale K, Lu Y, Bianchini G, Yang CY, Li Y, Li X, Chen CT, Mills GB, Hortobagyi GN, Mendelsohn J, Hung MC, Fan Z. Recombinant human erythropoietin antagonizes trastuzumab treatment of breast cancer cells via Jak2-mediated Src activation and PTEN inactivation. Cancer Cell 18(8):401-2, 11/2010. PMCID: PMC3022383.
14. Li X, Lu Y, Pan T, Fan Z. Roles of autophagy in cetuximab-mediated cancer therapy against EGFR. Autophagy 6(8):1066-1077, 11/2010. e-Pub 11/2010. PMID: 20864811.
15. Chen M, Gu J, Delclos GL, Killary AM, Fan Z, Hildebrandt MA, Chamberlain RM, Grossman HB, Dinney CP, Wu X. Genetic variations of the PI3K-AKT-mTOR pathway and clinical outcome in muscle invasive and metastatic bladder cancer patients. Carcinogenesis 31(8):1387-1391, 8/2010. e-Pub 6/2010. PMCID: PMC2915631.
16. Li X, Fan Z. The EGFR antibody cetuximab induces autophagy in cancer cells by downregulating HIF-1α and Bcl-2 and activating the beclin-1/hVps34 complex. Cancer Res 70(14):5942–52, 7/2010. PMCID: PMC2933174.
17. Cardó-Vila M, Giordano RJ, Sidman RL, Bronk LF, Fan Z, Mendelsohn J, Arap W, Pasqualini R. From combinatorial peptide selection to drug prototype (II): Targeting the epidermal growth factor receptor pathway. Proc Natl Acad Sci U S A 107(11):5118–5123, 3/2010. e-Pub 2/2010. PMCID: PMC2841862.
18. Chen M, Cassidy A, Gu J, Delclos GL, Fan Z, Yang H, Hildebrandt MA, Lin J, Ye Y, Chamberlain RM, Dinney CP, Wu X. Genetic variations in PI3K-AKT-mTOR pathway and bladder cancer risk. Carcinogenesis 30(12):2047-2052, 12/2009. PMCID: PMC2792319.
19. Cunningham MP, Thomas H, Marks C, Green M, Fan Z, Modjtahedi H. Co-targeting the EGFR and IGF-IR with anti-EGFR monoclonal antibody ICR62 and the IGF-IR tyrosine kinase inhibitor NVP-AEW541 in colorectal cancer cells. Int J Oncol 33(5):1107-13, 11/2008. PMID: 18949375.
20. Li X, Lu Y, Liang K, Pan T, Mendelsohn J, Fan Z. Requirement of hypoxia-inducible factor-1 alpha downregulation in mediating the antitumor activity of the anti-epidermal growth factor receptor monoclonal antibody cetuximab. Mol Cancer Ther 7(5):1207-1217, 2008. PMID: 18483308.
21. Lu Y, Liang K, Li X, Fan Z. Responses of cancer cells with wild-type or tyrosine kinase domain-mutated epidermal growth factor receptor (EGFR) to EGFR-targeted therapy are linked to downregulation of hypoxia-inducible factor-1 alpha. Mol Cancer 6(63):63 (1-13), 10/2007. PMCID: PMC2117021.
22. Lu Y, Li X, Liang K, Luwor R, Siddik ZH, Mills GB, Mendelsohn J, Fan Z. Epidermal growth factor receptor (EGFR) ubiquitination as a mechanism of acquired resistance escaping treatment by the anti-EGFR monoclonal antibody cetuximab. Cancer Res 67:8240-8247, 9/2007. PMID: 17804738.
23. Adams KE, Ke S, Kwon S, Liang F, Fan Z, Lu Y, Hirschi K, Mawad ME, Barry MA, Sevick-Muraca EM. Comparison of visible and near-infrared wavelength-excitable fluorescent dyes for molecular imaging of cancer. J Biomed Opt 12(2):1-9, Mar-Apr, 2007. PMID: 17477732.
24. Cunningham MP, Thomas H, Fan Z, Modjtahedi H. Responses of human colorectal tumor cells to treatment with the anti-epidermal growth factor receptor monoclonal antibody ICR62 used alone and in combination with the EGFR tyrosine kinase inhibitor gefitinib. Cancer Res 66:7708-7715, 8/2006. PMID: 16885373.
25. Li X, Lu Y, Jin W, Liang K, Mills GB, Fan Z. Autophosphorylation of Akt at threonine-72 and serine-246: A potential mechanism of regulation of Akt kinase activity. J Biol Chem 281:13837-13843, 2006. e-Pub 3/2006. PMID: 16549426.
26. Liang K, Lu Y, Li X, Zeng X, Glazer IR, Mills GB, Fan Z. Differential roles of phosphoinositide-dependent protein kinase-1 and Akt1 expression and phosphorylation in breast cancer cell resistance to paclitaxel, doxorubicin, and gemcitabine. Mol Pharmacol 70:1045-1052, 2006. e-Pub 6/2006. PMID: 16782806.
27. Li X, Luwor RB, Lu Y, Liang K, Fan Z. Enhancement of antitumor activity of the anti-EGF receptor monoclonal antibody cetuximab/C225 by perifosine in PTEN-deficient cancer cells. Oncogene 25:525-535, 2006. PMID: 16170346.
28. Luwor RB, Lu Y, Li X, Mendelsohn J, Fan Z. The antiepidermal growth factor receptor monoclonal antibody cetuximab/C225 reduces hypoxia-inducible factor-1 alpha, leading to transcriptional inhibition of vascular endothelial growth factor expression. Oncogene 24:4433-4441, 6/2005. PMID: 15806152.
29. Li X, Lu Y, Liang K, Liu B, Fan Z. Differential responses to doxorubicin-induced phosphorylation and activation of Akt in human breast cancer cells. Breast Cancer Res 7:R589-597, 2005. PMCID: PMC1242125.
30. Nakata E, Hunter N, Mason K, Fan Z, Ang KK, Milas L. C225 antiepidermal growth factor receptor antibody enhances the efficacy of docetaxel chemoradiotherapy. Int J Radiat Oncol Biol Phys 59:1163-1173, 7/2004. PMID: 15234052.
31. Liang K, Ang KK, Milas L, Hunter N, Fan Z. The epidermal growth factor receptor mediates radioresistance. Int J Radiat Oncol Biol Phys 57:246-254, 9/2003. PMID: 12909240.
32. Jin W, Wu L, Liang K, Liu B, Lu Y, Fan Z. Roles of the PI-3K and MEK pathways in Ras-mediated chemoresistance in breast cancer cells. Br J Cancer 89:185-191, 7/2003. PMCID: PMC2394213.
33. Knuefermann C, Lu Y, Liu B, Jin W, Liang K, Wu L, Schmidt M, Mills GB, Mendelsohn J, Fan Z. HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene 22:3205-3212, 5/2003. PMID: 12761490.
34. Liang K, Jin W, Knuefermann C, Schmidt M, Mills GB, Ang KK, Milas L, Fan Z. Targeting the phosphatidylinositol 3-kinase/Akt pathway for enhancing breast cancer cells to radiotherapy. Mol Cancer Ther 2:353-360, 4/2003. PMID: 12700279.
35. Sclabas GM, Fujioka S, Schmidt C, Fan Z, Evans DB, Chiao PJ. Restoring apoptosis in pancreatic cancer cells by targeting the nuclear factor-kappaB signaling pathway with the anti-epidermal growth factor antibody IMC-C225. J Gastrointest Surg 7:37-43, 2003. PMID: 12559183.
36. Liu B, Peng D, Lu Y, Jin W, Fan Z. A novel single amino acid deletion caspase-8 mutant in cancer cells that lost proapoptotic activity. J Biol Chem 277:30159-30164, 8/2002. PMID: 12055196.
37. Sweeney P, Karashima T, Kim SJ, Kedar D, Mian B, Huang S, Baker C, Fan Z, Hicklin DJ, Pettaway CA, Dinney CP. Anti-vascular endothelial growth factor receptor 2 antibody reduces tumorigenicity and metastasis in orthotopic prostate cancer xenografts via induction of endothelial cell apoptosis and reduction of endothelial cell matrix metalloproteinase type 9 production. Clin Cancer Res 8:2714-2724, 8/2002. PMID: 12171905.
38. Karashima T, Sweeney P, Slaton JW, Kim SJ, Kedar D, Izawa JI, Fan Z, Pettaway C, Hicklin DJ, Shuin T, Dinney CP. Inhibition of angiogenesis by the antiepidermal growth factor receptor antibody ImClone C225 in androgen-independent prostate cancer growing orthotopically in nude mice. Clin Cancer Res 8:1253-1264, 5/2002. PMID: 12006546.
39. Patrick CW, Zheng B, Schmidt M, Herman PS, Chauvin BP, Fan Z, Stark B, Evans GR. Dermal fibroblasts genetically engineered to release nerve growth factor. Ann Plast Surg 47:660-665, 12/2001. PMID: 11756838.
40. Nasu S, Ang KK, Fan Z, Milas L. C225 antiepidermal growth factor receptor antibody enhances tumor radiocurability. Int J Radiat Oncol Biol Phys 51:474-477, 10/2001. PMID: 11567823.
41. Schmidt M, Fan Z. Protection against chemotherapy-induced cytotoxicity by cyclin-dependent kinase inhibitors (CKI) in CKI-responsive cells compared with CKI-unresponsive cells. Oncogene 20:6164-6171, 9/2001. PMID: 11593424.
42. Liu B, Fang M, Lu Y, Lu Y, Mills GB, Fan Z. Involvement of JNK-mediated pathway in EGF-mediated protection against paclitaxel-induced apoptosis in SiHa human cervical cancer cells. Br J Cancer 85:303-311, 7/2001. PMCID: PMC2364054.
43. Wen X, Wu QP, Lu Y, Fan Z, Charnsangavej C, Wallace S, Chow D, Li C. Poly(ethylene glycol)-conjugated anti-EGF receptor antibody C225 with radiometal chelator attached to the termini of polymer chains. Bioconjug Chem 12:545-553, 7/2001. PMID: 11459459.
44. Liu B, Fan Z. The monoclonal antibody 225 activates caspase-8 and induces apoptosis through a tumor necrosis factor receptor family-independent pathway. Oncogene 20:3726-3734, 6/2001. PMID: 11439335.
45. Wang L, Liu B, Schmidt M, Lu Y, Wels W, Fan Z. Antitumor effect of an HER2-specific antibody-toxin fusion protein on human prostate cancer cells. Prostate 47:21-28, 4/2001. PMID: 11304726.
46. Liu B, Fang M, Lu Y, Mendelsohn J, Fan Z. Fibroblast growth factor and insulin-like growth factor differentially modulate the apoptosis and G1 arrest induced by anti-epidermal growth factor receptor monoclonal antibody. Oncogene 20:1913-1922, 4/2001. PMID: 11313939.
47. Schmidt M, McWatters A, White RA, Groner B, Wels W, Fan Z, Bast RC, Jr. Synergistic interaction between an anti-p185HER-2 pseudomonas exotoxin fusion protein [scFv(FRP5)-ETA] and ionizing radiation for inhibiting growth of ovarian cancer cells that overexpress HER-2. Gynecol Oncol 80:145-155, 2/2001. PMID: 11161852.
48. Liu B, Fang M, Schmidt M, Lu Y, Mendelsohn J, Fan Z. Induction of apoptosis and activation of the caspase cascade by anti-EGF receptor monoclonal antibodies in DiFi human colon cancer cells do not involve the c-jun N-terminal kinase activity. Br J Cancer 82:1991-1999, 6/2000. PMCID: PMC2363248.
49. Schmidt M, Lu Y, Liu B, Fang M, Mendelsohn J, Fan Z. Differential modulation of paclitaxel-mediated apoptosis by p21Waf1 and p27Kip1. Oncogene 19:2423-2429, 5/2000. PMID: 10828884.
50. Milas L, Mason K, Hunter N, Petersen S, Yamakawa M, Ang K, Mendelsohn J, Fan Z. In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody. Clin Cancer Res 6:701-708, 2/2000. PMID: 10690556.
51. Fang M, Liu B, Schmidt M, Lu Y, Mendelsohn J, Fan Z. Involvement of p21Waf1 in mediating inhibition of paclitaxel-induced apoptosis by epidermal growth factor in MDA-MB-468 human breast cancer cells. Anticancer Res 20:103-111, 2000. PMID: 10769641.
52. Ye D, Mendelsohn J, Fan Z. Androgen and epidermal growth factor down-regulate cyclin-dependent kinase inhibitor p27Kip1 and costimulate proliferation of MDA PCa 2a and MDA PCa 2b prostate cancer cells. Clin Cancer Res 5:2171-2177, 8/1999. PMID: 10473102.
53. Chou JL, Fan Z, DeBlasio T, Koff A, Rosen N, Mendelsohn J. Constitutive overexpression of cyclin D1 in human breast epithelial cells does not prevent G1 arrest induced by deprivation of epidermal growth factor. Breast Cancer Res Treat 55:267-83, 6/1999. PMID: 10517171.
54. Ciardiello F, Bianco R, Damiano V, De Lorenzo S, Pepe S, De Placido S, Fan Z, Mendelsohn J, Bianco AR, Tortora G. Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225. Clin Cancer Res 5:909-916, 4/1999. PMID: 10213228.
55. Ye D, Mendelsohn J, Fan Z. Augmentation of a humanized anti-HER2 mAb 4D5 induced growth inhibition by a human-mouse chimeric anti-EGF receptor mAb C225. Oncogene 18:731-738, 1/1999. PMID: 9989823.
56. Bromberg JF, Fan Z, Brown C, Mendelsohn J, Darnell JE, Jr. Epidermal growth factor-induced growth inhibition requires Stat1 activation. Cell Growth Differ 9:505-512, 7/1998. PMID: 9690618.
57. Fan Z, Shang BY, Lu Y, Chou JL, Mendelsohn J. Reciprocal changes in p27(Kip1) and p21(Cip1) in growth inhibition mediated by blockade or overstimulation of epidermal growth factor receptors. Clin Cancer Res 3:1943-1948, 11/1997. PMID: 9815583.
58. Peng D, Fan Z, Lu Y, DeBlasio T, Scher H, Mendelsohn J. Anti-epidermal growth factor receptor monoclonal antibody 225 up-regulates p27KIP1 and induces G1 arrest in prostatic cancer cell line DU145. Cancer Res 56:3666-3669, 8/1996. PMID: 8706005.
59. Wu X, Rubin M, Fan Z, DeBlasio T, Soos T, Koff A, Mendelsohn J. Involvement of p27KIP1 in G1 arrest mediated by an anti-epidermal growth factor receptor monoclonal antibody. Oncogene 12:1397-403, 4/1996. PMID: 8622855.
60. Wu X, Fan Z, Masui H, Rosen N, Mendelsohn J. Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin. J Clin Invest 95:1897-1905, 1995. PMID: 7706497.
61. Fan Z, Lu Y, Wu X, DeBlasio A, Koff A, Mendelsohn J. Prolonged induction of p21Cip1/WAF1/CDK2/PCNA complex by epidermal growth factor receptor activation mediates ligand-induced A431 cell growth inhibition. J Cell Biol 131:235-242, 1995. PMID: 7559780.
62. Tang ZY, Yu YQ, Zhou XD, Ma ZC, Yang BH, Lin ZY, Lu JZ, Liu KD, Fan Z, Zeng ZC. Treatment of unresectable primary liver cancer: with reference to cytoreduction and sequential resection. World J Surg 19:47-52, 1995. PMID: 7740810.
63. Fan Z, Lu Y, Wu X, Mendelsohn J. Antibody-induced epidermal growth factor receptor dimerization mediates inhibition of autocrine proliferation of A431 squamous carcinoma cells. J Biol Chem 269:27595-27602, 11/1994. PMID: 7961676.
64. Fan Z, Baselga J, Masui H, Mendelsohn J. Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well-established A431 cell xenografts. Cancer Res 53:4637-4642, 10/1993. PMID: 8402640.
65. Fan Z, Mendelsohn J, Masui H, Kumar R. Regulation of epidermal growth factor receptor in NIH3T3/HER14 cells by antireceptor monoclonal antibodies. J Biol Chem 268:21073-21079, 10/1993. PMID: 8407944.
66. Fan Z, Masui H, Altas I, Mendelsohn J. Blockade of epidermal growth factor receptor function by bivalent and monovalent fragments of 225 anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 53:4322-4328, 9/1993. PMID: 8364927.

Last updated: 9/1/2015