Zhen Fan, M.D.
Department of Experimental Therapeutics, Division of Cancer Medicine
Present Title & Affiliation
Primary Appointment
Professor, 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 tumor immunology. My current major research activity is to develop innovative bispecific antibody-based cancer therapies, with a focus on elements related to anti-tumor angiogenic immunotherapy.
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.
My current research projects focus 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.
Education & Training
Degree-Granting Education
| 1988 | Shanghai Medical University, School of Graduate Studies (now Fudan University Graduate School), Shanghai, CHN, MS, Histology/Embryology |
| 1985 | Shanghai Medical University (SMU), School of Medicine (now Fudan University Shanghai Medical College), Shanghai, CHN, MD, Clinical Medicine |
Selected Publications
Peer-Reviewed Articles
- Chaganty BKR, Qiu S, Gest A, Lu Y, Ivan C, Calin GA, Weiner LM, Fan Z. Trastuzumab upregulates PD-L1 as a potential mechanism of trastuzumab resistance through engagement of immune effector cells and stimulation of IFNγ secretion. Cancer Lett 430:47-56, 2018. e-Pub 2018. PMID: 29746929.
- Luo J, Hong Y, Lu Y, Qiu S, Chaganty BK, Zhang L, Wang X, Li Q, Fan Z. Acetyl-CoA carboxylase rewires cancer metabolism to allow cancer cells to survive inhibition of the Warburg effect by cetuximab. Cancer Lett 384:39-49, 2017. e-Pub 2016. PMID: 27693630.
- Lu H, Li X, Lu Y, Qiu S, Fan Z. ASCT2 (SLC1A5) is an EGFR-associated protein that can be co-targeted by cetuximab to sensitize cancer cells to ROS-induced apoptosis. Cancer Lett 381(1):23-30, 2016. e-Pub 2016. PMID: 27450723.
- Lu Y, Shi C, Qiu S, Fan Z. Identification and validation of COX-2 as a co-target for overcoming cetuximab resistance in colorectal cancer cells. Oncotarget 7(40):64766-64777, 2016. PMID: 27074568.
- Chaganty BK, Lu Y, Qiu S, Somanchi SS, Lee DA, Fan Z. Trastuzumab upregulates expression of HLA-ABC and T cell costimulatory molecules through engagement of natural killer cells and stimulation of IFNγ secretion. Oncoimmunology 5(4):e1100790, 2016. e-Pub 2015. PMID: 27141382.
- Ai Z, Lu Y, Qiu S, Fan Z. Overcoming cisplatin resistance of ovarian cancer cells by targeting HIF-1-regulated cancer metabolism. Cancer Lett 373(1):36-44, 2016. e-Pub 2016. PMID: 26801746.
- Khelwatty SA, Essapen S, Seddon AM, Fan Z, Modjtahedi H. Acquired resistance to anti-EGFR mAb ICR62 in cancer cells is accompanied by an increased EGFR expression, HER-2/HER-3 signalling and sensitivity to pan HER blockers. Br J Cancer 113(7):1010-9, 2015. e-Pub 2015. PMID: 26372697.
- Li X, Lu Y, Lu H, Luo J, Hong Y, Fan Z. AMPK-mediated energy homeostasis and associated metabolic effects on cancer cell response and resistance to cetuximab. Oncotarget 6(13):11507-18, 2015. e-Pub 2015. PMID: 25871473.
- 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, 2013. e-Pub 2013. PMID: 23707532.
- 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, 2012. e-Pub 2012. PMID: 22348829.
- 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, 2010. PMID: 21075308.
- Li X, Lu Y, Pan T, Fan Z. Roles of autophagy in cetuximab-mediated cancer therapy against EGFR. Autophagy 6(8):1066-1077, 2010. e-Pub 2010. PMID: 20864811.
- 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, 2010. PMID: 20634405.
- 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, 2010. e-Pub 2010. PMID: 20190183.
- 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.
- 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, 2005. PMID: 15806152.
- Liang K, Lu Y, Jin W, Ang KK, Milas L, Fan Z. Sensitization of breast cancer cells to radiation by trastuzumab. Mol Cancer Ther 2:1113-20, 2003. PMID: 14617784.
- 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 12(10). e-Pub 2013. PMID: 23920275.
- 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):89-98. e-Pub 2014. PMID: 24100272.
Grant & Contract Support
| Title: | Development of a novel anti-EGFR antibody-protamine recombinant protein for in vivo delivery of small interfering RNAs for cancer therapy |
| Funding Source: | Cancer Prevention Research Institute of Texas |
| Role: | Principal Investigator |
| Title: | Developing a novel recombinant antibody for treatment of oral cancer |
| Funding Source: | NIH/NIDCR |
| Role: | Principal Investigator |
| Title: | Targeting transformation of fibroblasts to cancer-associated fibroblasts for breast cancer therapy |
| Funding Source: | DOD/Congressionally Directed Medical Research Programs (DOD/CDMRP) |
| Role: | Principal Investigator |
| Title: | Mechanisms of tumor resistance to anti-HER/ErbB therapeutics |
| Funding Source: | NIH/NCI |
| Role: | Principal Investigator |
| Title: | Exploration of novel potential therapies for breast cancer |
| Funding Source: | The Breast Cancer Research Foundation |
| Role: | Principal Investigator |
| Title: | A novel targeted therapy for HNSCC based on a novel activity of cetuximab |
| Funding Source: | NIH/NCI |
| Role: | Principal Investigator |