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
My laboratory has a track record in investigating the mechanism of action by which trastuzumab (a HER2-targeting antibody) and cetuximab (an EGFR-targeting antibody), 2 FDA-approved therapeutic antibodies, inhibit cancer metabolism (i.e., Warburg effect), tumor angiogenesis, cancer cell stemness, and cancer cell interaction with tumor stroma in the treatment of metastatic breast cancer, colorectal cancer, or head and neck cancer. Through our published work, we also made significant contributions toward our understanding on how aberrations in cancer cell signaling molecules (e.g. Akt, MAPK, MEK, mTOR, PI3K, PTEN, AMPK, Brk, LKB1, HIF-1α, STATs) and signal pathways downstream to HER2 and EGFR render cancer cell resistance to the therapeutic antibodies.
Our current research focuses on 2 directions leveraging existing resources in the laboratory and our expertise in cancer biology, tumor immunology, and antibody engineering & therapies. One direction is to improve antitumor activity of therapeutic antibodies by developing novel bispecific antibody (BsAbs). We design novel platforms of BsAbs for gaining of new mechanism of action, through which BsAbs will exhibit new therapeutic activities that do not exist in simple mixture of 2 parental antibodies. We are currently developing several BsAbs and testing their therapeutic activities in syngeneic mouse tumor models and in PDXs hosted in humanized mice. Our goal is to develop second-generation antibody-based drugs that have multiple therapeutic activities and thus are expected to be more effective than first-generation antibody drugs currently approved to treat cancer patients, such as trastuzumab and cetuximab, especially for treatment of cancer metastasis. Another direction is to redirect preexisting immunity acquired through vaccination or infection of infectious viruses for treating cancer metastasis. Our strategy is to develop an antibody targeting-based therapeutic approach to trick host immune system to perceive cancer cells as infectious virus-infected cells and thereby launch immune responses to attack the cancer cells using powerful preexisting immunity acquired via vaccination or infection of an infectious virus. We have successfully validated this novel strategy in preclinical mouse tumor models.
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
- Lu H, Lu Y, Xie Y, Qiu S, Li X, Fan Z. Rational combination with PDK1 inhibition overcomes cetuximab resistance in head and neck squamous cell carcinoma. JCI Insight 4(19), 2019. e-Pub 2019. PMID: 31578313.
- 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 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.
- 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.
- 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.
- 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.
- 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.
- 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, 2014. e-Pub 2013. PMID: 24100272.
- 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):2187-99, 2013. e-Pub 2013. PMID: 23920275.
- 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.
- 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.
- 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, 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.
Grant & Contract Support
| Title: | Exploration of novel potential therapies for breast cancer |
| Funding Source: | Breast Cancer Research Foundation |
| Role: | Principal Investigator |
| Title: | PDK1, a preferred therapeutic target for the PI-3 kinase pathway in human breast cancer |
| Funding Source: | DOD/Congressionally Directed Medical Research Programs (DOD/CDMRP) |
| Role: | Principal Investigator |
| Title: | Role of PKB/Akt pathway in breast cancer chemotherapy |
| Funding Source: | DOD/Congressionally Directed Medical Research Programs (DOD/CDMRP) |
| Role: | Principal Investigator |
| Title: | Breast tumor kinase as a complementary target for sensitizing breast cancer to epidermal growth factor receptor-targeted therapy |
| Funding Source: | DOD/Congressionally Directed Medical Research Programs (DOD/CDMRP) |
| Role: | Principal Investigator |
| Title: | Unraveling a novel role of Brk in regulating EGFR in triple-negative breast cancer |
| 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: | 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 (CPRIT) |
| Role: | Principal Investigator |
| Title: | A novel role of EMMPRIN in activation of cancer-associated fibroblasts in breast cancer |
| Funding Source: | DOD/Congressionally Directed Medical Research Programs (DOD/CDMRP) |
| Role: | Principal Investigator |
| Title: | Developing a novel recombinant antibody for treatment of oral cancer |
| Funding Source: | NIH/NIDCR |
| Role: | Principal Investigator |
| Title: | A novel targeted therapy for HNSCC based on a novel activity of cetuximab |
| Funding Source: | NIH/NCI |
| Role: | Principal Investigator |
| Title: | Development of a novel strategy for tumor delivery of MHC-I-compatible peptides for cancer immunotherapy |
| Funding Source: | Cancer Prevention & Research Institute of Texas (CPRIT) |
| Role: | Principal Investigator |
| Title: | Developing novel bispecific antibodies for cancer treatment |
| Funding Source: | NIH/NCI |
| Role: | Principal Investigator |