Research Interests
Epithelial ovarian cancer continues to be the leading cause of death among gynecological malignancies. The lack of preventive strategies, early diagnostic methods and effective therapies to treat recurrent ovarian tumors creates a pressing need to understand its pathogenesis and to identify molecular targets for therapy. Cancer is a disease involving multi-step dynamic changes in the genome. However, the oncogenic events as well as their cooperation that promote malignant transformation and growth in ovarian carcinoma remain largely unknown. The work in our laboratory focuses on the characterization of the genetic and genomic alterations in human epithelial ovarian cancer and the development of novel strategies for both diagnosis and treatment of this disease.

The function of PIK3CA in ovarian cancer. Phosphatidylinositol 3-kinase is a novel intracellular transducer with lipid substrate specificity, which is involved in a wide range of cancer-associated signaling pathways. Gene encoding the catalytic subunit α of phosphoinositide 3-kinase (PIK3CA) has been implicated to hold a central position in ovarian malignancy. In the light of our recent results, we hypothesize that PIK3CA plays a key role in early events during malignant transformation of ovarian surface epithelium (OSE). Furthermore, the activation of PIK3CA may be critical for the maintenance and survival of established ovarian carcinoma, via at least two mechanisms, namely: (i) by promoting the survival and proliferation of tumor cells and (ii) by promoting angiogenesis and suppressing anti-tumor immune response. This study will provide critical insights into the function of PIK3CA in ovarian carcinoma pathogenesis and delineate the rationale for its therapeutic targeting.

The signature and function of microRNAs in ovarian cancer. Studies of the human cancer genome have so far focused heavily on the protein-coding genes, whereas our knowledge on the role of those functional, non-coding genomic sequences is at its infancy. Our current study intends to fill this gap in ovarian cancer. MicroRNAs (miRNAs) are ~22 nucleotide non-coding RNAs, which regulate the expression of protein-coding genes and are implicated in the control of a number of biological processes such as development; stem cell homeostasis; hematopoiesis as well as malignant transformation. In our lab, we have generated the first evidence that miRNAs exhibit widespread genomic gains and/or losses in ovarian cancer, resulting in concordant changes in mature miRNA gene expression. We further hypothesize that miRNA deregulation plays a critical role in ovarian malignant transformation and/or tumor progression, and that investigation of the miRNome in ovarian cancer will reveal novel biomarkers and targets for therapy. Given the power of miRNome for class prediction in cancer, we are hoping that yielded signatures will address two crucial clinical management issues, namely, the identification of early-stage high-risk disease in need for adjuvant therapy and the identification of patients that will not respond to standard chemotherapy in need for alternate frontline drugs.

Selected Publications:
Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 2003; 348:203-13.

Published with comment by Boon, T. and van Baren, N.: Immunosurveillance against cancer and immunotherapy - synergy or antagonism? N Engl J Med, 348: 252-254.

Zhang L, Yang N, Conejo-Garcia JR, Katsaros D, Mohamed-Hadley A, Fracchioli S, Schlienger K, Toll A, Levine B, Rubin SC, Coukos G. Expression of endocrine gland-derived vascular endothelial growth factor in ovarian carcinoma. Clin Cancer Res 2003; 9:264-72.
Zhang L, Yang N, Katsaros D, Huang W, Park JW, Fracchioli S, Vezzani C, Rigault de la Longrais IA, Yao W, Rubin SC, Coukos G. The oncogene phosphatidylinositol 3'-kinase catalytic subunit alpha promotes angiogenesis via vascular endothelial growth factor in ovarian carcinoma. Cancer Res 2003; 63:4225-31.

Zhang L, Yang N, Mohamed-Hadley A, Rubin SC, Coukos G. Vector-based RNAi, a novel tool for isoform-specific knock-down of VEGF and anti-angiogenesis gene therapy of cancer. Biochem Biophys Res Commun 2003; 303:1169-78.

Zhang L, Yang N, Park JW, Katsaros D, Fracchioli S, Cao G, O'Brien-Jenkins A, Randall TC, Rubin SC, Coukos G. Tumor-derived vascular endothelial growth factor up-regulates angiopoietin-2 in host endothelium and destabilizes host vasculature, supporting angiogenesis in ovarian cancer. Cancer Res 2003; 63:3403-12.

Yang N, Zhang L, Zhang Y, Kazazian HH, Jr. An important role for RUNX3 in human L1 transcription and retrotransposition. Nucleic Acids Res 2003; 31:4929-40.

Conejo-Garcia JR, Benencia F, Courreges MC, Gimotty PA, Khang E, Buckanovich RJ, Frauwirth KA, Zhang L, Katsaros D, Thompson CB, Levine B, Coukos G. Ovarian carcinoma expresses the NKG2D ligand Letal and promotes the survival and expansion of CD28- antitumor T cells. Cancer Res 2004; 64:2175-82.

Conejo-Garcia JR, Benencia F, Courreges MC, Kang E, Mohamed-Hadley A, Buckanovich RJ, Holtz DO, Jenkins A, Na H, Zhang L, Wagner DS, Katsaros D, Caroll R, Coukos G. Tumor-infiltrating dendritic cell precursors recruited by a beta-defensin contribute to vasculogenesis under the influence of Vegf-A. Nat Med 2004; 10:950-8.

Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004; 10:942-9.

Yang Y, Cui Y, Wang W, Zhang L, Bufford L, Sasaki S, Fan Z, Nishimura H. Molecular and functional characterization of a vasotocin-sensitive aquaporin water channel in quail kidney. Am J Physiol Regul Integr Comp Physiol 2004; 287:R915-24.

Zhang L, Yang N, Liang S, Barchetti A, Vezzani C, Huang J, O'Brien-Jenkins A, Rubin SC, Coukos G. RNA interference: a potential strategy for isoform-specific phosphatidylinositol 3-kinase targeted therapy in ovarian cancer. Cancer Biol Ther 2004; 3:1283-9.

Benencia F, Courreges MC, Conejo-Garcia JR, Buckanovich RJ, Zhang L, Carroll RH, Morgan MA, Coukos G. Oncolytic HSV exerts direct antiangiogenic activity in ovarian carcinoma. Hum Gene Ther 2005; 16:765-78.

Benencia F, Courreges MC, Conejo-Garcia JR, Mohamed-Hadley A, Zhang L, Buckanovich RJ, Carroll R, Fraser N, Coukos G. HSV oncolytic therapy upregulates interferon-inducible chemokines and recruits immune effector cells in ovarian cancer. Mol Ther 2005; 12:789-802.

Yang N, Zhang L, Kazazian HH, Jr. L1 retrotransposon-mediated stable gene silencing. Nucleic Acids Res 2005; 33:e57.

Zhang L, Yang N, Huang J, Buckanovich RJ, Liang S, Barchetti A, Vezzani C, O'Brien-Jenkins A, Wang J, Ward MR, Courreges MC, Fracchioli S, Medina A, Katsaros D, Weber BL, Coukos G. Transcriptional coactivator Drosophila eyes absent homologue 2 is up-regulated in epithelial ovarian cancer and promotes tumor growth. Cancer Res 2005; 65:925-32.

Cao G, Savani RC, Fehrenbach M, Lyons C, Zhang L, Coukos G, Delisser HM. Involvement of endothelial CD44 during in vivo angiogenesis. Am J Pathol 2006; 169:325-36.

Courreges MC, Benencia F, Conejo-Garcia JR, Zhang L, Coukos G. Preparation of apoptotic tumor cells with replication-incompetent HSV augments the efficacy of dendritic cell vaccines. Cancer Gene Ther 2006; 13:182-93.

Zhang L, Coukos G. MicroRNAs: a new insight into cancer genome. Cell Cycle 2006; 5:2216-9.

Zhang L, Huang J, Yang N, Greshock J, Megraw MS, Giannakakis A, Liang S, Naylor TL, Barchetti A, Ward MR, Yao G, Medina A, O'Brien-Jenkins A, Katsaros D, Hatzigeorgiou A, Gimotty PA, Weber BL, Coukos G. microRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci U S A 2006; 103:9136-41.

Zhang L, Huang J, Yang N, Liang S, Barchetti A, Giannakakis A, Cadungog MG, O'Brien-Jenkins A, Massobrio M, Roby KF, Katsaros D, Gimotty P, Butzow R, Weber BL, Coukos G. Integrative genomic analysis of protein kinase C (PKC) family identifies PKCiota as a biomarker and potential oncogene in ovarian carcinoma. Cancer Res 2006; 66:4627-35.

Gimotty PA, Zhang L, Alagkiozidis I, Cadungog M, Adams S, Chu C, Katsaros D, Coukos G. Immune prognostic factors in ovarian cancer: lessons from translational research. Dis Markers 2007; 23:445-52.

Greshock J, Nathanson K, Martin AM, Zhang L, Coukos G, Weber BL, Zaks TZ. Cancer cell lines as genetic models of their parent histology: analyses based on array comparative genomic hybridization. Cancer Res 2007; 67:3594-600.

Zhang L, Huang J, Yang N, Greshock J, Liang S, Hasegawa K, Giannakakis A, Poulos N, O'Brien-Jenkins A, Katsaros D, Butzow R, Weber BL, Coukos G. Integrative Genomic Analysis of Phosphatidylinositol 3'-Kinase Family Identifies PIK3R3 as a Potential Therapeutic Target in Epithelial Ovarian Cancer. Clin Cancer Res 2007; 13:5314-21.

Giannakakis A, Coukos G, Hatzigeorgiou A, Sandaltzopoulos R, Zhang L. miRNA genetic alterations in human cancers. Expert Opin Biol Ther 2007; 7:1375-86.

Giannakakis A, Sandaltzopoulos R, Greshock J, Liang S, Huang J, Hasegawa K, Li C, O'Brien-Jenkins A, Katsaros D, Weber BL, Simon C, Coukos G, Zhang L. miR-210 links hypoxia with cell cycle regulation and is deleted in human epithelial ovarian cancer. Cancer Biol Ther 2007; 7. 255-64.

Holtz DO, Krafty RT, Mohamed-Hadley A, Zhang L, Alagkiozidis I, Leiby B, Guo W, Gimotty PA, Coukos G. Should tumor VEGF expression influence decisions on combining low-dose chemotherapy with antiangiogenic therapy? Preclinical modeling in ovarian cancer. J Transl Med 2008; 6:2.

Huang Q, Gumireddy K, Schrier M, le Sage C, Nagel R, Nair S, Egan DA, Li A, Huang G, Klein-Szanto AJ, Gimotty PA, Katsaros D, Coukos G, Zhang L, Pure E, Agami R. The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis. Nat Cell Biol 2008; 10:202-10.

Zhang L, Volinia S, Bonome T, Calin GA, Greshock J, Yang N, Liu C-G, Giannakakis A, Alexiou P, Hasegawa K, Johnstone CN, Megraw MS, Adams S, Lassus H, Huang J, Kaur S, Liang S, Sethupathy P, Leminen A, Simossis VA, Sandaltzopoulos R, Naomoto Y, Katsaros D, Gimotty PA, DeMichele A, et al. Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer. Proc Natl Acad Sci U S A 2008; 0801615105.

Yang N, Coukos G, Zhang L. MicroRNA epigenetic alterations in human cancer: one step forward in diagnosis and treatment. Int J Cancer 2008; 122:963-8.

Yang N, Huang J, Greshock J, Liang S, Barchetti A, Hasegawa K, Kim S, Giannakakis A, Li C, O'Brien-Jenkins A, Katsaros D, Butzow R, Coukos G, Zhang L. Transcriptional regulation of PIK3CA oncogene by NF-kappaB in ovarian cancer microenvironment. PLoS ONE 2008; 3:e1758.