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.