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:
2003
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 348:203-13, 2003
(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, 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
63:4225-31, 2003
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 63:3403-12, 2003
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 9:264-72, 2003
2004
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 10:950-8, 2004
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 10:942-9,
2004
2005
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 65:925-32,
2005
2006
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 103:9136-41, 2006
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 66:4627-35, 2006
2007
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 13:5314-21, 2007
2008
Zhang L, Volinia S, Bonome T, Calin GA, Greshock J, Yang N,
Liu CG, 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, Huang Q,
Butzow R, Rustgi AK, Weber BL, Birrer MJ, Hatzigeorgiou AG,
Croce CM, Coukos G: Genomic and epigenetic alterations
deregulate microRNA expression in human epithelial ovarian
cancer. Proc Natl Acad Sci U S A 105:7004-9, 2008
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 10:202-10, 2008
Yang N, Coukos G, Zhang L: MicroRNA epigenetic alterations
in human cancer: one step forward in diagnosis and
treatment. Int J Cancer 122:963-8, 2008
Deng S, Calin GA, Croce CM, Coukos G, Zhang L: Mechanisms
of microRNA deregulation in human cancer. Cell Cycle
7:2643-6, 2008
Baira E, Greshock J, Coukos G, Zhang L: Ultraconserved
elements: Genomics, function and disease. RNA Biol 5, 2008
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 7:255-64, 2008
(Published with comment by Corn PG: Hypoxic regulation of
miR-210: shrinking targets expand HIF-1's influence.Cancer
Biol Ther. 2008 Feb;7(2):255-64.)
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 3:e1758, 2008
Yang N, Kaur S, Volinia S, Greshock J, Lassus H, Hasegawa
K, Liang S, Leminen A, Deng S, Smith L, Johnstone CN, Chen
XM, Liu CG, Huang Q, Katsaros D, Calin GA, Weber BL, Butzow
R, Croce CM, Coukos G, Zhang L: MicroRNA microarray
identifies Let-7i as a novel biomarker and therapeutic
target in human epithelial ovarian cancer. Cancer Res
68:10307-14, 2008 (Published as highlight article)
2009
Deng S, He L, Coukos G, Zhang L: Expression profile of
microRNA in epithelial cancer: diagnosis, classification
and prediction. Expert Opin Med Diagnostics 3:25-36, 2009
Liang S, Yang N, Pan Y, Deng S, Lin X, Yang X, Katsaros D,
Roby KF, Hamilton TC, Connolly DC, Coukos G, Zhang L:
Expression of Activated PIK3CA in Ovarian Surface
Epithelium Results in Hyperplasia but Not Tumor Formation.
PLoS ONE 4:e4295, 2009