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Kenneth P. Nephew Lab

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Ph.D., Ohio State University, 1991

Professor Cellular and Integrative Physiology and Obstetrics and Gynecology

Director, Graduate Education

Assistant Director for Basic Science Research

Program Leader, Walther Cancer Foundation

Email:  knephew@indiana.edu

Office Phone: (812) 855-9445

Lab Phone: (812) 855-1574  

IU Simon Cancer Center 

 

 

Give to The Ovarian Cancer Research Fund

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        Pictured from left to right,  Jessica Tang, Ali Ozes,Yinu Wang, and Nick Pulliam

Pictured from left to right,  Kenneth P. Nephew, David Miller, Fang Fang, Ali Ozes, Yinu Wang, Jessica Tang, Jay Pilrose, and Nick Pulliam.



                                                                                                                                                            Current Nephew Lab Members:

Faculty, Postdocs, Visiting Scholars
Fang Fang, MD, PhD; Research Assistant Professor
Quinyao Zuo, MD

Graduate Students
Ali Ozes, BS; PhD candidate
Nick Pulliam, BS
Jessica Tang, MS
Yinu Wang, BS

Research Associates
David F.B. Miller, BS
Jay Pilrose, MS

Undergraduates
Shokhi Goel

 

Current research studies are focused in the following areas:

  • Cancer epigenetics and epigenetic therapies
  • Translational research in female malignancies (ovarian cancer, breast cancer)
  • Nuclear receptors and steroid hormone action
  • Cancer Biomarkers

Active research projects ongoing in my lab are focused on cancer epigenetics, cancer stem cells, cancer biomarkers, and estrogen receptor biology. Graduate students, post doctoral fellows, research technicians, undergraduates, and senior research scientists are actively working in my laboratory on all of these important areas of cancer.

We have recently isolated and characterized human ovarian cancer initiating cells (also known as cancer stem cells) and have begun a comprehensive assessment of ovarian cancer stem/progenitor cell epigenetics. Our goal is to target the biologic pathways critical to ovarian tumor initiating cells. In addition, DNA methylation biomarkers may represent a promising approach for the assessment and management of ovarian cancer, an avenue of research my laboratory is currently pursuing in an ovarian cancer clinical trial.

Towards the understanding of cancer as a complex biological and biochemical system, we are using experimental and computational approaches to gain new insights into the development and progression of cancer through a systems-wide approach. Our Center for Integrative Cancer Biology is collaborating with colleagues at the University of Texas Health Science Center-San Antonio and the  Ohio State University. This integrative and multi-disciplinary effort incorporates a spectrum of new technologies, such as epigenomics and methylation microarrays, to generate computer and mathematical models that may predict cancer epigenetic processes.

We are investigating the antiproliferative effects of endocrine therapies on breast cancer cells. Many patients who initially respond to these therapies ultimately relapse, having acquired resistance. Unfortunately, resistance can lead to aggressive disease progression and metastasis, conferring poorer patient outlook. Thus, acquired resistance constitutes a significant clinical problem with all treatment approaches examined to date. To better understand acquired resistance and develop additional therapeutic strategies for the management of breast cancer, my laboratory has developed novel breast cancer cell culture models representing acquired resistance to tamoxifen, fulvestrant and aromatase inhibitors. These pre-clinical models representing breast cancer cells able to harness distinctly dissimilar pathways in response to the anti-hormone strategies currently in clinical use are a focus of my current and future breast cancer studies.

Research Funding (Active Grants)

DNA Methylation and Ovarian Cancer
NCI CA85289-08 (Nephew, K.)
The major goal of this competitive renewal project is to isolate and fully characterize ovarian cancer stem cells (OCSC) from tumor samples. The OCSC will be examined both in vivo and in vitro using xenograft models. Reponses of the OCSC to epigenetic therapies will also be assessed.

Interrogating Epigenetic Changes in Cancer Genomes (The Integrative Cancer Biology Program (ICBP): Centers for Cancer Systems Biology (CCSB)
NCI- U54 CA113001-07 (Huang, TH)
The major goals of this project are to utilize mathematical models to explore epigenetic changes associated with drug resistant cancer.  Genome wide approaches to examine DNA methylation, histone modifications, microRNAs, and gene expression will be the mainstay of this competitive renewal from the OSU-IU-CCSB.

An Epigenetic Strategy for Restoring Carboplatin Sensitivity in Ovarian Cancer
NCI- R01 CA182832 (Matei, D., Nephew, K.P.)
This project will identify the critical epigenetic (DNA methylation) events that govern the development of platinum resistance, which can then serve as predictive markers of response to epigenetic-targeting strategies.

Epigenetic Modulation of Platinum Anti-Tumor Activity in Ovarian Cancer
Ovarian Cancer Research Fund (Nephew, K.P.)
The long term goal of this project is to establish interventions targeting the epigenome as a new therapeutic strategy for ovarian cancer. 

MEK5-Erk5 pathways in survival signaling and tumor progression to drug resistance
NCI R01 CA125806-02 (Burow, M.)
The long-term goal of this research is to understand the role of the MEK5-Erk5 signaling pathway in the tumorigenesis and resistance of breast carcinoma with the goal of developing targeting strategies for therapeutic intervention.

Novel Bioconjugates as Probes of Estrogen Receptors
NIDKK R01 DK075376-04 (Weatherman, R.)
The long-term goal of this proposed research is to elucidate the molecular details of estrogen signaling in the context of other signaling pathways in the cell and how crosstalk with these signaling pathways dictate the response profiles of estrogen-mimicking drugs.Role:  Co-investigator

Testing Genotype-Hormone Associations in Circumpolar Ancestral and Descendant Populations
NSF ARC-1142201 (Vitzthum,V)

Goals (1) understand women’s  reproductive functioning is affected by and has potentially adapted to circumpolar physical environments, and (2)  consequences of biology-environment interactions for human demographic patterns and individual well-being in arctic populations.Role:  Co-investigator

Antitumor Activity Of SGI-110 In Combination With Platinum In Preclinical Models Of Treatment Naïve And Resistant, Recurrent Epithelial Ovarian Cancer
Astex Pharmaceuticals

The central goal for this project is that SGI-110 in combination with platinum exerts potent antitumor activity in preclinical models of treatment naïve and resistant, recurrent epithelial ovarian cancer.

Walther Cancer Foundation Postdoctoral Fellowship (Nephew)
Title:  Cancer Epigenetics 
Duration:  2010-2014
Role: MENTOR, Fang Fang, Postdoctoral Fellow

Representative Publications

  • Hsu P-Y, Hsu H-K, Singer GAC, Yan PS, Rodriguez BAT, Liu JC, Weng YI, Deatherage DE, Chen Z, Pereira JS, Lopez R, Russo J, Wang Q, Lamartiniere CA, Nephew KP, Huang TH-M. 2010  Estrogen-mediated epigenetic repression of large chromosomal regions through DNA looping.  Genome Res, 20:733-44 PMC2877570
  • Fang F, Balch C, Schilder S, Breen T, Zhang S, Shen C, Li L, Kulesavage C, Snyder AJ, Nephew KP*, Matei DE*.  2010  A phase I and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent, platinum-resistant, epithelial ovarian cancer. Cancer, 116:4043-53 (*corresponding authors) PMC2930033
  • Rao X Di Leva G Li M, Fang F, Hartman-Frey C, Burow  ME,  Croce C,  Nephew KP. 2011  MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways.  Oncogene,30:1082-97 PMC3342929
  • Garofalo M, Romano G, Di Leva G, Nuovo G, Jeon YG, Ngankeu A, Sun J, Lovat F, Alder H, Condorelli G, Engelman KA, Ono M, Rho JK, Volinia S, Nephew KP, Croce CM. 2011 EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers. Nat Med, 18:74-82 PMC3467100
  • Vaughan S, Coward JI, Bast RC Jr, Berchuck A, Berek JS, Brenton JD, Coukos G, Crum CC, Drapkin R, Etemadmoghadam D, Friedlander M, Gabra H, Kaye SB, Lord CJ, Lengyel E, Levine DA, McNeish IA, Menon U, Mills GB, Nephew KP, Oza AM, Sood AK, Stronach EA, Walczak H, Bowtell DD, Balkwill FR 2011  Rethinking ovarian cancer: recommendations for improving outcomes.  Nat Rev Cancer 11:719-25 PMC3380637
  • Matei D, Fang F, Shen C, Schilder J, Arnold A, Zeng Y, Berry WA, Huang TH, Nephew KP. 2012 Epigenetic resensitization to platinum in ovarian cancer Cancer Res, 72:2197-2205 PMID: 22549947
  • Rao X, Evans J, Chae H, Kim S, Yan P, Liu Y, Pilrose J, Miller D, Rhee J-K, Huang Y-W, Gu F,  Gray JW, Huang TH-M, Nephew KP. 2012  CpG island shore methylation regulates caveolin-1 in breast cancer  Oncogene, 10: 1-10 PMID: 23128390
  • Miller FD, Yan PS, Buechlein A, Rodriguez BA, Yilmaz AS; Goel S; Lin H, Bridgette Collins-Burow B, Rhodes LV, Braun C; Pradeep S, Rupaimoole R, Dalkilic M, Sood AK; Burow ME, Tang H, Huang TH,  Liu Y, Rusch DB, Nephew KP.  A new method for stranded whole transcriptome RNA-seq, Methods, in press
  • Huang RL, Gu F, Kirma NB,  Ruan J, Chen CL, Wang HC,  Liao YP, Chang CC,  Yu MH, Thompson IM, Huang HC, Huang TMH, Lai HC,  Nephew KP.  Comprehensive methylome analysis of ovarian tumors reveals hedgehog signaling pathway regulators as prognostic DNA methylation biomarkers.  Epigenetics, in press

  • Hsu PY, Hsu HK, Lan X,6  Yan PS, Labanowska J, Heerema N, Hsiao TZ, Chiu YC,  Liu Y,9  Li L, Nephew KP, Thompson IM, Li R, Sharp ZD, Chen Y,Kirma NB, Jin VX, Huang THM  Amplification of distant estrogen response elements (DERE) amplification drives breast cancer progression and tamoxifen resistance.  Cancer Cell, in press
  • Lengyel E, Burdette J, Kenny H, Matei D, Pilrose J,  Nephew KP, Hale B, Stack MS. Epithelial ovarian cancer experimental models.  Oncogene, in press

 

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