Dr. Rita Nahta's career goal is to become an independent researcher focused on the molecular mechanisms of drug resistance in breast cancer with a specific interest in targeted therapeutics and growth factor receptors. This K01 Award will assist her transition to a fully independent scientific investigator. The next year or two will be critical for polishing her molecular biology skills and developing new skills in the areas of nanotechnology and animal models under the mentorship of Drs. Francisco J. Esteva and Mien-Chie Hung. The M. D. Anderson Cancer Center offers an excellent collaborative environment for implementation of the proposed research plan. Drs. Esteva and Hung are highly regarded among the scientific community, and Dr. Nahta will benefit from their combined expertise in the areas of signal transduction, drug resistance, molecular therapeutics, cell cycle regulation and translational research. The Breast Cancer Translational Research Laboratory, which is directed by Dr. Esteva, is an integral component of the Breast Cancer Research Program directed by Dr. Hung. The stimulating intellectual and scientific environment of this program will greatly enhance Dr. Nahta's career development. Dr. Nahta's current research focus is on the molecular mechanisms of resistance to the HER-2-targeted antibody Herceptin. Using an in vitro model of Herceptin resistance that she developed, she observed the following: 1) HER-2 forms a unique heterodimer with IGF-IR in resistant cells. HER-2 in this complex is phosphorylated, suggesting cross-talk from IGF-IR to HER-2;2) p27kip1, which lies downstream of both HER-2 and IGF-IR, is downregulated in resistant cells. Ectopic expression of p27kip1 restores Herceptin sensitivity. Based on these findings, the central hypothesis of this application is that Herceptin resistance is mediated by increased binding of HER-2 to IGFIR with subsequent degradation of p27kip1 in breast cancer cells.
Our specific aims are to: 1) Characterize the interaction between HER-2 and IGF-IR;2) Define the molecular mechanism by which HER-2/IGF-IR downregulates p27kip1;3) Investigate HER-2/IGF-IR as a therapeutic target in vivo. We will use GST pulldown assays, nanotechnology, protein assays, PCR, siRNAtransfection, and in vivo mouse studies. Our studies will ultimately allow the identification of tumors most likely to respond to Herceptin, and will guide the development of more effective targeted therapies for HER-2-overexpressing breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
3K01CA118174-05S1
Application #
7922250
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lohrey, Nancy
Project Start
2009-08-01
Project End
2012-07-31
Budget Start
2009-08-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2009
Total Cost
$109,620
Indirect Cost
Name
Emory University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Griner, Samantha E; Wang, Katherine J; Joshi, Jayashree P et al. (2013) Mechanisms of Adipocytokine-Mediated Trastuzumab Resistance in HER2-Positive Breast Cancer Cell Lines. Curr Pharmacogenomics Person Med 11:31-41
Nahta, R (2012) Pharmacological strategies to overcome HER2 cross-talk and Trastuzumab resistance. Curr Med Chem 19:1065-75
Gayle, Sylvia S; Arnold, Samuel L M; O'Regan, Ruth M et al. (2012) Pharmacologic inhibition of mTOR improves lapatinib sensitivity in HER2-overexpressing breast cancer cells with primary trastuzumab resistance. Anticancer Agents Med Chem 12:151-62
Nahta, Rita (2012) New developments in the treatment of HER2-positive breast cancer. Breast Cancer (Dove Med Press) 4:53-64
Nahta, Rita (2012) Deciphering the role of insulin-like growth factor-I receptor in trastuzumab resistance. Chemother Res Pract 2012:648965
Ozbay, Tuba; Nahta, Rita (2011) Delphinidin Inhibits HER2 and Erk1/2 Signaling and Suppresses Growth of HER2-Overexpressing and Triple Negative Breast Cancer Cell Lines. Breast Cancer (Auckl) 5:143-54
Crawford, Anatasha; Nahta, Rita (2011) Targeting Bcl-2 in Herceptin-Resistant Breast Cancer Cell Lines. Curr Pharmacogenomics Person Med 9:184-190
Joshi, Jayashree P; Brown, Nicole E; Griner, Samantha E et al. (2011) Growth differentiation factor 15 (GDF15)-mediated HER2 phosphorylation reduces trastuzumab sensitivity of HER2-overexpressing breast cancer cells. Biochem Pharmacol 82:1090-9
Ozbay, Tuba; Durden, Donald L; Liu, Tongrui et al. (2010) In vitro evaluation of pan-PI3-kinase inhibitor SF1126 in trastuzumab-sensitive and trastuzumab-resistant HER2-over-expressing breast cancer cells. Cancer Chemother Pharmacol 65:697-706
Nahta, R; Shabaya, S; Ozbay, T et al. (2009) Personalizing HER2-targeted therapy in metastatic breast cancer beyond HER2 status: what we have learned from clinical specimens. Curr Pharmacogenomics Person Med 7:263-274

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