Dr. Naoto T. Ueno
The University of Texas MD Anderson Cancer Center
Department of Breast Medical Oncology
My primary research interest is dissecting the molecular events related to cytotoxicity induced by chemotherapy or targeted therapy for breast cancer and ovarian cancer. Understanding these molecular events will help us develop novel diagnostic tools and innovative targeted therapies involving gene therapy or small molecules for patients with breast and ovarian cancer. Our research group is particularly interested in inflammatory breast cancer, triple negative breast cancer, and clear cell carcinoma of the ovary.
My major goal is to develop novel molecular diagnostic and therapeutic strategies by exploiting properties of the epithelial growth factor receptor (EGFR), ERK-modulating molecule PEA15, and the mitotic checkpoint-regulating protein mitotic arrest deficiency protein 2 (MAD2).
PEA-15 Gene Therapy in Breast and Ovarian Cancer. The adenovirus type 5 gene E1A can induce apoptosis or downregulate HER2 overexpression in cancer cells. Our preclinical findings led to the initiation of a phase I trial of E1A gene therapy for women with breast or ovarian cancer, which we completed in 1997 (J Clin Oncol 19:3422, 2001). The results showed that E1A could be successfully delivered to cancer cells by means of DC-Chol cationic liposomes. I have extended these phase I results by opening two phase II clinical trials of E1A gene therapy for women with ovarian cancer with the support of M. D. Anderson Cancer Center’s Ovarian Cancer SPORE. I have also shown that E1A can sensitize tumor cells to paclitaxel both in vitro and in animal models of breast and ovarian cancer (Clin Cancer Res 6:250, 2000; Oncogene 15:953, 1997). My laboratory has discovered PEA-15 is part of the mechanism of E1A antitumor effect via apoptosis (Oncogene.25:79, 2006). We have developed preclinical model of PEA-15 gene therapy in ovarian cancer (Cancer Res 68:9302-10, 2008). This work is funded by an NIH R01 grant.
Role of EGFR in Breast Cancer. Another focus of my laboratory is to clarify the role of EGFR signaling in breast cancer. We have discovered multiple phosphoproteins that seem to determine whether disease will or will not respond to EGFR-targeting therapy, such as the EGFR inhibitor erlotinib or anti-EGFR antibody. We are currently developing assays to identify which patients will respond to EGFR-targeting therapy (Mol Cancer Ther 6:2168, 2007; Cancer Res. 67:5779, 2007). This work is funded by an NIH R01 grant.
Role of the Mitotic Checkpoint in Breast Cancer Sensitivity to Paclitaxel. We are also investigating whether the presence of a functional mitotic checkpoint in tumor cells can be used as a marker of sensitivity to paclitaxel in breast cancer. MAD2 and BubR1 are components of the mitotic checkpoint that can regulate cyclin-dependent kinase-1 (CDK1) and may reflect mitotic checkpoint functionality. Our hypothesis is that paclitaxel-induced death of breast cancer cells requires the presence of a functional mitotic checkpoint (Mol Cancer Ther 4:1039, 2005; Cancer Res 64:2502, 2004). Our current goal is to determine whether a rapid increase in CDK1 activity in vitro after paclitaxel treatment can be used to identify which breast tumors will respond to taxanes (Breast Cancer Res 11:R12, 2009). We are currently conducting a prospective study to test the validity of CDK1 as a molecular marker of disease response in collaboration with the Department of Breast Medical Oncology. This effort is supported by a grant from Susan G. Komen for the Cure.
Inflammatory Breast Cancer Preclinical Program. Inflammatory breast cancer (IBC) has clinical characteristics (angiogenesis, active EGFR and HER2 pathways, active epithelial-to-mesenchymal transition, etc.) unlike those of the more common non-IBC. IBC also carries a substantially worse prognosis, with significantly shorter overall survival. Even though IBC and non-IBC seem to be quite different diseases, the standard treatment at this time is the same for both, in part because of a lack of understanding of the biological factors that influence disease course and outcome in (Nat Rev Clin Oncol 6:387-94, 2009). This lack of knowledge hinders the development of treatments and the identification of biomarkers unique to IBC. To fill this gap, we are creating a translational research program focused on understanding the molecular and immunological characteristics of IBC. Our long-term goal is to elucidate the molecular characteristics of IBC to help us develop clinically relevant diagnostic tools and novel therapeutic approaches to be tested in clinical trials. Our research group has already found that certain molecular markers can be targeted in IBC, and we have successfully developed both in vitro and in vivo IBC models.
I am currently a faculty member of the Department of Breast Medical Oncology at MD Anderson Cancer Center. I oversee all of the departments’ clinical trials related to IBC, and bone metastasis in breast cancer. Most of these trials are linked with my translational research activities.
Our research group is dedicated to both clinical and translational research in breast cancer and ovarian cancer. We have published numerous papers related to both basic and clinical cancer research in prestigious peer-reviewed journals, including Cancer Research, Journal of Clinical Oncology, Oncogene, and Clinical Cancer Research. We also have presented and have been invited to present several major talks on stem cell transplantation and breast and ovarian cancers at national and international meetings. Our future goal is to translate the knowledge gained in my laboratory into improved survival for patients with advanced breast cancer and ovarian cancer.
Program in Cancer Biology
Office: MDA CPB5.3506 (Unit 1354)
Ph.D. - The University of Texas Graduate School of Biomedical Sciences at Houston - 1999
M.D. - Wakayama Medical College - 1989