Breast cancer outcome has improved significantly over the last 10 years. However, an important number of patients still relapse, while others receive unnecessary therapy as we are unable to distinguish whether patients have low-risk or high-risk disease. Breast cancer behavior is regulated, in part, by the PI3K/PTEN/AKT signaling pathway, which interact bidirectionally with hormone receptors and further interacts at multiple levels, creating a complex signaling network. My hypothesis is that breast cancer tumors can be classified by changes in protein signaling in the PI3K/PTEN/AKT pathway and that tumor response to specific therapeutic regimens can be predicted and improved by identifying and targeting this pathway.
My specific aims are: (1) To classify breast cancers by characterizing the functional proteomic expression/activation signature of the PI3K/PTEN/AKT signal transduction cascade, (2) To determine whether the proposed functional proteomics-based classification reflects response to preoperative taxane (paclitaxel or docetaxel) and 5-fluoruracil, doxorubicin/epirrubicin, and cyclophosphamide (paclitaxel-FA/EC) chemotherapy, and (3) To determine whether a therapeutic intervention targeting the PI3K/PTEN/AKT pathway in combination with chemotherapy is an effective treatment for triple receptor (ER, PR, and HER2)- negative locally advanced breast cancer (LABC). We will perform reverse-phase protein microarray analysis (RPPA) of 90 frozen preoperative breast cancer samples and analyze the PI3K/PTEN/AKT cascade. The data will be used as a training set to define a breast cancer signaling profile associated with response to preoperative chemotherapy. We will obtain a validation set of 50 samples and apply the proteomic profile to determine its specificity and sensitivity in predicting response to therapy. We will develop a phase II randomized clinical trial in women with triple receptor-negative LABC in which patients will be treated with either standard chemotherapy (docetaxel followed by FEC) or docetaxel plus RAD001 followed by FEC. This study will reveal whether the addition of an mTOR inhibitor to standard neoadjuvant chemotherapy in patients with triple receptor-negative breast cancer causes molecular changes (inhibition/activation) in the PI3K/PTEN/AKT pathway and the clinical effects of this intervention. This study will lead to a better understanding of the mechanisms underlying the wide variation in breast cancer behavior and therapy responsiveness and will also identify other therapeutic targets in patients for whom conventional therapy is inadequate. At the same time it will provide me with the experience, knowledge, and skills necessary to launch and conduct an independent translational research career in breast oncology. The outcome of this project is expected to position me to submit a competitive R01 application during the fourth year of the proposed award.
|Parinyanitikul, Napa; Lei, Xiudong; Chavez-MacGregor, Mariana et al. (2015) Receptor status change from primary to residual breast cancer after neoadjuvant chemotherapy and analysis of survival outcomes. Clin Breast Cancer 15:153-60|
|Gonzalez-Angulo, Ana M; Krop, Ian; Akcakanat, Argun et al. (2015) SU2C phase Ib study of paclitaxel and MK-2206 in advanced solid tumors and metastatic breast cancer. J Natl Cancer Inst 107:|
|Chae, Young Kwang; Gonzalez-Angulo, Ana Maria (2014) Implications of functional proteomics in breast cancer. Oncologist 19:328-35|
|Subbiah, Ishwaria M; Gonzalez-Angulo, Ana Maria (2014) Advances and future directions in the targeting of HER2-positive breast cancer: implications for the future. Curr Treat Options Oncol 15:41-54|
|Liu, Shuying; Meng, Xiaolong; Chen, Huiqin et al. (2014) Targeting tyrosine-kinases and estrogen receptor abrogates resistance to endocrine therapy in breast cancer. Oncotarget 5:9049-64|
|Gonzalez-Angulo, A M; Akcakanat, A; Liu, S et al. (2014) Open-label randomized clinical trial of standard neoadjuvant chemotherapy with paclitaxel followed by FEC versus the combination of paclitaxel and everolimus followed by FEC in women with triple receptor-negative breast cancer†. Ann Oncol 25:1122-7|
|Hayashi, Naoki; Manyam, Ganiraju C; Gonzalez-Angulo, Ana M et al. (2014) Reverse-phase protein array for prediction of patients at low risk of developing bone metastasis from breast cancer. Oncologist 19:909-14|
|Gagliato, Debora de Melo; Gonzalez-Angulo, Ana M; Lei, Xiudong et al. (2014) Clinical impact of delaying initiation of adjuvant chemotherapy in patients with breast cancer. J Clin Oncol 32:735-44|
|Chavez-Macgregor, Mariana; Liu, Shuying; De Melo-Gagliato, Debora et al. (2014) Differences in gene and protein expression and the effects of race/ethnicity on breast cancer subtypes. Cancer Epidemiol Biomarkers Prev 23:316-23|
|Gonzalez-Angulo, A M; Blumenschein Jr, G R (2013) Defining biomarkers to predict sensitivity to PI3K/Akt/mTOR pathway inhibitors in breast cancer. Cancer Treat Rev 39:313-20|
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