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Andrea Bild

Assistant Professor of Oncological Sciences and of Pharmacology and Toxicology

B.S. University of Florida, Gainsville

Ph.D. University of Colorado, Denver

Research

References

 

Andrea Bild's PubMed Literature Search

Research

Understanding the biological and clinical diversity of cancer is an opportune area for the application of genomic approaches. Molecular-profiling studies, such as DNA microarray and next-generation sequencing analyses, have the potential to describe the complexity of cancer phenotypes, and provide an opportunity to link these phenotypes to clinically relevant information, such as therapeutic strategies. My lab focuses on the signal transduction pathways that contribute to the oncogenic processes such as tumor initiation or progression with the ultimate goal of identifying novel therapeutic strategies.

1. Prediction of breast cancer susceptibility in high risk women using exon-level expression profiling, and identification of novel susceptibility genes. Current methods for quantifying a woman's risk of developing disease are limited in their ability to accurately assess individual disease predisposition. At best, those patients that are defined as highest risk (ie. BRCA1/2 mutation carriers) have an approximate 30% to 60% risk of developing cancer by age 60, and are left facing difficult decisions about medical management, including prophylactic mastectomy and oophorectomy. Our goal was to develop a genomic model for breast cancer risk that is sensitive and specific at determining an individual's "true risk" for breast cancer. Our current studies are focused on validating novel oncogenic pathways and genes identified by our biomarker, and in investigating the genetic variation that contributes to the gene expression deregulation found in high-risk subjects that develop breast cancer. Overall, we expect these experiments to identify the genetic changes that underlie cancer predisposition, and assist clinicians and patients in determining the appropriate preventative measures. .

2. Epigenetic changes and therapeutic intervention strategies in breast cancer phenotypes. Treating unselected cancer patients with drugs dilutes proof of efficacy when only a fraction of patients respond to therapy. To help guide optimal drug selection for patients, we conduct a meta-analysis on thousands of tumor samples from datasets representing diverse cancer phenotypes. We leverage drug sensitivity signatures in these genomic analyses to guide preclinical studies, and offer a proof of concept on drug classes currently undergoing early phase clinical trials. Our genomic and experimental results suggest that a relatively low toxicity histone deacetylase inhibitor, valproic acid, may target aggressive breast cancers. Preclinical studies using both cell lines and patient tumors grown in 3-dimensional in vitro and orthotopic in vivo models provide an efficient and highly relevant assessment of drug sensitivity in tumor phenotypes, and validate our genomic analyses. Together, our results show that high-throughput transcriptional profiling can significantly impact drug selection for breast cancer patients

3. Deregulation of the phosphatidylinositol 3-kinase pathway in the airway epithelium of smokers may be an early event in the development of lung cancer. Using genomic oncogenic pathway signatures, we observe a significant increase in the phosphatidylinositol 3-kinase (PI3K) pathway in the normal airway cells of smokers with lung cancer or dysplastic lesions, suggesting PI3K is activated prior to tumorigenesis. Myo-inositol inhibits the PI3K pathway in vitro and treatment of patients with myo-inositol leads to a decrease of PI3K and regression of dysplastic lesions. Our work suggests that additional lung cancer chemoprevention trials focused on PI3K pathway activity as a target and an intermediate endpoint of efficacy are warranted. We have also moved forward with novel studies in the airway epithelium tissue in order to uncover pathway deregulation in different pulmonary disease states.

4. Valproic Acid Signature Trial. The ultimate goal of my research program is to translate our research findings at the bench to the benefit of cancer patients. Based on our ongoing research, we have initiated a Phase I clinical trial (VAST: Valproic Acid Signature Trial) to assess the accuracy of our valproic acid response and HDAC pathway signatures in a prospective clinical trial setting.

References