My postdoctoral research focuses on 2 major areas in cancer therapeutics. One is identifying new targets in inflammatory breast cancer (which I will refer to as IBC throughout this page and my blog), and designing approaches to target these aberrations such as by small molecule inhibitors or monoclonal antibodies. In particular, my research is focused on uncovering useful combinations of agents that when utilized together under specific conditions, act synergistically. The other major area of emphasis in my work is on understanding mechanisms of resistance to targeted therapies in breast cancer (including but not solely focused on IBC).
Inflammatory Breast Cancer Project
Inflammatory breast cancer is a rare, aggressive form of breast cancer, accounting for between 2 and 5% of total breast cancer cases in the US each yeaar. Current understanding of what makes this disease so aggressive, is still rudimentary, and there are no molecular targets that have made it into clinical use, unlike some other tumor types such as lung cancer, in which we are making steady progress in improving clinical outcomes by targeting tumor-specific proteins. Being inspired by some of the current work in targeted therapy in lung cancer (for example), as well as some of the work underway in my laboratory on a new targeted therapy for triple-negative breast cancer, I have decided on a 2-pronged approach to finding new druggable targets. After a literature search of IBC, I have identified some potential targets, that I am beginning to evaluate in my cell line models. In addition, in collaboration with the MDACC IBC clinic who began a collaboration with my laboratory to look at a cell-cycle target, cyclin E in IBC. This work was recently funded by a competitive Department of Defense Breast Cancer Research Program postdoctoral fellowship for 3 years, in which I will perform combination drug screens in cell lines, and animal models to generate the preliminary data I would need to co-run a clinical trial in a few years in patients.
In the future, I plan to perform high-throughput screens to look for genes that potentiate cell death in IBC cells which I can then find drugs to target.
Resistance to targeted therapies in breast cancer
The drugs I am specifically studying are trastuzumab (also known as Herceptin) which is a monoclonal antibody that inhibits HER2, which is overexpressed in about 25-30% of breast cancer as a whole (and about 40% in IBC). The other drug of interest is lapatinib, which is a small molecule tyrosine kinase inhibitor of EGFR, which is a receptor like HER2 that is upstream of several major pro-survival pathways in cells, and is upregulated in breast cancers and several other cancers like lung cancer and glioblastoma as well. Both of these drugs, while showing promising results both pre-clinically and in patients, have activity only for limited periods of time because of both intrinsic resistance factors as acquired bypass signaling pathways. If we understand what these factors are, perhaps we can combine different drugs to block these escape mechanisms or design novel agents which target the upstream aberrations (HER2 or EGFR) without inducing these downstream pathways. I am using a large panel of breast cancer cell lines that have been cultured for months in herceptin, lapatinib or a combination of both drugs, which selects for cells that have acquired resistance to them (the sensitive cells are killed within the first few days of treatment). By doing detailed characterization of these cells, from gene expression, small RNA analysis to proteomics, I am hoping to uncover common signaling pathways/proteins that are changed and figure out ways of targeting them.