Our research focuses on the identification of new targets and predictive biomarkers using a variety of molecular tools including proteomic profiling by reverse phase protein array. Projects in my laboratory encompass areas such as developing biomarkers of therapeutic response and acquired resistance as well as discriminating the molecular changes that drive the acquisition of resistance. Most projects in my group are translational in nature – focusing on projects that can be rapidly moved from the lab to the clinic. Current projects include:
PARP inhibition in SCLC
One of the early successes of my lab has been our pre-clinical work showing the effectiveness of single agent PARP inhibition in SCLC (Byers et al, 2012 & Cardnell et al, 2013) which has directly resulted in the clinical testing of these in SCLC patients. Additional pre-clinical projects have explored drug combinations such as PARP/PI3K (Cardnell et al, 2016) and have identified SLFN11 as a mechanism of innate and acquired resistance to PARP inhibition in SCLC (Stewart et al, 2017). We are also, in collaboration with other institutions and pharmaceutical partners, spearheading biomarker discovery in samples from patients treated on a number of clinical trials testing PARP inhibition in SCLC (Pietanza et al, 2018).
CHK1 as a therapeutic target in SCLC
Building on the same work that identified PARP as a potential target in SCLC, my lab has recently shown that SCLC is sensitive to CHK1 inhibition (Sen et al, 2017). Ongoing projects in the lab include developing biomarkers of response and mechanisms of resistance to CHK1 inhibition, and exploring potential combination treatments including CHK1 inhibition.
Immuno-Oncology in SCLC
Recently, frontline treat treatment for SCLC has changed from chemotherapy to chemotherapy with the addition of an immune checkpoint inhibitor. Building on this, and our expertise in targeting the DNA damage response (DDR) pathways with PARP and CHK1 inhibitors, we have shown striking responses in animal models treated with combinations of DDR inhibitors and an immune checkpoint inhibitor through activation of an innate immune response (Sen et al, 2019). Ongoing projects in the lab include testing additional drug combinations and alternative strategies for engaging the immune system for the treatment of SCLC patients.
Epithelial to mesenchymal transition in lung cancer
As part of studies completed in collaboration with John V. Heymach, M.D., Ph.D. and the TCGA we have developed a lung-specific and a pan-cancer EMT score that based on gene expression that predicts the EMT status of a cancer and response to agents such as EGFR and AXL inhibitors (Byers et al, 2013 & Mak et al, 2015). Ongoing projects in my lab in collaboration with Drs. Heymach and Gibbons within THNMO and with industry partners are exploring the potential of AXL inhibitors to reverse EMT, in addition to testing AXL inhibitors in combination with other agents such as PARP inhibitor (Balaji et al, 2017) and developing biomarkers of response/resistance to these.
Working with the thoracic biomarker working group (lead by myself and Jing Wang, Ph.D.), we are utilizing computational approaches to identify new therapeutic targets and markers of response. Projects include “DISARM” (Differential Sensitivity Analysis of Resistant Malignancies) which addresses the simple, yet vexing question of “If a cancer is resistant to drug X, to what drug(s) is it sensitive?” (Gay et al, 2019).