Donald Patrick McDonnell

The research in our group is focused on the development and application of mechanism based approaches to identify novel therapeutics for use in the treatment and prevention of hormonally responsive cancers. Our exploitation of the estrogen and androgen receptors and their signaling pathways has resulted in the discovery of several drugs/drug combinations that are currently being evaluated in the clinic (or approved for clinical use). Etacstil, the first oral Selective Estrogen Receptor Downregulator (SERD) was identified by trainees in our group and its efficacy in preclinical models of advanced breast cancer and subsequently in the clinic, validated ER as a therapeutic target in late stage breast cancer. We subsequently repurposed the ER modulators, elacestrant (FDA approved, Jan 2023) and lasofoxifene (currently in ELAINE-1, ELAINE-2 and ELAINE-3 clinical trials) for use in metastatic breast cancer. These new drugs will have a very significant impact on the treatment of patients with late stage metastatic breast cancer and it is anticipated that the results of ongoing clinical trials will support their use in early stage disease. Recently, we have expanded the scope of our studies to explore the roles of nuclear receptors in regulating immune cell function. Leveraging insights from recent work in the laboratory we have developed strategies to modulate the transcriptional activity of ER in tumor associated macrophages, NK cells, eosinophils and in the tumor stroma to increase tumor immunity and increase the efficacy of immune checkpoint inhibitors (ICBs). We are leveraging the insights from this work to explore the utility of using select endocrine therapies as a means to increase the efficacy of ICBs in different cancers with a specific focus on triple negative breast cancer. The androgen receptor has been a target of interest to the group for many years and emerging from this work are drugs which target this receptor in ways that are distinct from existing therapeutics. We believe that these new treatment modalities will have particular utility in the treatment of late stage prostate cancer.