A major focus of my laboratory is the discovery of new drugs for the treatment of cancer, primarily breast cancer and solid pediatric cancers. Our historic focus has been on the identification of novel microtubule-targeting agents from natural products and synthetic chemistry efforts. This work continues and we are also evaluating diverse natural product extracts for activity against specific types of cancer, including the molecularly defined subtypes of triple negative breast cancer and pediatric solid tumors. We conduct the initial discovery in mechanism-based and mechanism blind screens, we use bioassay-guided fractionation, in collaboration with our chemistry collaborators to identify the active constituents, and then we conduct mechanistic studies on the pure compounds and on synthetic and natural analogs.
In addition to our drug discovery efforts, a second major initiative is identifying the molecular mechanisms of action of chemically diverse microtubule targeting agents. While microtubule targeting drugs have been used successfully for decades for breast and pediatric cancers, we still do not fully understand why these drugs are effective and which patients will respond best to the different drugs. We are investigating how these drugs differentially interfere with interphase signaling events important for oncogenesis. I was initially trained in cardiovascular pharmacology and then developed expertise in drug discovery, cell biology and molecular oncology. The long-term goal of our research is to develop more effective therapies for the treatment of cancer.
Dybdal-Hargreaves NF, Risinger, AL, Mooberry SL. Regulation of E-cadherin localization by microtubule targeting agents: rapid promotion of cortical E-cadherin through p310Cas/Src inhibition by eribulin. In press Oncotarget, 2018.
Robles AJ, McCowen S, Cai S, Glassman M, Ruiz F, Cichewicz RH, McHardy SF, Mooberry SL. Structure-activity relationships of new natural product-based diaryloxazoles with selective activity against androgen receptor-positive breast cancer cells. J. Med. Chem 60, 9275-9289, 2017.
Risinger AL, Li J, Du L, Benavides R, Robles, AJ, Cichewicz RH, Kuhn, J, Mooberry SL. Pharmacokinetic analysis and in vivo antitumor efficacy of taccalonolides AF and AJ. J. Nat Prod. 80:409-414, 2017.
Robles AJ, Cai S, Cichewicz RH, Mooberry SL. Selective activity of deguelin identifies therapeutic targets for androgen receptor-positive breast cancer. Breast Cancer Res Treat. 157:475-488, 2016.
Du L, Robles AJ, King JB, Powell DR, Miller AN, Mooberry, SL, Cichewicz RH. Crowdsourcing Natural Products Discovery to Access Uncharted Dimensions of Fungal Metabolite Diversity Angew Chem Int Ed Eng. 53:804-809, 2014.
Li J, Risinger AL, Peng J, Chen Z, Hu L, Mooberry SL. Potent taccalonolides, AF and AJ, inform significant structure activity relationships and tubulin as the binding site of these microtubule stabilizers. J Am Chem Soc. 133: 19064-19067, 2011.