April Risinger, Ph.D.
Our lab is focused on the discovery and preclinical development of novel natural products that have anticancer potential. We identify new agents from natural products, including marine organisms and plants, to identify new drug leads. After discovering new agents we identify their molecular mechanisms of action. This includes identifying the cellular binding site of these compounds and how they affect the proliferation, viability and cell biology of cancer cells. We also evaluate the antitumor efficacy of these agents in animal models of cancer.
One of the most exciting classes of compounds we have isolated are the taccalonolides, which are microtubule stabilizing agents isolated from plants of the genus Tacca. Microtubule stabilizers, including the taxanes, are some of the most widely used and effective drugs employed in the treatment of human cancer, however drug resistance and toxic side effects limit their use. Similar to the effects of the taxanes, the taccalonolides cause microtubule stabilization, leading to the mitotic arrest and death of cancer cells and antitumor activity in mouse models. However, the taccalonolides have efficacy in clinically relevant drug resistant models both in vitro and in vivo, suggesting they may be useful in the treatment of drug resistant human cancers.
Although the taccalonolides possess several properties of classical microtubule stabilizers, we have discovered that they work through a distinct mechanism of action compared to all other classes of microtubule stabilizing drugs. These findings include the ability of the taccalonolides to form distinct mitotic spindle structures and their propensity to affect interphase microtubules at much lower relative concentrations than the taxanes. The latter finding is of great interest given recent studies suggesting that the anticancer effects of microtubule targeting agents may be due in large part to their interphase effects.
Our recent isolation of taccalonolides with potency in the low nanomolar range provided the first indication that this class of drugs interacts directly with tubulin. Intriguingly, the kinetic profile of tubulin polymerization observed in the presence of these potent taccalonolides is unlike that observed with other stabilizers, further suggesting that the taccalonolides interact with tubulin in a manner that is markedly distinct from other classes of microtubule targeting agents. The unique biochemical and cell biological properties of these potent taccalonolides, together with the excellent in vivo antitumor activity observed for this class of agents in drug resistant tumor models, reveal the potential of the taccalonolides as a new class of anticancer drugs. My current research is focused on identifying the taccalonolide(s) that have the greatest potential for clinical development and fully characterizing their cell biological and antitumor activities.
Massachusetts Institute of Technology (MIT)
|• drug discovery||• cancer|
|• natural products||• microtubule targeted agents|
Awards & Accomplishments
- Voelcker Fund Young Investigator Award 2017
- Barbara Bowman Postdoctoral Award and Fellowship 2012
- DOD CDMRP Breast Cancer Research Program Postdoctoral Fellowship 2009 – 2012
- Best Undergraduate Thesis in Molecular Genetics, Texas A&M University 2000
Appointments, Boards, Committees and Memberships
- American Society for Pharmacognosy Scientific Organizing Committee 2015
- UT Health Graduate School of Biomedical Sciences Postdoctoral Advisory Committee 2011
- Cancer Therapy and Research Center, Experimental Therapeutics Program 2008 – present
Du L, Risinger AL*, Mitchell CA, You J, Stamps BW, Pan N, King JB, Bopassa JC, Judge SIV, Yang Z, Stevenson BS, Cichewicz RH. Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides. Proc Natl Acad Sci U S A. 114(43):E8957-E8966. 2017. *Co-first authorship
Risinger AL, Li J, Du L, Benavides R, Robles AJ, Cichewicz RH, Kuhn JG, Mooberry SL. Pharmacokinetic Analysis and in Vivo Antitumor Efficacy of Taccalonolides AF and AJ. J Nat Prod. 80(2):409-414. 2017.
Lee B, Bohmann J, Reeves T, Levenson C, Risinger AL*. α- and β-Santalols Directly Interact with Tubulin and Cause Mitotic Arrest and Cytotoxicity in Oral Cancer Cells. J Nat Prod. 78 (6):1357-1362. 2015 *Corresponding Author
Risinger AL, Li J, Bennett MJ, Rohena CC, Peng J, Schriemer DC, Mooberry SL. Taccalonolide binding to tubulin imparts microtubule stability and potent in vivo activity. Cancer Research, 73(22):6780-6792. 2013.
A full bibliography can be found at: https://www.ncbi.nlm.nih.gov/sites/myncbi/april.risinger.1/bibliography/54318209/public/?sort=date&direction=ascending