April L  Risinger, Ph.D.

Dr. April Risinger's 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 they 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.

The 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. Our 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.

• Professional Background

  Education

  • 2014 - Postdoctoral Training - Pharmacology - The University of Texas Health Science Center at San Antonio
  • 2007 - PhD - Cell Biology - Massachusetts Institute of Technology (MIT)
  • 2000 - BS - Biochemistry - Texas A&M University

  Appointments

  • 1/2014 - Assistant Professor - The University of Texas Health Science Center at San Antonio, Pharmacology, San Antonio

• Research & Grants

  Grants

  R01 CA219948 (Risinger, PI)                                                            

  04/17/2018 – 04/16/2023

  NIH/NCI

  Optimization of a Novel Class of Microtubule Stabilizers

  The goals of this project are to optimize the pharmacokinetic parameters of naturally derived taccalonolides through semi-synthesis and identify biomarkers of response to these compounds.

   

  Voelcker Young Investigator Award (Risinger, PI)                                   

  07/01/2018 – 06/30/2021

  Microtubule stabilizer-mediated disruption of oncogenic signaling

  Early Investigator award to evaluate the effects of MTAs on coordination of cytoskeletal-mediated oncogenic signaling and trafficking

   

   

   

• Publications

  Selected Publications

  Du L, Yee SS, Ramachandran K, Risinger AL. Elucidating target specificity of the taccalonolide covalent microtubule stabilizers employing a combinatorial chemical approach. Nature Communications, 11(1):654. 2020.

  Kil YS, Risinger AL, Petersen CL, Mooberry SL, Cichewicz RH. Leucinostatins from Ophiocordyceps spp. and Purpureocillium spp. Demonstrate Selective Antiproliferative Effects in Cells Representing the Luminal Androgen Receptor Subtype of Triple Negative Breast Cancer. J Nat Prod. 83(6):2010-2024. 2020.

  Kil YS, Risinger AL, Petersen CL, Liang H, Grkovic T, O'Keefe BR, Mooberry SL, Cichewicz RH. Using the Cancer Dependency Map to Identify the Mechanism of Action of a Cytotoxic Alkenyl Derivative from the Fruit of Choerospondias axillaris. J Nat Prod. 83(3):584-592. 2020.

  Risinger AL and Du L. Targeting and extending the eukaryotic druggable genome with natural products: cytoskeletal targets of natural products. Natural Product Reports, 37(5):634-652. 2020. 

  Kaul R, Risinger AL, Mooberry SL. Eribulin rapidly inhibits TGF-β-induced Snail expression and can induce Slug expression in a Smad4-dependent manner. Br J Cancer. 121(7):611-621. 2019. 

  Huang Y, Li Z, Risinger AL, Enslow BT, Zeman CJ 4th, Gong J, Yang Y, Schanze KS. Fluorescence spectral shape analysis for nucleotide identification. PNAS. 116(31):15386-15391. 2019.

  Grant CV, Carver CM, Hastings SD, Ramachandran K, Muniswamy M, Risinger AL, Beutler JA, Mooberry SL. Triple-negative breast cancer cell line sensitivity to englerin A identifies a new, targetable subtype. Breast Cancer Res Treat. 177(2):345-355. 2019.

  Sharp AM, Lertphinyowong S, Yee SS, Paredes D, Gelfond J, Johnson-Pais TL, Leach RJ, Liss M, Risinger AL, Sullivan AC, Thompson IM, Morilak DA. Vortioxetine reverses medial prefrontal cortex-mediated cognitive deficits in male rats induced by castration as a model of androgen deprivation therapy for prostate cancer. Psychopharmacology (Berl). 236(11):3183-3195. 2019.

  Balaguer FA, Mühlethaler T, Estévez-Gallego J, Calvo E, Giménez-Abián JF, Risinger AL, Sorensen EJ, Vanderwal CD, Altmann KH, Mooberry SL, Steinmetz MO, Oliva MÁ, Prota AE, Díaz JF. Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands. Int J Mol Sci. 20(6). pii: E1392. 2019.

  Kaul R, Risinger AL, Mooberry SL. Microtubule-Targeting Drugs: More than Antimitotics. J Nat Prod. 82(3):680-685. 2019.

  Cai S, Risinger AL, Petersen CL, Grkovic T, O'Keefe BR, Mooberry SL, Cichewicz RH. Anacolosins A-F and Corymbulosins X and Y, Clerodane Diterpenes from Anacolosa clarkii Exhibiting Cytotoxicity toward Pediatric Cancer Cell Lines. J Nat Prod. 82(4):928-936. 2019.

  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.

  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.

  Danielsson J, Sun DX, Chen XY, Risinger AL, Mooberry SL, Sorensen EJ. A Stereocontrolled Annulation of the Taccalonolide Epoxy Lactone onto the Molecular Framework of trans-Androsterone. Org Lett. 19(18):4892-4895. 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.

  Risinger AL, Riffle SM, Lopus M, Jordan MA, Wilson L, Mooberry SL.  The taccalonolides and paclitaxel cause distinct effects on microtubule dynamics and aster formation.  Molecular Cancer, 13(1):41. 2014.

  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.

  Risinger AL, Peng J, Rohena CC, Aguilar HR, Frantz DE, Mooberry SL. The bat flower: a source of microtubule-destabilizing and -stabilizing compounds with synergistic antiproliferative actions.  Journal of Natural Products, 76(10):1923-1929. 2013. 

  Risinger AL, Westbrook CD, Encinas A, Mülbaier M, Schultes CM, Wawro S, Lewis, JD, Janssen B, Giles FJ, Mooberry SL.  ELR510444, a novel microtubule disruptor with multiple mechanisms of action.  Journal of Pharmacology and Experimental Therapeutics 336(3):652-660, 2011.