April Risinger, Ph.D.
Associate Professor and Greehey Distinguished Chair in Targeted Molecular Therapeutics
The research in the Risinger Laboratory is in the area of cancer pharmacology with a focus on microtubule targeted agents and other natural products for the treatment of drug resistant solid tumors. There are three overarching goals of our research, including the identification of biomarkers that can guide a more rational choice among clinically approved microtubule targeted agents for the treatment of women with breast cancer or gynecological malignancies, the development of novel classes of microtubule targeted agents that retain efficacy in drug-resistant disease, and identifying strategies to alleviate the toxicities associated with the use of microtubule-targeted agents and other chemotherapeutics.
Drug Discovery and Development
Each of the unique classes of microtubule-targeted chemotherapeutics currently in clinical use or preclinical evaluation was originally identified as a natural product. Therefore, we collaborate closely with natural product chemists to identify and characterize novel natural compounds for their potential as cancer therapeutics as well as with synthetic medicinal chemists to optimize their potential for translation into the clinic. This includes our long-standing work on the identification and optimization of covalent microtubule targeted agents, including the plant-derived taccalonolides. My laboratory found that the taccalonolides bind covalently to a distinct site on tubulin from other stabilizers with a high degree of specificity that allows them to retain efficacy in clinically relevant drug resistant models both in vitro and in vivo. I am an inventor on two issued patents on this class of microtubule stabilizers and we have active projects in the laboratory focused on optimizing their pharmacokinetic properties and improving tumor targeting. We are also actively working on the optimization of other covalent microtubule targeted natural products, including pironetin and zampanolide, for the treatment of drug resistant human cancers.
Improving the Targeted use of Approved Chemotherapeutics
In addition to identifying new therapeutics, my laboratory is also actively investigating the underappreciated mechanistic differences between microtubule targeted agents currently approved for the treatment of cancer to guide their more rational and targeted use in the clinic. We have identified that the microtubule destabilizer eribulin is unique from the microtubule stabilizing taxanes in its ability to acutely activate the cGAS-STING pathway independent of its antimitotic effects through a mechanism involving mitochondrial DNA release. We further found that eribulin is highly synergistic with STING agonists in clinical development and able to promote improved antitumor immunity and tumor regression in vivo. We are also uncovering differences between the effects of these clinically approved drugs on cytoskeletal mediators implicated in oncogenesis. These preclinical findings have led to collaborations with our Mays Cancer Center to test the hypothesis that our findings can be used to identify molecular biomarkers to support the rational use of these drugs in combination with immunotherapeutics as well as guide the choice between microtubule stabilizing and destabilizing chemotherapeutics in the treatment of breast cancer patients where both classes of agents are approved and currently used with no molecular guidance.
Improving treatment by alleviating toxic side effects
Some of the major hurdles to effective cancer treatment are the toxic side effects associated with microtubule targeted agents and other chemotherapeutics. I am actively collaborating with neuroscientists and pain researchers to characterize and alleviate the neuropathic and cognitive deficits associated with cancer therapy. These collaborations have led to the development of models that allow monitoring of both the neurological and antitumor activities of chemotherapeutics in the same animal so that we can identify interventions that mitigate the deleterious side effects of these drugs without compromising their anticancer efficacy.
BS Biochemistry, Texas A&M University, College Station, TX
PhD Cellular Biology, Massachusetts Institute of Technology, Cambridge, MA
|• drug discovery||• cancer|
|• natural products||• microtubule targeted agents|
Awards & Accomplishments
Select Honors and Awards
2000 Best Undergraduate Thesis in Molecular Genetics, Texas A&M University
2012 Barbara Bowman Postdoctoral Award and Fellowship
2017 Voelcker Young Investigator Award
2022 Jack L. Beal Award for best paper by an earlier career investigator in the
Journal of Natural Products
2008-present Member, Mays Cancer Center, UT Health San Antonio
2014-2018 Assistant Professor/Research Track, UT Health San Antonio
2018-2022 Assistant Professor/Tenure Track, UT Health San Antonio
2022-present Associate Professor with Tenure, UT Health San Antonio
Select Boards, Committees and Memberships
2017-2020 Scientific Advisory Board, Terrona LLC, San Antonio, TX
2019-present Physiology and Pharmacology Discipline Graduate Student Oversight Committee
2021-present Mays Cancer Center Shared Resource Committee
2022-present Center for Innovative Drug Discovery Steering Committee
2022 VPR Task Force for Women in Science
2022-present Physiology and Pharmacology Graduate Student Recruitment Committee
2022-present Standing Member, DMP Study Section, NIH
Past Lab Members
Samantha Yee, Ph.D.
Charles Fermaintt, Ph.D.
Takahashi-Ruiz L, Morris JD, Crews P, Johnson TA, Risinger AL. In Vivo Evaluation of (-)-Zampanolide Demonstrates Potent and Persistent Antitumor Efficacy When Targeted to the Tumor Site. Molecules 27(13):4244. 2022.
Yee SS, Risinger AL. Efficacy of a covalent microtubule stabilizer in taxane-resistant ovarian cancer models. Molecules 26(13):4077. 2021
Fermaintt CS, Takahashi-Ruiz L, Liang H, Mooberry SL, Risinger AL. Eribulin activates the cGAS-STING pathway via the cytoplasmic accumulation of mtDNA. Molecular Pharmacology doi:10.1124/molpharm.121.000297. 2021
Risinger AL, Hastings S, Du L. Taccalonolide C-6 analogues, including paclitaxel hybrids, demonstrate improved microtubule polymerizing activities. The Journal of Natural Products 84(6):1799-1805. 2021. *Paper selected for the Jack L. Beal Award from the American Society of Pharmacognosy
Fermaintt CS, Peramuna T, Cai S, Takahashi-Ruiz L, Essif JN, Grant CV, O’Keefe BR, Mooberry SL, Cichewicz RH, Risinger AL. Yuanhuacine is a potent and selective inhibitor of the basal-like 2 subtype of triple negative breast cancer with immunogenic potential. Cancers 13(11):2834. 2021.
Matthew S, Chen QY, Ratnayake R, Fermaintt CS, Lucena-Agell D, Bonato F, Prota AE, Lim ST, Wang X, Díaz JF, Risinger AL, Paul VJ, Oliva MÁ, Luesch H. Gatorbulin-1, a distinct cyclodepsipeptide chemotype, targets a seventh tubulin pharmacological site. Proceedings of the National Academy of Sciences USA (PNAS) 118(9): e2021847118. 2021.
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.
Clanton NA, Hastings SD, Foultz GB, Contreras JA, Yee SS, Arman HD, Risinger AL, Frantz DE. Synthesis and biological evaluations of electrophilic steroids inspired by the taccalonolides. ACS Medicinal Chemistry Letters 11(12):2534-2543. 2020.
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 236(11):3183-3195. 2019.
LoCoco PM, Risinger AL, Smith HR, Chavera TS, Berg KA, Clarke WP. Pharmacological augmentation of nicotinamide phosphoribosyltransferase (NAMPT) protects against paclitaxel-induced peripheral neuropathy. eLife 10(6): E29626. 2017.
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. Proceedings of the National Academy of Sciences USA (PNAS) 114(43):E8957-E8966. 2017.