Researcher Profiles
Michael R. Savona, M.D.
Vanderbilt University Medical Center
2017 Funding Recipient
The Role of MCL-1 in Myelodysplastic Syndromes
Discovery Research Grant 2017
PROJECT SUMMARY
The incidence and impact of myelodysplastic syndromes (MDS) are underestimated, and while the available treatments have improved, they remain insufficient. This is likely, in part, due to the complexity of MDS, and the heterogeneity of cells involved in the disease. Despite this complexity, all MDS cells have proteins that control apoptosis, or programmed cell death, which is dysregulated in MDS. Proteins compete to block apoptosis (anti-ˇapoptotic) or promote apoptosis (pro-ˇapoptotic). Making attempts to target these proteins provides an opportunity to improve therapy for MDS. Venetoclax (ABT-ˇ199) is a new therapy that specifically inhibits the anti-ˇapoptotic protein, BCL-ˇ2. Venetoclax has also been used in clinical trials in acute myeloid leukemia (AML) yielding impressive rates of response;; however, many MDS cells tend to make more of another anti-ˇapoptotic protein, induced myeloid cell leukemia-ˇ1 (MCL-ˇ1). In fact, increased MCL-ˇ1 has been shown to be a resistance mechanism for many cancers that fail to respond to BCL-ˇ2 inhibition in the laboratory and in clinical trials. In MDS, we know that the MCL-ˇ 1 levels increase when MDS samples are treated with BCL-ˇ2 inhibitors, and that BCL-ˇ2 inhibitors are more effective when MCL-ˇ1 levels are low, so MCL-ˇ1 is a logical candidate protein to target in patients with MDS. We have shown that MCL-ˇ1 inhibitors are effective in the laboratory against AML patient samples that are dependent on MCL-ˇ1 protein and have built on previous work that helps to define which leukemia cells are likely to respond to MCL-ˇ1 inhibition, and which cells are likely to respond to BCL-ˇ2 inhibition. We have tested AML cells that arose from MDS and found similar results. Thus, in the first year of our Evans DRG, we have tested many MDS samples and shown response to selective inhibitors of anti-ˇapoptotic proteins. Further developing this knowledge in MDS will help us learn which of these kinds of therapies are most appropriate for a given MDS, if synergy can be obtained by combining these agents, and how to best prepare for thoughtful design of clinical trials with MCL-ˇ1 inhibitors in the clinic.
PUBLICATIONS
Taekyu Lee,Zhiguo Bian,Bin Zhao,Leah J. Hogdal,John L. Sensintaffar,Craig M. Goodwin,Johannes Belmar,Subrata Shaw,James C. Tarr,Nagarathanam Veerasamy,Shannon M. Matulis,Brian Koss,Melissa A. Fischer,Allison L. Arnold,DeMarco V. Camper,Carrie F. Browning,Olivia W. Rossanese,Amit Budhraja,Joseph Opferman,Lawrence H. Boise,Michael R. Savona,Anthony Letai,Edward T. Olejniczak,Stephen W. Fesik, Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors, FEBS Letters 2016, doi: 10.1002/1873-3468.12497
Haley E. Ramsey, Melissa A. Fischer1, Taekyu Lee, Agnieszka E. Gorska, Maria Pia Arrate, Londa Fuller, Kelli L. Boyd, Stephen A. Strickland, John Sensintaffar, Leah J. Hogdal, Gregory D. Ayers, Edward T. Olejniczak, Stephen W. Fesik, Michael R. Savona, A Novel MCL-Inhibitor Combined with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous Leukemia, Cancer Discovery 2018, doi: 10.1158/2159-8290.CD-18-0140
Susu Zhang,Yue Zhao,Tiffany M. Heaster,Melissa A. Fischer,Kristy R. Stengel,Xiaofan Zhou,Haley Ramsey,Ming-Ming Zhou,Michael R. Savona,Melissa C. Skala,Scott W. Hiebert, BET inhibitors reduce cell size and induce reversible cell cycle arrest in AML, Journal of Cellular Biochemistry 2018, doi: 10.1002/jcb.28005
Taekyu Lee, Plamen P. Christov, Subrata Shaw, James C. Tarr, Bin Zhao, Nagarathanam Veerasamy, Kyu Ok Jeon, Jonathan J. Mills, Zhiguo Bian, John L. Sensintaffar, Allison L. Arnold, Stuart A. Fogarty, Evan Perry, Haley E. Ramsey, Rebecca S. Cook, Melinda Hollingshead, Myrtle Davis Millin, Kyung-min Lee, Brian Koss, Amit Budhraja, Joseph T. Opferman, Kwangho Kim, Carlos L. Arteaga, William J. Moore, Edward T. Olejniczak, Michael R. Savona, and Stephen W. Fesik, Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer, Journal of Medicinal Chemistry 2019, doi:10.1021/acs.jmedchem.8b01991
Shanshan Pei, Daniel A. Pollyea, Annika Gustafson, Brett M. Stevens, Mohammad Minhajuddin, Rui Fu, Kent A. Riemondy, Austin E. Gillen, Ryan M. Sheridan, Jihye Kim, James C. Costello, Maria L. Amaya, Anagha Inguva, Amanda Winters, Haobin Ye, Anna Krug, Courtney L. Jones, Biniam Adane, Nabilah Khan, Jessica Ponder, Jeffrey Schowinsky, Diana Abbott, Andrew Hammes, Jason R. Myers, John M. Ashton, Travis Nemkov, Angelo D’Alessandro, Jonathan A. Gutman, Haley E. Ramsey, Michael R. Savona, Clayton A. Smith, Craig T. Jordan, Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia, Discovery 2020, doi:10.1158/2159-8290.CD-19-0710
Melissa A. Fischer, Sharon Y. Friedlander, Maria P. Arrate, Hua Chang, Agnieszka E. Gorska, Londa D. Fuller, Haley E. Ramsey, Trinayan Kashyap, Christian Argueta, Sophie Debler, Michael Byrne, Matthew T. Villaume, Aaron C. Shaver, William Senapedis, Yosef Landesman, Erkan Baloglu, Sharon Shacham, Michael R. Savona, Venetoclax response is enhanced by selective inhibitor of nuclear export compounds in hematologic malignancies, Blood Advances 2020, doi: 10.1182/bloodadvances.2019000359
Melissa A. Fischer, Yuanbin Song, Maria P. Arrate, Rana Gbyli, Matthew T. Villaume, Brianna N. Smith, Merrida A. Childress, Thomas P. Stricker, Stephanie Halene, Michael R. Savona, Selective inhibition of MCL1 overcomes venetoclax-resistance in a murine model of myelodysplastic syndromes, haematolgocia 2022, doi:10.3324/haematol.2022.280631