Brett Stevens, Ph.D.
2019 Funding recipient
Characterization and Targeting of Metabolic Vulnerabilities of Myelodysplastic Stem Cells
EvansMDS Young Investigator Award
High risk MDS continues to have few effective treatment strategies creating a large unmet clinical need. Through past work I have shown that MDS stem cells contribute to the ineffective treatment of many patients. This work on the characterization of MDS stem cells showed distinct vulnerabilities due to specific reliance on multiple metabolic factors. One of these factors was increased translation of proteins specific to MDS stem cells. At the University of Colorado, we therefore established a phase I clinical study in high risk MDS to investigate protein translation inhibition as a strategy. To this end, preliminary results show 6 of 7 patients on this study have undergone a hematologic response and 5 of 6 of these patients have received a successful bone marrow transplant. These results surpass the historical response seen with hypomethylating agents. We have begun to investigate the MDS stem cells in these patients and have confirmed increased reliance on translation suggesting we are successfully targeting MDS stem cells. Furthermore, investigation of energy metabolism in high risk MDS patients has revealed a reliance on one form of energy utilization. We have begun to investigate patients receiving the agent Venetoclax, a known inhibitor of energy metabolism, for the drugs ability to target MDS stem cells.
Early results suggest successful targeting of MDS stem cells resulting in deep responses. Collectively, these early results have potential to make major progress in the successful treatment of MDS patients.
Winters AC, Gutman JA, Purev E, Nakic M, Tobin J, Chase S, Kaiser J, Lyle L, Boggs C, Halsema K, Schowinsky JT, Rosser J, Ewalt MD, Siegele B, Rana V, Schuster S, Abbott D, Stevens BM, Jordan CT, Smith C, Pollyea D, Real-world experience of venetoclax with azacitidine for untreated patients with acute myeloid leukemia, Blood Advances 2019 DOI: 10.1182/bloodadvances.2019000243
Hernandez G, Mills TS, Rabe JL, Chavez JS, Kuldanek S, Kirkpatrick G, Noetzli L, Jubair WK, Zanche M, Myers JR, Stevens BM, Fleenor CJ, Adane B, Dinarello CA, Ashton J, Jordan CT, Di Paola J, Hagman JR, Holers VM, Kuhn KA, Pietras EM. Pro-inflammatory cytokine blockade attenuates myeloid expansion in a murine model of rheumatoid arthritis, Haematologica 2020 DOI: 10.3324/haematol.2018.197210
Pei S, Pollyea DA, Gustafson A, Stevens BM, Minhajuddin M, Fu R, Riemondy KA, Gillen AE, Sheridan RM, Kim J, Costello JC, Amaya ML, Inguva A, Winters A, Ye H, Krug A, Jones CL, Adane B, Khan N, Ponder J, Schowinsky J, Abbott D, Hammes A, Myers JR, Ashton JM, Nemkov T, D’Alessandro A, Gutman JA, Ramsey HE, Savona MR, Smith CA, Jordan CT, Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia Cancer Discovery 2020 DOI: 10.1158/2159-8290.CD-19-0710
Walker ZJ, VanWyngarden MJ, Stevens BM, Abbott D, Hammes A, Langouët-Astrie C, Smith CA, Palmer BE, Forsberg PA, Mark TM, Jordan CT, Sherbenou DW, Measurement of ex vivo resistance to proteasome inhibitors, IMiDs, and daratumumab during multiple myeloma progression, Blood Advances 2020, DOI: 10.1182/bloodadvances.2019000122
Jones CL, Stevens BM, Pollyea DA, et al., Nicotinamide Metabolism Mediates Resistance to Venetoclax in Relapsed Acute Myeloid Leukemia Stem Cells, Cell Stem Cell 2020 DOI: :10.1016/j.stem.2020.07.021
Brett M. Stevens*, Courtney L. Jones*, Daniel A. Pollyea*, Rachel Culp-Hill, Angelo D’Alessandro, Amanda Winters , Anna Krug, Diana Abbott , Madeline Goosman, Shanshan Pei, Haobin Ye, Austin E. Gillen, Michael W. Becker, Michael R. Savona , Clayton Smith, and Craig T. Jordan, Fatty acid metabolism underlies venetoclax resistance in acute myeloid leukemia stem cells, Nature Cancer 2020 (accepted for publication).