Omar Abdel-Wahab, M.D., Ph.D.
2016 Grant Recipient
Biology and Therapeutic Targeting of Spliceosome-Mutant MDS: Elucidating Critical Targets, Transcripts, and Collaborating Events in Spliceosomal-Mutant MDS
Programmatic Research Grant 2016
Patients with myelodysplastic syndromes (MDS) are prone to infection, bleeding, and fatigue (as a consequence of low blood counts) and are at extremely high risk of developing acute myeloid leukemia (AML). The currently approved drugs for MDS (azacitidine, decitabine, lenalidomide) can modify the burden of disease in some patients, but the responses are not sustained. The only potentially curative therapy for MDS is bone marrow transplantation, but >90% of MDS patients are unable to undergo transplantation because of advanced age or concurrent medical problems. Clearly, novel therapeutic approaches are needed for MDS. A recurring theme across oncology is that the best path to highly effective therapy begins with a thorough understanding of why cancer develops. Until recently, our understanding of the genetic causes of MDS was extremely limited. In the past several years, we have gained new insights, largely through unbiased sequencing studies (where the order of building blocks in the genome is determined, and mutations–“spelling errors”–are identified). We and several other groups recently made a surprising discovery. In MDS patient samples, we found a high frequency of mutations in components of the “spliceosome.” The spliceosome is a structure found in all cells that modifies RNA. RNA is the “second messenger” that relays instructions from DNA (the molecule that contains our genes, the instruction manual for all cells) to protein (the molecules that carry out most functions within cells). The modification of RNA performed by the spliceosome is called splicing. During splicing, pieces of genes not necessary to direct protein formation are removed. Importantly, the pieces of genes that are important for protein formation are shuffled during splicing. The net result is that one gene can direct the formation of more than one protein. We predicted that mutations in the spliceosome would lead to altered splicing. We now have strong evidence that this is the case, but how (or if) altered splicing contributes to MDS is completely unknown. Further investigation is needed to determine: 1) how splicing mutations contribute to MDS, and 2) whether these mutations represent an avenue for development of novel MDS therapies.
This Programmatic Research Grant application has three projects with distinct, but complementary goals. Project 1 (led by Dr. Matthew Walter, Washington University), will generate novel genetically-engineered mouse strains that express the most common spliceosome mutation that we identified. We will use well-established techniques to determine whether these model systems exhibit the pattern of abnormal splicing that we see in MDS patient samples. Project 2 (led by Dr. Omar Abdel-Wahab, Memorial Sloan Kettering), will perform mechanistic studies to understand which abnormally spliced products are functionally important for the development of MDS phenotypes. Project 3 (led by Dr. Timothy Graubert, Massachusetts General Hospital), will use cell lines to identify an “Achilles heel” that could point towards potential new drug targets for MDS. Any vulnerabilities that we uncover will be tested in human and mouse blood-forming cells to confirm that normal cells are not adversely affected and that the observations are not restricted to cells grown in the laboratory.
Information gained from this project will be shared with Evans Foundation awardees at regular meetings and with the broader scientific community through publications and presentations at national meetings. Tools developed by the project will be made available to other investigators so that advances in our understanding of MDS can be made more rapidly.
Summary of Project 2
Our originally funded proposal for the EvansMDS foundation was aimed at furthering our understanding of RNA splicing factor mutations in MDS. Since these mutations impact the RNA splicing of hundreds of RNAs, identifying those RNA molecules which are most important deregulated in splicing to drive the disease has been a major question. In the last year of EvansMDS funding we have completed an initial effort to identify mis-spliced genes that are most critical to the MDS disease process. This was performed in an unbiased manner and the data are now being analyzed.
In addition to the above, we have made substantial progress in helping to identify a new drug for clinical use that targets MDS cells with RNA splicing factors. These include the discovery that a class of compounds that degrade an RNA splicing factor may have important therapeutic efficacy in MDS and related myeloid leukemias such as acute myeloid leukemia. Importantly, these drugs, known as “the anticancer sulfonamides”, have already demonstrated safety in cancer patients from prior phase I and phase II clinical trials. We are now working with Eisai Pharmaceuticals to initiate a phase II clinical trial of the oral sulfonamide drug E7820 in patients with MDS and related myeloid leukemias with an RNA splicing factor mutation that are relapsed or refractory to conventional therapies.
Finally, in addition to the above work, we have identified an exciting new intersection of mutations affecting RNA splicing in MDS with mutations affecting the metabolic system (in a gene called IDH2 (or isocitrate dehydrogenase 2)). Mutations in the RNA splicing factor SRSF2 and IDH2 cause leukemia when combined in mice and both serve as excellent therapeutic targets. Excitingly, a drug targeting mutant IDH2 was recently FDA-approved for acute myeloid leukemia patients with an IDH2 mutation. Our data now identify that combining drugs targeting RNA splicing with those targeting mutant IDH2 may work together for those patients with combined IDH2 and SRSF2 mutations.
Seiler M, Yoshimi A (co-first author), Darman R, Chan B, Keaney G, Thomas M, Agrawal AA, Caleb B, Csibi A, Sean E, Fekkes P, Karr C, Klimek V, Lai G, Lee L, Kumar P, Lee SC, Liu X, Mackenzie C, Meeske C, Mizui Y, Padron E, Park E, Pazolli E, Peng S, Prajapati S, Taylor J, Teng T, Wang J, Warmuth M, Yao H, Yu L, Zhu P, Abdel-Wahab O, Smith PG, Buonamici S, H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers, Nat Med 2018 May;24(4):497-504. doi:10.1038/nm.4493
Lee SC, North K, Kim E, Jang E, Obeng E, Lu SX, Liu B, Inoue D, Yoshimi A, Ki M, Yeo M, Zhang XJ, Kim MK, Cho H, Chung YR, Taylor J, Durham BH, Kim YJ, Pastore A, Monette S, Palacino J, Seiler M, Buonamici S, Smith PG, Ebert BL, Bradley RK, Abdel-Wahab O, Synthetic Lethal and Convergent Biological Effects of Cancer-Associated Spliceosomal Gene Mutations Cancer Cell 2018 Aug 13;34(2):225-241.e8. doi:10.1016/j.ccell.2018.07.003
Dr. Abdel-Wahab was featured in a recent article in the Oncology Times.