Clinical Trials Under Way
Hoffmann-La Roche’s phase 1 trial for the oral nutlin derivative RG7112, reported in 2016, demonstrated clinical activity against relapsed/refractory AML and CLL, a “proof of concept” demonstration that MDM2 inhibition can restore p53 function and clinical response in hematologic malignancies.16
“RG7112 showed sufficient clinical activity to lead to p53 stabilization and transcriptional activation of p53 target genes in extremely poor prognosis (relapsed/refractory) AML patients and in CLL/sCLL patients,” wrote the authors of a recent review.9 “In AML, RG7112 administration showed clinical activity as monotherapy, particularly in relapsed/refractory AML with some patients reaching complete remission and hematopoietic recovery, allowing subsequent transplantation.”
Researchers are also pursuing several clinical studies of the nutlin derivative RG7388 (idasanutlin) as a potential treatment for a range of hematologic cancers and disorders, including thrombocythemia and polycythemia vera.
Several preclinical, early phase clinical dose-finding, and safety studies of nutlins, including idasanutlin and RG7112, were reported at the 2017 American Society of Hematology (ASH) 59th Annual Meeting & Exposition in Atlanta, Georgia.
- Merkel O, Taylor N, Prutsch N, et al. When the guardian sleeps: reactivation of the p53 pathway in cancer. Mut Res. 2017;773:1-13. doi: 10.1016/j.mrrev.2017.02.003
- Manojlovic Z, Christofferson A, Liang WS, et al. Comprehensive molecular profiling of 718 multiple myelomas reveals significant differences in mutation frequencies between African and European descent cases. PLoS Genet. 2017;13:e1007087. doi: 10.1371/journal.pgen.1007087
- Nag S, Qi J, Srivenugopal KS, Wang M, Zhang R. The MDM2-p53 pathway revisited. J Biomed Res. 2013;27:254-71.
- Abdi J, Rastgoo N, Li L, Chen W, Chang H. Role of tumor suppressor p53 and micro-RNA interplay in multiple myeloma pathogenesis. J Hematol Oncol. 2017;10:169. doi: 10.1186/s13045-017-0538-4
- Kojima K, Ishizawa J, Andreeff M. Pharmacological activation of wild-type p53 in the therapy of leukemia. Exp Hematol. 2016;44:791-8.
- McCubrey JA, Lertpiriyapong K, Fitzgerald TL, et al. Roles of TP53 in determining therapeutic sensitivity, growth, cellular senescence, invasion, and metastasis. Adv Biol Regul. 2017;63:32-48. doi: 10.1016/j.jbior.2016.10.001
- Teoh PJ, Chng WJ. p53 abnormalities and potential therapeutic targeting in multiple myeloma. Biomed Res Int. 2014;717919. doi: 10.1155/2014/717919
- Duffy MJ, Synnott NC, McGowan PM, Crown J, O’Connor D, Gallagher WM. p53 as a target for the treatment of cancer. Cancer Treat Rev. 2014;40:1153-60. doi: 10.1016/j.ctrv.2014.10.004
- Tisato V, Voltan R, Gonelli A, Secchiero P, Zauli G. MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer. J Hematol Oncol. 2017;10:133. doi: 10.1186/s13045-017-0500-5
- Lehmann S, Bykov VJ, Ali D, et al. Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J Clin Oncol. 2012;30:3633-9.
- Saha MN, Yang Y, Chang H. Targeting p53 by small molecule p53 activators in multiple myeloma. J Hematol Oncol. 2012;5(Supp. 1):A7.
- Herrero AB, Rojas EA, Misiewicz-Krzeminska I, Krzeminski P, Gutierrez NC. Molecular mechanisms of p53 deregulation in cancer: an overview in multiple myeloma. Int J Mol Sci. 2016;30:17.
- Burgess A, Chia KM, Haupt S, Thomas D, Haupt Y, Lim E. Clinical overview of MDM2/X-targeted therapies. Frontiers Oncol. 2016;6:7. doi: 10.3389/fonc.2016.00007
- Lee DM, Kim IY, Seo MJ, Kwon MR, Choi KS. Nutlin-3 enhances bortezomib sensitivity of p53-defective cancer cells by inducing paraptosis. Exp Molec Med. 2017;49:e365. doi: 10.1038/emm.2017.112
- Saha MN, Jiang H, Jayakar J, Reece D, Branch DR, Chang H. MDM2 antagonist nutlin plus proteasome inhibitor Velcade combination displays a synergistic anti-myeloma activity. Cancer Biol Ther. 2010;9:936-944.
- Andreeff M, Kelly KR, Yee K, et al. Results of the phase I trial of RG7112, a small-molecule MDM2 antagonist in leukemia. Clin Cancer Res. 2016;22:868-76. doi: 10.1158/1078-0432.CCR-15-0481