Page 20 - 2019_12-Haematologica-web

2334
Editorials
use. In addition, the issue of sparing non-tumor tissue from unwanted p53 accumulation and apoptosis remains unresolved.
Selective targeting of a p53-dependent apoptotic defect
In this issue of Haematologica, Ciardullo et al.24 offer a novel strategy for the treatment of CLL. They demon- strated that a representative of the new generation of MDM2 inhibitors has a strong anti-tumor effect in CLL.
The authors found that the compound RG7388, a sec- ond-generation MDM2 inhibitor with improved potency, stability and pharmacokinetics,25 decreases the viability of CLL tumor cells, regardless of patients’ phenotype or risk status. Importantly, the authors observed that RG7388 affects normal and tumor cells differently. They showed that MDM2 inhibition led to p53 transcriptional activa- tion in both normal and tumor cells. However, while RG7388 treatment of CLL cells induced p53 transcription- al activation and subsequent upregulation of mostly pro- apoptotic genes, PUMA, BAX, TNFRSF10B and FAS, such activation was not evident in either mature blood cells or hematopoietic (CD34+) progenitors isolated from patients’ bone marrow. In contrast, p53 activation in these non-tumor cells predominantly led to MDM2 upregulation, thus preventing the induction of unwanted apoptosis coupled with RG7388-induced p53 reactiva- tion. This differential effect is very promising and is con- sistent with the minimal toxicity of RG7388 in normal hematopoietic tissue.
Future prospective
It is well established that TP53 alterations in CLL are associated with poor outcome following a variety of treatments. Given the clinical heterogeneity of CLL, in which TP53 alterations even when present at low levels compromise patients’ outcome,26 there is a constant need to invent new therapeutic strategies for this malignancy.
Ciardullo et al.24 also showed that CLL tumors harbor- ing small TP53 subclones responded well to RG7388, pre- sumably by virtue of debulking the main tumor popula- tion that harbors wildtype p53. The authors concluded that TP53 mutational status is not the determinant of the response to this new generation of MDM2 inhibitors. This observation is encouraging, as it suggests that RG7388 could be effective in a wide range of CLL cases in which other therapeutic options are exhausted. For tumors that harbor small TP53 mutant subclones, howev- er, additional therapies that specifically target p53 func- tional loss might be required.
Taken together, in the light of the improved potency and bioavailability of the second-generation MDM2 inhibitors that are now available for clinical use, the study by Ciardullo et al. provides the rationale for an additional therapeutic option for patients with CLL.
Acknowledgments
The author is grateful to Bloodwise for financial support (ref 14031).
References
1. Damle RN, Calissano C, Chiorazzi N. Chronic lymphocytic leukaemia: a disease of activated monoclonal B cells. Best Pract Res Clin Haematol. 2010;23(1):33-45.
2. Zhang S, Kipps TJ. The pathogenesis of chronic lymphocytic leukemia. Annu Rev Pathol. 2014;9:103-18.
3. Strati P, Jain N, O'Brien S. Chronic lymphocytic leukemia: diagnosis and treatment. Mayo Clin Proc. 2018;93(5):651-664.
4. Puente XS, Jares P, Campo E. Chronic lymphocytic leukemia and mantle cell lymphoma: crossroads of genetic and microenvironment interactions. Blood. 2018;131(21):2283-2296.
5. Puente XS, López-Otín C. The evolutionary biography of chronic lymphocytic leukemia. Nat Genet. 2013;45(3):229-231.
6. Landau DA, Carter SL, Getz G, Wu CJ. Clonal evolution in hemato- logical malignancies and therapeutic implications. Leukemia. 2014;28(1):34-43.
7. Ten Hacken E, Burger J. Molecular pathways: targeting the microen- vironment in chronic lymphocytic leukemia- focus on the B cell receptor. Clin Cancer Res. 2014;20(3):548-556.
8. Oppezzo P, Dighiero G. Role of the B-cell receptor and the microen- vironment in chronic lymphocytic leukemia. Blood Cancer J. 2013;3:e149.
9. Hallek M. Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies. Blood. 2013;122(23):3723-3734.
10. Ghia P, Hallek M. Management of chronic lymphocytic leukemia. Haematologica. 2014;99(6):965-972.
11. SkowronskaA,ParkerA,AhmedG,etal.BiallelicATMinactivation significantly reduces survival in patients treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 trial. J Clin Oncol. 2012;30(36):4524-4532.
12. O'Brien S, Furman RR, Coutre S, et al. Single-agent ibrutinib in treat- ment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018;131(17):1910-1919.
13. Liu Y, Tavana O, Gu W. p53 modifications: exquisite decorations of the powerful guardian. J Mol Cell Biol. 2019;11(7):564-577.
14. Sanz G, Singh M, Peuget S, Selivanova G. Inhibition of p53 inhibitors: progress, challenges and perspectives. J Mol Cell Biol. 2019;11(7):586-599.
15. Cheok CF, Lane DP. Exploiting the p53 pathway for therapy. Cold Spring Harb Perspect Med. 2017;7(3):1-15.
16. Wang S, Zhao Y, Aguilar A, Bernard D, Yang CY. Targeting the MDM2-p53 protein-protein interaction for new cancer therapy: progress and challenges. Cold Spring Harb Perspect Med. 2017;7(5):1-11.
17. Chène P. Inhibiting the p53-MDM2 interaction: an important target for cancer therapy. Nat Rev Cancer. 2003;3(2):102-109.
18. Shangary S, Wang S. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. Annu Rev Pharmacol Toxicol. 2009;49:223-241.
19. Tisato V, Voltan R, Gonelli A, Secchiero P, Zauli G. MDM2/X inhibitors under clinical evaluation: perspectives for the manage- ment of hematological malignancies and pediatric cancer. J Hematol Oncol. 2017;10(1):133.
20. Azer SA. MDM2-p53 Interactions in human hepatocellular carcino- ma: what is the role of Nutlins and new therapeutic options? J Clin Med. 2018;7(4):1-19.
21. BaroneG,TweddleDA,ShohetJM,etal..MDM2-p53interactionin paediatric solid tumours: preclinical rationale, biomarkers and resist- ance. Curr Drug Targets. 2014;15(1):114-123.
22. Coll-Mulet L, Iglesias-Serret D, Santidrián AF, et al. MDM2 antago- nists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells. Blood. 2006;107(10):4109-4114.
23. Biswas S, Killick E, Jochemsen AG, Lunec J. The clinical develop- ment of p53-reactivating drugs in sarcomas - charting future thera- peutic approaches and understanding the clinical molecular toxicol- ogy of Nutlins. Expert Opin Investig Drugs. 2014;23(5):629-645.
24. Ciardullo C, Aptullahoglu E, Woodhouse L, et al. Non-genotoxic MDM2 inhibition selectively induces a pro-apoptotic p53 gene sig- nature in chronic lymphocytic leukemia cells. Haematologica 2019;104(12):2429-2442.
25. Ding Q, Zhang Z, Liu JJ, et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem. 2013;56(14):5979-5983.
26. Rossi D, Khiabanian H, Spina V, et al. Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia. Blood. 2014;123(14):2139-2147.
haematologica | 2019; 104(12)