Page 16 - Haematologica April 2020

Editorials
merase I inhibitor that also inhibits HIF-1α, was used for References
treatment of these mice which affected homing and reten- tion of CLL cells in protective microenvironments, as shown by reduced spleen weight and decreased coloniza- tion of spleen and/or BM with CLL cells, and prolonged survival of mice. As knockdown of HIF-1α did not cause apoptosis of CLL cells in vitro or in vivo, the authors sug- gested that the pro-apoptotic effect of EZN-2208 towards CLL cells in vivo may be caused by mechanisms that do not depend on HIF-1α inhibition.
To further explore the potential of HIF-1α targeting in CLL, Griggio et al. used the previously described HIF-1α inhibitor BAY 87-2243 which acts by inhibiting mitochon- drial complex I activity and hypoxia-induced mitochondr- ial reactive oxygen species production, thus achieving reduction of HIF-1α level with relatively higher specificity than other drugs.16 BAY 87-2243 was shown to suppress hypoxia-induced HIF-1 target gene expression in vitro at low nanomolar concentrations and to harbor anti-tumor efficacy in xenograft mouse models of lung carcinoma and melanoma.16,17 Pharmacological inhibition of HIF-1α with BAY87-2243 in primary CLL cells induced cell death in vitro, regardless of the TP53 mutational status, with a gen- erally weaker effect under hypoxia or in co-culture with stromal cells.3 Pre-clinical testing of this drug in the Eμ- TCL1 adoptive transfer model of CLL resulted in lower numbers of malignant B cells in the BM and among them a higher frequency of apoptotic cells. In all other organs that are affected by CLL, including spleen and blood where the majority of leukemia cells accumulate, HIF-1α inhibition had no effect. Combination treatment of BAY87-2243 with fludarabine or ibrutinib showed higher rates of CLL cell death in vitro compared to monotherapy, which was independent of functional TP53. Therefore, the authors suggest that HIF-1α inhibition renders TP53- disrupted CLL cells sensitive to fludarabine treatment.
Even though treatment options for CLL have improved tremendously within the last decade, dysfunctional TP53 is still associated with inferior patient outcome.18 The development of novel treatment strategies is, therefore, extremely important for this patient group, as well as in the light of overcoming or avoiding therapy resistance to novel targeted therapies due to clonal evolution and/or selection of clones with aggressive phenotype, including disrupted TP53 status.
Acknowledgment
I would like to thank Daniel Mertens, Deyan Yosifov, and Michaela Reichenzeller for their critical review and helpful com- ments on the manuscript.
1. The Nobel Prize in Physiology or Medicine 2019. NobelPrize.org. Nobel Media AB 2020. Wed. 12 Feb 2020. <https://www.nobel- prize.org/prizes/medicine/2019/press-release/>
2. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721-732.
3. Griggio V, Vitale C, Todaro M, et al. HIF-1α is overexpressed in leukemic cells from TP53-disrupted patients and is a promising ther- apeutic target in chronic lymphocytic leukemia. Haematologica. 2019;105(4):1042-1054.
4. Ghosh AK, Shanafelt TD, Cimmino A, et al. Aberrant regulation of pVHL levels by microRNA promotes the HIF/VEGF axis in CLL B cells. Blood. 2009;113(22):5568-5574.
5. Close V, Close W, Kugler SJ, et al. FBXW7 mutations reduce binding of NOTCH1, leading to cleaved NOTCH1 accumulation and target gene activation in CLL. Blood. 2019;133(8):830-839.
6. KoczulaKM,LudwigC,HaydenR,etal.MetabolicplasticityinCLL: adaptation to the hypoxic niche. Leukemia. 2016;30(1):65-73.
7. HannaBS,ÖztürkS,SeiffertM.Beyondbystanders:Myeloidcellsin chronic lymphocytic leukemia. Mol Immunol. 2019;110:77-87.
8. Serra S, Vaisitti T, Audrito V, et al. Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvi- ronment. Blood Adv. 2016;1(1):47-61.
9. Valsecchi R, Coltella N, Belloni D, et al. HIF-1α regulates the interac- tion of chronic lymphocytic leukemia cells with the tumor microen- vironment. Blood. 2016;127(16):1987-1997.
10. Yosifov DY, Idler I, Bhattacharya N, et al. Oxidative stress as candi- date therapeutic target to overcome microenvironmental protection of CLL. Leukemia. 2020;34(1):115-127.
11. Lamb J, Crawford ED, Peck D, et al. The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and Disease. Science. 2006;313(5795):1929-1935.
12. Hammond EM, Giaccia AJ. The role of p53 in hypoxia-induced apoptosis. Biochem Biophys Res Commun. 2005;331(3):718-725. 13. Sánchez-Puig N, Veprintsev DB, Fersht AR. Binding of Natively
Unfolded HIF-1α ODD Domain to p53. Mol Cell.
2005;17(1):11-21.
14. Madan E, Parker TM, Pelham CJ, et al. HIF-transcribed p53 chaper-
ones HIF-1α. Nucleic Acids Res. 2019;47(19):10212-10234.
15. Bhattarai D, Xu X, Lee K. Hypoxia-inducible factor-1 (HIF-1) inhibitors from the last decade (2007 to 2016): A “structure–activity
relationship” perspective. Med Res Rev. 2018;38(4):1404-1442.
16. Ellinghaus P, Heisler I, Unterschemmann K, et al. BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activa- tion has antitumor activities by inhibition of mitochondrial complex
I. Cancer Med. 2013;2(5):611-624.
17. Schöckel L, Glasauer A, Basit F, et al. Targeting mitochondrial com-
plex I using BAY 87-2243 reduces melanoma tumor growth. Cancer
Metab. 2015;3:11.
18. Tausch E, Beck P, Schlenk RF, et al. Prognostic and predictive role of
gene mutations in chronic lymphocytic leukemia: results from the pivotal phase III study COMPLEMENT1. Haematologica. 2020 Jan 9. [Epub ahead of print]
858
haematologica | 2020; 105(4)