Page 211 - Haematologica April 2020

HIF-1α in TP53-disrupted CLL cells
leads to an impaired hematopoiesis and a reduced output of innate immune cells into the blood; and ii) impaired functions of different immune cell subsets.19,42 Overall, this evidence endorses the concept of HIF-1α inhibition as a very promising therapeutic strategy in CLL.
In the era of new targeted treatments, ibrutinib has determined a dramatic change in the therapeutic land- scape and has become the standard of care for the major- ity of CLL patients.43-45 However: i) ibrutinib is not suitable for all CLL patients and may have limited availability in several countries; ii) complete responses are infrequent, and indefinite drug administration is usually needed to maintain a clinical response; and iii) the development of ibrutinib resistance in CLL cells has been demonstrated.46,47 Even more importantly, TP53dis CLL patients show a sub- optimal long-term response to ibrutinib,48 and TP53-mutated CLL cells have a lower sensitivity to ibruti- nib cytotoxicity in vitro.34 Since our data show that TP53dis samples are characterized by higher levels and function of HIF-1α (which is a crucial target to overcome the constitu- tive and inducible drug resistance of CLL cells), we hypothesized that the combination of BAY87-2243 and ibrutinib might be an attractive approach for in vitro test- ing. We found that dual targeting of HIF-1α alongside BTK function produces a synergistic cytotoxic activity towards primary CLL cells, also in the presence of TP53 abnormal- ities; thus suggesting the possibility of improving ibrutinib efficacy through this novel therapeutic association.
Overall, our data indicate that HIF-1α is over-expressed in CLL cells, especially in the presence of TP53 aberra- tions, and that it is susceptible to further upregulation through microenvironmental stimuli. From the transla- tional standpoint, the pharmacologic compound BAY87- 2243, a selective inhibitor of HIF-1α, displays potent anti-
tumor properties and warrants further pre-clinical evalua- tion in this disease setting, also in combination with other therapies. Indeed, on one hand, the synergism of BAY87- 2243 and fludarabine may provide the rationale for future clinical application in countries with limited access to ibrutinib, particularly for the treatment of high-risk patients carrying TP53 abnormalities. On the other hand, BAY87-2243 coupled with ibrutinib may offer a rational combination to increase the proportion of minimal resid- ual disease negative remissions, thus reducing the devel- opment of CLL clones with resistant mutations.
Funding
The authors would like to thank: Italian Association for Cancer Research (AIRC IG15232 and AIRC IG21408) (CR), (AIRC IG13119, AIRC IG16985, AIRC IG2174) (MM), (AIRC IG17622) (VGa), (AIRC 5x1000 project 21198, Metastatic disease: the key unmet need in oncology) (GG), (AIRC 5x1000 Special Programs MCO-10007 and 21198) (RF); Fondazione Neoplasie Sangue (Fo.Ne.Sa), Torino, Italy; University of Torino (local funds ex-60%) (MC); Ministero della Salute, Rome, Italy (Progetto Giovani Ricercatori GR-2011-02347441 [RB], GR-2009-1475467 [R.Bomben], and GR-2011-02351370 [MDB]). Fondazione Cassa di Risparmio di Torino (CRT) (VGr was recipient of a fellowship), Fondazione “Angela Bossolasco” Torino, Italy (VGr was recipient of the “Giorgio Bissolotti e Teresina Bosio” fellowship), the Italian Association for Cancer Research (AIRC, Ref 16343 VGr was recipient of the “Anna Nappa” fellowship and MT is currently the recipient of a fellow- ship from AIRC Ref 19653). Associazione Italiana contro le Leucemie, Linfomi e Mieloma (AIL) (CV was recipient of a fel- lowship). Pezcoller Foundation in collaboration with SIC (Società Italiana Cancerologia) (CV was a recipient of a "Fondazione Pezcoller - Ferruccio ed Elena Bernardi" fellowship).
References
1. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet Lond Engl. 2010;376(9747):1164-1174.
2. Zenz T, Vollmer D, Trbusek M, et al. TP53 mutation profile in chronic lymphocytic leukemia: evidence for a disease specific profile from a comprehensive analysis of 268 mutations. Leukemia. 2010; 24(12): 2072-2079.
3. Parikh SA. Chronic lymphocytic leukemia treatment algorithm 2018. Blood Cancer J. 2018;8(10):93.
4. Sutton L-A, Rosenquist R. Deciphering the molecular landscape in chronic lymphocytic leukemia: time frame of disease evolution. Haematologica. 2015;100(1):7-16.
5. Zenz T, Eichhorst B, Busch R, et al. TP53 mutation and survival in chronic lympho- cytic leukemia. J Clin Oncol. 2010;28(29): 4473-4479.
6. Gonzalez D, Martinez P, Wade R, et al. Mutational status of the TP53 gene as a pre- dictor of response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial. J Clin Oncol. 2011;29(16):2223-2229.
7. Campo E, Cymbalista F, Ghia P, et al. TP53
aberrations in chronic lymphocytic leukemia: an overview of the clinical impli- cations of improved diagnostics. Haematologica. 2018;103(12):1956-1968.
8. Seiffert M, Dietrich S, Jethwa A, Glimm H, Lichter P, Zenz T. Exploiting biological diver- sity and genomic aberrations in chronic lym- phocytic leukemia. Leuk Lymphoma. 2012; 53(6):1023-1031.
9. Gaidano G, Rossi D. The mutational land- scape of chronic lymphocytic leukemia and its impact on prognosis and treatment. Hematol Am Soc Hematol Educ Program. 2017;2017(1):329-337.
possible targets of cancer. Cell Biosci.
2017;762.
15. Semenza G. Signal transduction to hypoxia-
inducible factor 1. Biochem Pharmacol.
2002; 64(5-6):993-998.
16. 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.
17. Valsecchi R, Coltella N, Belloni D, et al. HIF- 1α regulates the interaction of chronic lym- phocytic leukemia cells with the tumor microenvironment. Blood. 2016; 127(16): 1987-1997.
18. Koczula KM, Ludwig C, Hayden R, et al. Metabolic plasticity in CLL: adaptation to the hypoxic niche. Leukemia. 2016;30(1):65-
10. Thompson PA, Burger JA. Bruton’s tyrosine
kinase inhibitors: first and second genera-
tion agents for patients with Chronic Lymphocytic Leukemia (CLL). Expert Opin 73.
Investig Drugs. 2018;27(1):31-42.
11. O’Brien S, Furman RR, Coutre S, et al. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018;
131(17):1910-1919.
12. Masoud GN, Li W. HIF-1α pathway: role,
regulation and intervention for cancer thera-
py. Acta Pharm Sin B. 2015;5(5):378-389. 13. Semenza GL. Targeting HIF-1 for cancer
therapy. Nat Rev Cancer. 2003;3(10):721. 14. Singh D, Arora R, Kaur P, Singh B, Mannan R, Arora S. Overexpression of hypoxia- inducible factor and metabolic pathways:
19. Serra S, Vaisitti T, Audrito V, et al. Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvironment. Blood Adv. 2016;1(1):47.
20. Rigoni M, Riganti C, Vitale C, et al. Simvastatin and downstream inhibitors cir- cumvent constitutive and stromal cell- induced resistance to doxorubicin in IGHV unmutated CLL cells. Oncotarget. 2015;6(30):29833-29846.
21. Hientz K, Mohr A, Bhakta-Guha D, Efferth T. The role of p53 in cancer drug resistance and targeted chemotherapy. Oncotarget.
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