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Review

Targeted small molecule therapy and inhibitors for lymphoma

, , ORCID Icon &
Received 07 Oct 2023, Accepted 21 May 2024, Published online: 17 Jul 2024

References

  • Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. doi:10.3322/caac.21660
  • The World Health Organization. The 5th edition of the World Health Organization classifification of haematolymphoid tumours. Leukemia. Brisbane (AU): Exon Publications; 2022.
  • Li X, Peterson YK, Inks ES, et al. Class I HDAC inhibitors display different antitumor mechanism in leukemia and prostatic cancer cells depending on their p53 status. J Med Chem. 2018;61(6):2589–2603. doi:10.1021/acs.jmedchem.8b00136
  • Cao HY, Li L, Xue SL, et al. Chidamide: targeting epigenetic regulation in the treatment of hematological malignancy. Hematol Oncol. 2023;41(3):301–309. doi:10.1002/hon.3088
  • Pinto A, Filippi RD, Zinzani P, et al. A first-in-human trial of the novel multi-action therapy tinostamustine (EDO-S101) in patients with Relapsed/Refractory (R/R) Hodgkin lymphoma (HL). Hematol Oncol. 2019;37(Suppl. 2):326. doi:10.1002/hon.137_2630
  • Landsburg DJ, Barta SK, Ramchandren R, et al. Fimepinostat (CUDC-907) in patients with relapsed/refractory diffuse large B cell and high-grade B-cell lymphoma: report of a Phase II trial and exploratory biomarker analyses. Br J Haematol. 2021;195(2):201–209. doi:10.1111/bjh.17730
  • West AC, Johnstone RW. New and emerging HDAC inhibitors for cancer treatment. J Clin Invest. 2014;124(1):30–39. doi:10.1172/JCI6973
  • Farag AB, Ewida HA, Ahmed MS. Design, synthesis, and biological evaluation of novel amide and hydrazide based thioether analogs targeting Histone deacteylase (HDAC) enzymes. Eur J Med Chem. 2018;148:73–85. doi:10.1016/j.ejmech.2018.02.011
  • Zhang L, Han Y, Jiang Q, et al. Trend of histone deacetylase inhibitors in cancer therapy: isoform selectivity or multitargeted strategy. Med Res Rev. 2015;35(1):63–84. doi:10.1002/med.21320
  • Peixoto P, Cartron PF, Serandour AA, et al. From 1957 to nowadays: a brief history of epigenetics. Int J Mol Sci. 2020;21(20):7571. doi:10.3390/ijms21207571
  • Wagner FF, Olson DE, Gale JP, et al. Potent and selective inhibition of histone deacetylase 6 (HDAC6) does not require a surface-binding motif. J Med Chem. 2013;56(4):1772–1776. doi:10.1021/jm301355j
  • Thurn KT, Thomas S, Moore A, et al. Rational therapeutic combinations with histone deacetylase inhibitors for the treatment of cancer. Future Oncol. 2011;7(2):263–283. doi:10.2217/fon.11.2
  • Zhang Y, Sun Z, Jia J, et al. Overview of histone modification. Adv Exp Med Biol. 2021;1283:1–16. doi:10.1007/978-981-15-8104-5_1
  • Luan Y, Li J, Bernatchez JA, et al. Kinase and histone deacetylase hybrid inhibitors for cancer therapy. J Med Chem. 2019;62(7):3171–3183. doi:10.1021/acs.jmedchem.8b00189
  • Ellmeier W, Seiser C. Histone deacetylase function in CD4+ T cells. Nat Rev Immunol. 2018;18(10):617–634. doi:10.1038/s41577-018-0037-z
  • Fu RG, Sun Y, Sheng WB, et al. Designing multi-targeted agents: an emerging anticancer drug discovery paradigm. Eur J Med Chem. 2017;136:195–211. doi:10.1016/j.ejmech.2017.05.016
  • Zhang H, Lv H, Jia X, et al. Clinical significance of enhancer of zeste homolog 2 and histone deacetylases 1 and 2 expression in peripheral T-cell lymphoma. Oncol Lett. 2019;18(2):1415–1423. doi:10.3892/ol.2019.10410
  • Romano M, Vitaglione P, Sellitto S, D'Argenio G. ADDENDUM: nutraceuticals for protection and healing of gastrointestinal mucosa. Curr Med Chem. 2014;21(28):3310. doi:10.2174/092986732128140825173622
  • Bérubé G. An overview of molecular hybrids in drug discovery. Expert Opin Drug Discov. 2016;11(3):281–305. doi:10.1517/17460441.2016.1135125
  • He S, Dong G, Wang Z, et al. Discovery of novel multiacting topoisomerase I/II and histone deacetylase inhibitors. ACS Med Chem Lett. 2015;6(3):239–243. doi:10.1021/ml500327q
  • Liu J, Li JN, Wu H, et al. The status and prospects of epigenetics in the treatment of lymphoma. Front Oncol. 2022;12:874645. doi:10.3389/fonc.2022.874645
  • Zain J, O'Connor OA. Targeting histone deacetyalses in the treatment of B- and T-cell malignancies. Invest New Drugs. 2010;28(Suppl. 1):S58–S78. doi:10.1007/s10637-010-9591-3
  • Cao L, Yao H, Yu L, et al. Synthesis and evaluation of sulfonamide derivatives targeting EGFR790M/L858R mutations and ALK rearrangement as anticancer agents. Bioorg Med Chem. 2023;85:117241. doi:10.1016/j.bmc.2023.117241
  • Chen Y, Li H, Tang W, et al. 3D-QSAR studies of HDACs inhibitors using pharmacophore-based alignment. Eur J Med Chem. 2009;44(7):2868–2876. doi:10.1016/j.ejmech.2008.12.008
  • Bordeaux ZA, Reddy SV, Lee K, et al. Differential response of mycosis fungoides cells to vorinostat. Int J Mol Sci. 2023;24(9):8075. doi:10.3390/ijms24098075
  • Liu JN, Kong XS, Huang T, et al. Clinical implications of aberrant PD-1 and CTLA4 expression for cancer immunity and prognosis: a pan-cancer study. Front Immunol. 2020;11:2048. doi:10.3389/fimmu.2020.02048
  • Cuesta-Mateos C, Terrón F, Herling M. CCR7 in blood cancers-review of its pathophysiological roles and the potential as a therapeutic target. Front Oncol. 2021;11:736758. doi:10.3389/fonc.2021.736758
  • Siddiqi T, Frankel P, Beumer JH, et al. Phase I study of the Aurora kinase A inhibitor alisertib (MLN8237) combined with the histone deacetylase inhibitor vorinostat in lymphoid malignancies. Leuk Lymphoma. 2020;61(2):309–317. doi:10.1080/10428194.2019.1672052
  • Mei M, Chen L, Godfrey J, et al. Pembrolizumab plus vorinostat induces responses in patients with Hodgkin lymphoma refractory to prior PD-1 blockade. Blood. 2023;142(16):1359–1370. doi:10.1182/blood.2023020485
  • Arora SP, Tenner L, Sarantopoulos J, et al. Modulation of autophagy: a Phase II study of vorinostat plus hydroxychloroquine versus regorafenib in chemotherapy-refractory metastatic colorectal cancer(mCRC). Br J Cancer. 2022;127(6):1153–1161. doi:10.1038/s41416-022-01892-6
  • Grant C, Rahman F, Piekarz R, et al. Romidepsin: a new therapy for cutaneous T-cell lymphoma and a potential therapy for solid tumors. Expert Rev Anticancer Ther. 2010;10(7):997–1008. doi:10.1586/era.10.88
  • El Omari N, Lee LH, Bakrim S, et al. Molecular mechanistic pathways underlying the anticancer therapeutic efficiency of romidepsin. Biomed Pharmacother. 2023;164:114774. doi:10.1016/j.biopha.2023.114774
  • O'Connor OA, Özcan M, Jacobsen ED, et al. Randomized Phase III study of alisertib or investigator's choice (selected single agent) in patients with relapsed or refractory peripheral T-cell lymphoma. J Clin Oncol. 2019;37(8):613–623. doi:10.1200/JCO.18.00899
  • Falchi L, Ma H, Klein S, et al. Combined oral 5-azacytidine and romidepsin are highly effective in patients with PTCL: a multicenter Phase II study. Blood. 2021;137(16):2161–2170. doi:10.1182/blood.2020009004
  • lyer SP, Huen A, Ai WZ, et al. Safety and efficacy of tenalisib in combination with romidepsin in patients with relapsed/refractory T-cell lymphoma: results from a Phase I/II open-label multicenter study. Haematologica. 2024;109(1):209–219. doi:10.3324/haematol.2022.281875
  • Kenny RG, Ude Z, Docherty JR, et al. Vorinostat and Belinostat, hydroxamate-based anti-cancer agents, are nitric oxide donors. J. Inorg. Biochem. 2020;206:110981. doi:10.1016/j.jinorgbio.2019.110981
  • El Omari N, Bakrim S, Khalid A, et al. Anticancer clinical efficiency and stochastic mechanisms of belinostat. Biomed Pharmacother. 2023;165:115212. doi:10.1016/j.biopha.2023.115212
  • Jamaluddin MS, Hu PW, Jan Y, et al. Short communication: the broad-spectrum histone deacetylase inhibitors vorinostat and panobinostat activate latent HIV in CD4(+) T cells in part through phosphorylation of the T-loop of the CDK9 subunit of P-TEFb. AIDS Res Hum Retroviruses. 2016;32(2):169–173. doi:10.1089/AID.2015.034
  • O'Connor OA, Horwitz S, Masszi T, et al. Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: results of the pivotal Phase II BELIEF (CLN-19) study. J Clin Oncol. 2015;33(23):2492–2499. doi:10.1200/JCO.2014.59.2782
  • Johnston PB, Cashen AF, Nikolinakos PG, et al. Belinostat in combination with standard cyclophosphamide, doxorubicin, vincristine and prednisone as first-line treatment for patients with newly diagnosed peripheral T-cell lymphoma. Exp Hematol Oncol. 2021;10(1):15. doi:10.1186/s40164-021-00203-8
  • Xu K, Ramesh K, Huang V, et al. Final report on clinical outcomes and tumor recurrence patterns of a pilot study assessing efficacy of belinostat (PXD-101) with chemoradiation for newly diagnosed Glioblastoma. Tomography. 2022;8(2):688–700. doi:10.3390/tomography8020057
  • Cheng T, Kiser K, Grasse L, et al. Expression of histone deacetylase (HDAC) family members in bortezomib-refractory multiple myeloma and modulation by panobinostat. Cancer Drug Resist. 2021;4(4):888–902. doi:10.20517/cdr.2021.44
  • Slingerland M, Hess D, Clive S, et al. A Phase I, open-label, multicenter study to evaluate the pharmacokinetics and safety of oral panobinostat in patients with advanced solid tumors and various degrees of hepatic function. Cancer Chemother Pharmacol. 2014;74(5):1089–1098. doi:10.1007/s00280-014-2594-6
  • Zaja F, Salvi F, Rossi M, et al. Single-agent panobinostat for relapsed/refractory diffuse large B-cell lymphoma: clinical outcome and correlation with genomic data. A Phase II study of the Fondazione Italiana Linfomi. Leuk Lymphoma. 2018;59(12):2904–2910. doi:10.1080/10428194.2018.1452208
  • Maly JJ, Christian BA, Zhu X, et al. A Phase I/II trial of panobinostat in combination with lenalidomide in patients with relapsed or refractory Hodgkin lymphoma. Clin Lymphoma Myeloma Leuk. 2017;17(6):347–353. doi:10.1016/j.clml.2017.05.008
  • Hu B, Younes A, Westin JR, et al. Phase-I and randomized Phase-II trial of panobinostat in combination with ICE (ifosfamide, carboplatin, etoposide) in relapsed or refractory classical Hodgkin lymphoma. Leuk Lymphoma. 2018;59(4):863–870. doi:10.1080/10428194.2017.1359741
  • Liu W, Tolar P, Song W, et al. Editorial: BCR signaling and B cell activation. Front Immunol. 2020;11:45. doi:10.3389/fimmu.2020.00045
  • Dhillon S. Orelabrutinib: first approval. Drugs. 2021;81(4):503–507. doi:10.1007/s40265-021-01482-5
  • Munakata W, Tobinai K. Tirabrutinib hydrochloride for B-cell lymphomas. Drugs Today (Barc). 2021;57(4):277–289. doi:10.1358/dot.2021.57.4.3264113
  • Mao Y, Liu GF, Li J, et al. Phase I clinical study of orally-dosed HBW-3220 in patients with relapsed/refractory B-cell lymphoma. J Clin Oncol. 2023;41(Suppl. 16):e19532. doi:10.1200/jco.2023.41.16_suppl.e19532
  • Huntington SF, Schuster SJ, Ding W, et al. DTRMWXHS-12, a novel Bruton tyrosine kinase inhibitor, in combination with everolimus and pomalidomide in patients with relapsed/refractory lymphomas: an open-label, multicenter, Phase Ia/Ib study. Am J Hematol. 2023;98(5):739–749. doi:10.1002/ajh.26888
  • Liu D, Xu W, Lin B, et al. HZ-A-018, a novel inhibitor of Bruton tyrosine kinase, exerts anti-cancer activity and sensitizes 5-FU in gastric cancer cells. Front Pharmacol. 2023;14:1142127. doi:10.3389/fphar.2023.1142127
  • Liu J, Chen C, Wang D, et al. Emerging small-molecule inhibitors of the Bruton's tyrosine kinase (BTK): current development. Eur J Med Chem. 2021;217:113329. doi:10.1016/j.ejmech.2021.113329
  • Pal Singh S, Dammeijer F, Hendriks RW. Role of Bruton's tyrosine kinase in B cells and malignancies. Mol Cancer. 2018;17(1):57. doi:10.1186/s12943-018-0779-z
  • Weber ANR, Bittner Z, Liu X, et al. Bruton's tyrosine kinase: an emerging key player in innate immunity. Front Immunol. 2017;8:1454. doi:10.3389/fimmu.2017.01454
  • Ran F, Liu Y, Xu Z, et al. Recent development of BTK-based dual inhibitors in the treatment of cancers. Eur J Med Chem. 2022;233:114232. doi:10.1016/j.ejmech.2022.114232
  • Liu XJ, Liu X, Pang XJ, et al. Progress in the development of small molecular inhibitors of the Bruton's tyrosine kinase (BTK) as a promising cancer therapy. Bioorg Med Chem. 2021;47:116358. doi:10.1016/j.bmc.2021.116358
  • Zain R, Vihinen M. Structure-function relationships of covalent and non-covalent BTK inhibitors. Front Immunol. 2021;12:694853. doi:10.3389/fimmu.2021.694853
  • Miao Y, Medeiros LJ, Li Y, et al. Genetic alterations and their clinical implications in DLBCL. Nat Rev Clin Oncol. 2019;16(10):634–652. doi:10.1038/s41571-019-0225-1
  • Guo Y, Liu Y, Hu N, et al. Discovery of Zanubrutinib (BGB-3111), a novel, potent, and selective covalent inhibitor of bruton's tyrosine kinase. J Med Chem. 2019;62(17):7923–7940. doi:10.1021/acs.jmedchem.9b00687
  • Ten Hacken E, Sivina M, Kim E, et al. Functional differences between IgM and IgD signaling in chronic lymphocytic leukemia. J Immunol. 2016;197(6):2522–2531. doi:10.4049/jimmunol.1600915
  • Tasso B, Spallarossa A, Russo E, et al. The development of BTK inhibitors: a five-year update. Molecules. 2021;26(23):7411. doi:10.3390/molecules2623741
  • Wu P, Nielsen TE, Clausen MH. FDA-approved small-molecule kinase inhibitors. Trends Pharmacol Sci. 2015;36(7):422–439. doi:10.1016/j.tips.2015.04.005
  • Barr PM. Efficacy in the margins of NHL with ibrutinib. Blood. 2017;129(16):2207–2208. doi:10.1182/blood-2017-02-769042
  • Dreyling M, Jurczak W, Jerkeman M, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, Phase III study. Lancet. 2016;387(10020):770–778. doi:10.1016/S0140-6736(15)00667-4
  • Wanquet A, Birsen R, Lemal R, et al. Ibrutinib responsive central nervous system involvement in chronic lymphocytic leukemia. Blood. 2016;127(19):2356–2358. doi:10.1182/blood-2016-02-697193
  • Zhou H, Hu P, Yan X, et al. Ibrutinib in chronic lymphocytic leukemia: clinical applications, drug resistance, and prospects. Onco Targets Ther. 2020;13:4877–4892. doi:10.2147/OTT.S249586
  • Smith CI. From identification of the BTK kinase to effective management of leukemia. Oncogene. 2017;36(15):2045–2053. doi:10.1038/onc.2016.34
  • Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): a covalent bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther. 2017;363(2):240–252. doi:10.1124/jpet.117.242909
  • Byrd JC, Harrington B, O'Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 2016;374(4):323–332. doi:10.1056/NEJMoa1509981
  • Byrd JC, Woyach JA, Furman RR, et al. Acalabrutinib in treatment-naive chronic lymphocytic leukemia. Blood. 2021;137(24):3327–3338. doi:10.1182/blood.2020009617
  • Seymour JF, Byrd JC, Ghia P, et al. Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial. Blood. 2023;142(8):687–699. doi:10.1182/blood.2022018818
  • Syed YY. Zanubrutinib: first approval. Drugs. 2020;80(1):91–97. doi:10.1007/s40265-019-01252-4
  • Wu J, Liu C, Tsui ST, et al. Second-generation inhibitors of Bruton tyrosine kinase. J Hematol Oncol. 2016;9(1):80. doi:10.1186/s13045-016-0313-y
  • Thompson PA, Tam CS. Pirtobrutinib: a new hope for patients with BTK inhibitor-refractory lymphoproliferative disorders. Blood. 2023;141(26):3137–3142. doi:10.1182/blood.2023020240
  • Li N, Sun Z, Liu Y, et al. Abstract 2597: BGB-3111 is a novel and highly selective Bruton's tyrosine kinase (BTK) inhibitor. Cancer Res. 2015;75(Suppl. 15):2597. doi:10.1158/1538-7445.AM2015-2597
  • Kaptein A, Bruin GD, Hoek EV, et al. Potency and selectivity of BTK inhibitors in clinical development for B-cell malignancies. Blood. 2018;132(Suppl. 1):1871. doi:10.1182/blood-2018-99-109973
  • Nierengarten MB. Zanubrutinib more effective and better tolerated than ibrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. Cancer. 2023;129(10):1466. doi:10.1002/cncr.34811
  • Qin S, Xia Y, Miao Y, et al. Zanubrutinib plus bendamustine and CD20 monoclonal antibody as treatment for mantle cell lymphoma. Hematol Oncol. 2023;41(Suppl. 2):753–754. doi:10.1002/hon.3165_601
  • Sawalha Y, Bond DA, Alinari L. Evaluating the therapeutic potential of zanubrutinib in the treatment of Relapsed/Refractory mantle cell lymphoma: evidence to date. Onco Targets Ther. 2020;13:6573–6581. doi:10.2147/OTT.S238832
  • Keam SJ. Pirtobrutinib: first approval. Drugs. 2023;83(6):547–553. doi:10.1007/s40265-023-01860-1
  • Gomez EB, Ebata K, Randeria HS, et al. Preclinical characterization of Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor. Blood. 2023;142(1):62–72. doi:10.1182/blood.2022018674
  • Estupiñán HY, Wang Q, Berglöf A, et al. BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib. Leukemia. 2021;35(5):1317–1329. doi:10.1038/s41375-021-01123-6
  • Wang Y, Coombs CC, Shah NN, et al. Long-term safety with ≥12 months of pirtobrutinib in relapsed/refractory B-cell malignancies. Hematol Oncol. 2023;41(Suppl. 2):480–481. doi:10.1002/hon.3164_353
  • Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized Phase III trial. J Clin Oncol. 2021;39(31):3441–3452. doi:10.1200/JCO.21.01210
  • Garcia-Galiano D, Borges BC, Allen SJ, et al. PI3K signalling in leptin receptor cells: role in growth and reproduction. J Neuroendocrinol. 2019;31(5):e12685. doi:10.1111/jne.12685
  • Wang T, Sun X, Qiu L, et al. The oral PI3Kδ inhibitor linperlisib for the treatment of relapsed and/or refractory follicular lymphoma: a Phase II, single-arm, open-label clinical trial. Clin Cancer Res. 2023;29(8):1440–1449. doi:10.1158/1078-0432.CCR-22-2939
  • Fukuhara N, Suehiro Y, Kato H, et al. Parsaclisib in Japanese patients with relapsed or refractory B-cell lymphoma (CITADEL-111): A Phase Ib study. Cancer Sci. 2022;113(5):1702–1711. doi:10.1111/cas.15308
  • Zelenetz AD, Jurczak W, Ribrag V, et al. Efficacy and safety of zandelisib administered by intermittent dosing (ID) in patients with relapsed or refractory (R/R) follicular lymphoma (FL): primary analysis of the global Phase II study TIDAL. J Clin Oncol. 2022;40(Suppl. 16):7511–7511. doi:10.1200/jco.2022.40.16_suppl.7511?af=r
  • Cao J, Ji D, Li Z, et al. Updated results from a Phase IB study of Amdizalisib, a novel inhibitor of phosphoinositide 3-kinase-delta (PI3Kδ), in patientswith relapsed or refractory lymphoma. Hematol Oncol. 2023;41(Suppl. 2):13–17. doi:10.1002/hon.3165_653
  • Al Hasan M, Sabirianov M, Redwine G, et al. Binding and selectivity studies of phosphatidylinositol 3-kinase (PI3K) inhibitors. J Mol Graph Model. 2023;121:108433. doi:10.1016/j.jmgm.2023.108433
  • Roskoski R Jr. Properties of FDA-approved small molecule phosphatidylinositol 3-kinase inhibitors prescribed for the treatment of malignancies. Pharmacol Res. 2021;168:105579. doi:10.1016/j.phrs.2021.105579
  • Bilanges B, Posor Y, Vanhaesebroeck B. PI3K isoforms in cell signalling and vesicle trafficking. Nat Rev Mol Cell Biol. 2019;20(9):515–534. doi:10.1038/s41580-019-0129-z
  • Xue C, Li G, Lu J, et al. Crosstalk between circRNAs and the PI3K/AKT signaling pathway in cancer progression. Signal Transduct Target Ther. 2021;6(1):400. doi:10.1038/s41392-021-00788-w
  • Akbari Dilmaghani N, Safaroghli-Azar A, Pourbagheri-Sigaroodi A, et al. The PI3K/Akt/mTORC signaling axis in head and neck squamous cell carcinoma: possibilities for therapeutic interventions either as single agents or in combination with conventional therapies. IUBMB Life. 2021;73(4):618–642. doi:10.1002/iub.2446
  • Falasca M, Hamilton JR, Selvadurai M, et al. Class II phosphoinositide 3-kinases as novel drug targets. J Med Chem. 2017;60(1):47–65. doi:10.1021/acs.jmedchem.6b00963
  • O'Bryan JP. Pharmacological targeting of RAS: recent success with direct inhibitors. Pharmacol Res. 2019;139:503–511. doi:10.1016/j.phrs.2018.10.021
  • Maffei A, Lembo G, Carnevale D. PI3 Kinases in diabetes mellitus and its related complications. Int J Mol Sci. 2018;19(12):4098. doi:10.3390/ijms19124098
  • Mazloumi Gavgani F, Smith Arnesen V, Jacobsen RG, et al. Class I phosphoinositide 3-kinase PIK3CA/p110α and PIK3CB/p110β isoforms in endometrial cancer. Int J Mol Sci. 2018;19(12):3931. doi:10.3390/ijms1912393
  • Zhang M, Zhang X. The role of PI3K/AKT/FOXO signaling in psoriasis. Arch Dermatol Res. 2019;311(2):83–91. doi:10.1007/s00403-018-1879-8
  • Nur Husna SM, Tan HT, Mohamud R, et al. Inhibitors targeting CDK4/6, PARP and PI3K in breast cancer: a review. Ther Adv Med Oncol. 2018;10:1758835918808509. doi:10.1177/175883591880850
  • Franco R, Martínez-Pinilla E, Navarro G, et al. Potential of GPCRs to modulate MAPK and mTOR pathways in Alzheimer's disease. Prog Neurobiol. 2017;149–150:21–38. doi:10.1016/j.pneurobio.2017.01.004
  • Cisse O, Quraishi M, Gulluni F, et al. Downregulation of class II phosphoinositide 3-kinase PI3K-C2β delays cell division and potentiates the effect of docetaxel on cancer cell growth. J Exp Clin Cancer Res. 2019;38(1):472. doi:10.1186/s13046-019-1472-9
  • Kim J, Guan KL. mTOR as a central hub of nutrient signalling and cell growth. Nat Cell Biol. 2019;21(1):63–71. doi:10.1038/s41556-018-0205-1
  • Sirico M, D'Angelo A, Gianni C, et al. Current state and future challenges for PI3K inhibitors in cancer therapy. Cancers (Basel). 2023;15(3):703. doi:10.3390/cancers15030703
  • Murugan AK. mTOR: role in cancer, metastasis and drug resistance. Semin Cancer Biol. 2019;59:92–111. doi:10.1016/j.semcancer.2019.07.003
  • Nunnery SE, Mayer IA. Management of toxicity to isoform α-specific PI3K inhibitors. Ann Oncol. 2019;30(Suppl. 10):x21–x26. doi:10.1093/annonc/mdz440
  • Cheah CY, Fowler NH. Idelalisib in the management of lymphoma. Blood. 2016;128(3):331–336. doi:10.1182/blood-2016-02-702761
  • von Tresckow J, Heyl N, Robrecht S, et al. Treatment with idelalisib in patients with chronic lymphocytic leukemia – real world data from the registry of the German CLL Study Group. Ann Hematol. 2023;102(11):3083–3090. doi:10.1007/s00277-023-05314-2
  • Špaček M, Smolej L, Šimkovič M, et al. Idelalisib plus rituximab versus ibrutinib in the treatment of relapsed/refractory chronic lymphocytic leukaemia: a real-world analysis from the Chronic Lymphocytic Leukemia Patients Registry (CLLEAR). Br J Haematol. 2023;202(1):40–47. doi:10.1111/bjh.18736
  • Krause G, Hassenrück F, Hallek M. Copanlisib for treatment of B-cell malignancies: the development of a PI3K inhibitor with considerable differences to idelalisib. Drug Des Devel Ther. 2018;12:2577–2590. doi:10.2147/DDDT.S142406
  • Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PI3K in cancer: impact on tumor cells, their protective stroma, angiogenesis, and immunotherapy. Cancer Discov. 2016;6(10):1090–1105. doi:10.1158/2159-8290.CD-16-0716
  • Dreyling M, Santoro A, Mollica L, et al. Final safety and efficacy results of copanlisib monotherapy in patients with relapsed or refractory iNHL: 6-year follow-up of CHRONOS-1. Hematol Oncol. 2023;41(Suppl. 2):560–562. doi:10.1002/hon.3164_420
  • Balakrishnan K, Peluso M, Fu M, et al. The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (Duvelisib), overcomes signals from the PI3K/AKT/S6 pathway and promotes apoptosis in CLL. Leukemia. 2015;29(9):1811–1822. doi:10.1038/leu.2015.105
  • Flinn IW, O'Brien S, Kahl B, et al. Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies. Blood. 2018;131(8):877–887. doi:10.1182/blood-2017-05-786566

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