The Peripheral T-Cell Lymphomas. Группа авторов
to transcription factors and activate nearby target genes controlling cellular identity). Thus, BETs contribute to the development and progression of malignancies by both activating and potentiating the expression of key oncogenes [119].
Although BET mutations or translocations are rare, BETs can be overexpressed [120]. Consequently, BET inhibition has been shown to be effective in preclinical studies across multiple types of cancers, including breast, neuroendocrine, ovarian, and hematological malignancies, as well as in rhabdomyosarcoma and glioma [121–125]. BET inhibitors appear to be active in CTCL, EBV‐associated lymphoproliferative disease and primary effusion lymphoma and have been shown to decrease the rate of tumor growth and disease progression in mouse xenograft models [126–128]. Several phase I trials designed to test BET inhibitors, including molibresib, CC‐90010, and INCB054329, are currently ongoing for patients with various advanced‐stage malignancies. In December 2018, data from 27 patients with various subtypes of non‐Hodgkin lymphoma treated with molibresib were presented at the American Society of Hematology annual meeting. The overall response rate among the entire cohort was 18.5%, with one patient with DLBCL having a sustained complete remission after receiving treatment for 54 weeks. Also of note, three of six patients with TCL had a partial response [129]. However, at the time of writing no further studies with molibresib were planned for lymphoma.
Protein Arginine Methyltransferases Inhibitors
Protein arginine methyltransferases inhibitors (PRMTs) catalyze the monomethylation or dimethylation of arginine residues on histone and non‐histone proteins. A total of nine human PRMTs are known to exist, although PRMT5 seems to be the most relevant to oncogenesis. PRMT5 is a type II PRMT that specifically catalyzes the symmetrical dimethylation of arginine residues located on the H3 or H4 proteins, resulting in gene silencing [118]. PRMT5 might also have a role in the development of TCLs. Similar to EBV‐transformed lymphoma, PRMT5 expression is upregulated in human T‐cell lymphotropic virus type 1 (HTLV)‐transformed ATLL, and PRMT5 inhibition was shown to have selective cytotoxic effects on HTLV+ lymphoma cells [130]. Overexpression of PRMT5 in ATLL seems to interact with oncogenic CCND1, MYC, and NOTCH1 in driving lymphomagenesis and might also directly silence p53 [131]. No PRMT inhibitors have thus far received FDA approval, and the first clinical trial designed to investigate a PRMT5 inhibitor (GSK3326595) commenced in 2016 for patients with solid tumors or non‐Hodgkin lymphoma (NCT02783300). Despite this lack of clinical evidence, a growing body of data from preclinical studies has demonstrated a potentially important role of this class of drug, specifically for the treatment of lymphoid malignancies. Activating mutations in PRMT5 have not been reported in patients with lymphoma, although PRMT5 is overexpressed in different subtypes and might potentially serve as a biomarker.
Combination Therapies Involving Epigenetic Targeting Agents
One of the more exciting areas in PTCL research involves the development of combination therapies that target, either in part or in unison, some of the dysregulated epigenetic biology discussed above. While these experiences are discussed in more detail in other chapters (and is summarized here in Table 3.3), it is becoming increasingly clear that drugs targeting the epigenome may well form the cornerstone of future PTCL‐directed combination therapies. As this experience evolves, it will be incumbent on the scientific community to decipher, as best it can, the relationships between clinical activity of these combinations and the underlying epigenetic biology. In this fashion, it will be likely that very targeted epigenetic predicated platforms could emerge in a subtype directed manner.
Future Directions
As discussed above, there are many lines of evidence that suggest that the T‐cell malignancies harbor many lesions that underscore its gross epigenetic dysregulation. In addition, it is clear that efficacy of epigenetic‐based monotherapies, which exhibit a clear lineage specific selectivity in the TCL, is only the first step in trying to leverage our growing understanding of these diseases in a treatment focused fashion in is limited. Combinations of drugs predicated on a HDAC inhibitor backbone appear to improve the efficacy of these agents, as demonstrated in phase I and phase II trials investigating HDAC or DNMT inhibitors. The combination of epigenetic modulating agents with immunotherapy provides perhaps the most exciting avenue for future research. Histone modification typically results in closed chromatin states at the MHC class II promoters, and in MCL and DLBCL cells this can be reversed by HDAC inhibition, thus enhancing antigen‐specific immune recognition and activation [137, 138]. In addition, DNMT inhibitors seem to increase sensitivity to immune‐checkpoint inhibition [139, 140]. Presently, a number of studies are systematically exploring the combination of immune checkpoint inhibitors with many of the agents descried above (romidepsin, decitabine, azacytidine, pralatrexate) as well as with various doublet combinations (ex 5‐azacytidine plus romidepsin, decitabine plus pralatrexate, and pralatrexate plus romidepsin). It is anticipated that, in the near future, these two‐ or three‐drug combinations will lead to a paradigm change in the disease, with a shift from the indiscriminate cytotoxic effects of chemotherapy, to likely immunoepigenetic‐based platforms.
Table 3.3 Combination agents targeting the T‐cell lymphoma epigenome.
| Drug combinations | Class/Mechanism | Disease | Patients (n) | ORR (%) | CR (%) | Median PFS (months) | Median DOR (months) | Refs. |
|---|---|---|---|---|---|---|---|---|
| Panobinostat/Bortezomib | HDACi and proteasome inhibitor | PTCL | 25 | 43 | 22 | 2.6 | 5.6 | [132] |
| Romidepsin/Pralatrexate | HDACi and folate antagonist | PTCL/CTCL | 14 | 71 | 29 | 4.4 | 4.3 | [133] |
| Romidepsin/Alisertib | HDACi and Aurora A kinase inhibitor | PTCL/CTCL | 3 | 33 | 33 | > 6 | nr | [134] |
| Romidepsin/Duvelisib | HDACi and PI3Kδ, −γ inhibitor | PTCL/CTCL | 11 | 64 | 36 | nr | nr | [135] |
| Romidepsin/Lenalidomide | HDACi and immunomodulatory agent | PTCL/CTCL | 10 | 50 | 0 | 13.5 weeks | nr | [136] |
| Romidepsin/Azacitidine | AITL | PTCL | 14 | 73 | 54 |
7.9
|