Intrinsic and Extrinsic Factors That Influence Epigenetics
Cristina Camprubí, Joan Blanco in Epigenetics and Assisted Reproduction, 2018
The first pharmacological agent used to deliberately alter the epigenome was the demethylating agent 5-AzaC. 5-AzaC was initially tested as a treatment against leukemia in mice (87) and is currently approved by the FDA (since 2004) for the chemotherapeutical treatment of the myelodysplastic syndrome (88). In addition to 5-AzaC, there are currently a number of other epigenetic drugs approved for clinical use by the FDA (89): Decitabine (5-aza-2′-deoxycytidine) is also a hypomethylating agent with similar therapeutic applications as 5-AzaC for the treatment of myelodysplastic syndrome; Tranylcypromine and phenelzine are lysine demethylase inhibitors initially approved as anti-depressants, but currently also tested for cancer treatment; Trichostatin-A, Vorinostat, Panobinostat, and Belinostat are HDAC inhibitors (of the hydroxamic acids group) employed in the treatment of lymphoma and leukemia; Mocetinostat is an HDAC inhibitor from the benzamides group also employed for the treatment of myelodysplastic syndrome; Romidepsin is an HDAC I and II inhibitor with cyclic tetrapeptide antibiotic and antineoplastic activity approved for the treatment of patients with cutaneous T-cell lymphoma, used after they have been administered with systemic therapy (89). In addition, three epigenetic drugs based on the action of miRNAs have entered clinical trials: Miravirsen and RG-101 for the treatment of hepatitis C, and MRX34 for the treatment of cancer (89). Table 6.2 summarizes the current status of pharmacological agents that alter the epigenome.
The Emerging Role of Histone Deacetylase Inhibitors in the Treatment of Lymphoma
Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey in Innovative Leukemia and Lymphoma Therapy, 2019
Butyrate, phenylbutyrate, and valproic acid were among the first drugs that were shown to have HDAC inhibitory activity, with phenylbutyrate and valproate having a significant clinical experience in cervical (33) and breast cancers, melanoma, and other solid tumors (34). In hematologic malignancies, valproate has been used in the treatment of AML with all-transretinoic acid (ATRA) producing one complete remission (CR) and a response rate of 5% (35). Other studies in patients with AML studied combinations with valproate and the hypomethylating agent 5-aza-2′-deoxycytidine with an overall response rate (ORR) of 22%, and a remarkable CR rate of 19% (36). A recent report by Zain et al. described a CR in a patient with diffuse large B-cell lymphoma refractory to previous lines of therapy following monotherapy with valproate alone (37).
Chronic Myeloid Leukaemia
Tariq I. Mughal in Precision Haematological Cancer Medicine, 2018
Whilst qualified responses with TKIs have been observed in patients with CML in the accelerated phase, most tend not to be durable. The activity of TKIs in BT is even less impressive with a median survival of less than 9 months. Currently, both dasatinib and bosutinib, but not nilotinib are licensed for BT. Another useful drug licensed for CP and accelerated phase disease-resistant to at least two TKIs, is omacetaxine mepesuccinate, an inhibitor of protein synthesis. The drug is often associated with severe myelosuppression, which has limited its use. In younger patients, it might be reasonable to offer patients in frank BT, and an acute leukaemia type of chemotherapy in combination with a TKI which they might not have received prior to BT, or an appropriate clinical trial assessing one of the newer drugs and then consider allo-SCT if a second CP is achieved. At present, the MD Anderson Hospital (Houston) has a TKI plus hypomethylating agent trial underway that looks promising, but clearly, it is difficult to make firm recommendations at present. Lastly, a report from Peter Valent (Vienna) of the use of a rotation of ponatinib and bosutinib, to induce persistent deep MR in an older patient with multi-resistant blast crisis, is interesting and merits further study.
Hedgehog pathway inhibition as a therapeutic target in acute myeloid leukemia
Published in Expert Review of Anticancer Therapy, 2019
Rory M. Shallis, Jan Philipp Bewersdorf, Prajwal C. Boddu, Amer M. Zeidan
In further support of the reliance of leukemic cell survival upon HH signaling is the observation that exposure to HH ligand or SMO inhibition induces apoptosis of CD34+ leukemic cells [70,77,78]. The addition of the natural (plant steroidal alkaloid) SMO inhibitor cyclopamine has demonstrated the ability to reduce CD34+ leukemic cell line chemoresistance to cytarabine and doxorubicin [70,79]. Such data suggest that employing agents which inhibit HH pathway activation may restore myeloid leukemic cell sensitivity to conventional frontline AML chemotherapeutic agents. Indeed, initial in vitro and ex vivo studies of AML cell lines treated with an SMO inhibitor (SMOi) have shown preclinical activity. The SMOis vismodegib (GDC0449) and erismodegib (LDE225 or sonidegib) have been shown to increase intracellular concentrations of doxorubicin, restore respective chemosensitivity and demonstrate modest activity in AML cell lines without an appreciable molecular or genetic signature predictive of response [77,78,80]. One study was able to demonstrate the synergy between an SMOi and the addition of a hypomethylating agent (HMA), specifically azacitidine, in AML [80]. SMO and GLI3 silencing by siRNA augmented the chemosensitivity of AML cell lines to azacitidine [80].
Development of new agents for peripheral T-cell lymphoma
Published in Expert Opinion on Biological Therapy, 2019
Yuta Ito, Shinichi Makita, Kensei Tobinai
Several preclinical studies demonstrated that marked synergistic effects from the combination therapy of a hypomethylating agent and HDAC inhibitor [89–91]. Based on these results, a phase I/II study of oral azacitidine and romidepsin in patients with malignant lymphomas is ongoing [92]. In the phase I part, 27 patients with B-cell NHL (8 patients, 27%), T-cell NHL (10 patients, 33%) and Hodgkin lymphoma/other subtypes (12 patients, 40%) were enrolled. The MTD was azacitidine 300 mg/day, on days 1 to 14, and romidepsin 14 mg/m2 on days 8, 15, and 22. Among the 25 evaluable patients, the ORR was 28% (7 out of 25 patients), including 4 patients with CR. Notably, the ORR and CR rate in patients with PTCL were 83% (5/6) and 50% (3/6), respectively. These findings encouraged further clinical development of this combination, especially for the treatment of PTCL. Recently, an interim result of the phase II portion was presented at the 60th ASH annual meeting [93]. Among the 16 efficacy evaluable patients with T-cell lymphomas, the ORR was 75% (12 of 16 patients) including 7 patients attaining CR. Notably, among the 8 patients with AITL or PTCL with TFH phenotype, 7 of 8 patients obtained objective responses including 4 CRs. The study is actively accruing (NCT01998035) [94] and further evaluation in large number of patients is warranted.
The advances in therapy of blastic plasmacytoid dendritic cell neoplasm
Published in Expert Opinion on Investigational Drugs, 2018
Daniel Kerr, Lubomir Sokol
For BPDCN patients who are elderly/frail and not candidates for aggressive therapy, there are limited data for low-intensity regimens (Table 1). 5-Azacitidine is a hypomethylating agent that is approved for myelodysplastic syndromes and has been shown to improve survival and decrease progression to AML in this disease [23]. A case series of two BPDCN patients with cutaneous and bone marrow involvement showed excellent initial response with complete or near-complete resolution of skin lesions after one course of 5-azacitidine as first-line therapy; however, both patients subsequently died of pulmonary sepsis at 8 and 9 months [24]. Both patients received five cycles of treatment and one developed severe neutropenia associated with their fatal sepsis. Another case series reported three patients treated with first-line 5-azacitidine (two with <5% marrow involvement, one with chronic myelomonocytic leukemia in the marrow but no evidence of BPDCN), and all three patients had initial regression of their skin lesions; however, all developed subsequent progression of cutaneous disease (PD) [25]. The median survival was longer in this series (17 months) with one patient alive at 25 months. While the survival was longer in this series, the response to 5-azacitidine was not durable (progression at 6, 7, and 14 cycles).
Related Knowledge Centers
- Azacitidine
- Decitabine
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- Epigenetic Therapy
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- Myelodysplastic Syndrome
- Acute Myeloid Leukemia