Panobinostat in combination with bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma: an open-label, multicentre phase 2 trial

Tan, Daryl; Phipps, Colin; Hwang, William Ying Khee; Tan, Soo Yong; Yeap, Chun Hsien; Chan, Yiong Huak; Tay, Kevin; Lim, Soon Thye; Lee, Yuh Shan; Kumar, Sathish; Ng, Siew‐Cheok; Fadilah, S A W; Kim, Won Seog; Goh, Yeow Tee

doi:10.1016/s2352-3026(15)00097-6

Cited by 53 publications

(38 citation statements)

References 33 publications

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“…Clinical efficacy for proteasome and HDAC inhibitor combination therapy has been well established in myeloma (San‐Miguel et al , ; Berdeja et al , ), while such combinations are actively being investigated in the context of PTCL (Tan et al , ) the underlying biological rationale for selection of these combinations is undefined. We investigated the genome‐wide impact of ixazomib and belinostat combinations by evaluating the transcriptomic changes by comparing the transcriptome of single agent and combination drug treatment in Jurkat cells.…”

Section: Resultsmentioning

confidence: 99%

Combinatorial ixazomib and belinostat therapy induces NFE2L2‐dependent apoptosis in Hodgkin and T‐cell lymphoma

et al. 2019

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Equal contribution. SummaryIxazomib activity and transcriptomic analyses previously established in T cell (TCL) and Hodgkin (HL) lymphoma models predicted synergistic activity for histone deacetylase (HDAC) inhibitory combination. In this present study, we determined the mechanistic basis for ixazomib combination with the HDAC inhibitor, belinostat, in HL and TCL cells lines (ixazomib-sensitive/resistant clones) and primary tumour cells. In ixazomib-treated TCL and HL cells, transient inhibition followed by full recovery of proteasomal activity observed was accompanied by induction of proteasomal gene expression with NFE2L2 (also termed NRF2) as a prominent upstream regulator. Downregulation of both NFE2L2 and proteasomal gene expression (validated by quantitative real time polymerase chain reaction) occurred with belinostat treatment in Jurkat and L428 cells. In addition, CRISPR/Cas9 mediated knockdown of NFE2L2 in Jurkat cells resulted in a significant decrease in cell viability with ixazomib compared with untreated control cells. Using transcriptomic and proteasomal activity evaluation of ixazomib, belinostat, or ixazomib + belinostat treated cells, we observed that NFE2L2, proteasome gene expression and functional recovery were abrogated by ixazomib + belinostat combination, resulting in synergistic drug activity in ixazomib-sensitive and -resistant cell lines and primary cells. Altogether, these results suggest that the synergistic activity of ixazomib + belinostat is mediated via inhibition NFE2L2-dependent proteasomal recovery and extended proteasomal inhibition culminating in increased cell death.

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Section: Resultsmentioning

confidence: 99%

Combinatorial ixazomib and belinostat therapy induces NFE2L2‐dependent apoptosis in Hodgkin and T‐cell lymphoma

et al. 2019

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“…Another pan-HDACI, panobinostat, also has been recently approved by the FDA for refractory multiple myeloma [19]. Panobinostat may be effective for refractory CTCL and is currently being evaluated in an ongoing clinical study for peripheral T-cell lymphoma [20]. The Class I-specific HDACI, romidepsin, is also approved for the treatment of refractory CTCL [21] and is being investigated in ongoing clinical trials for other peripheral T-cell lymphomas [22].…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase inhibitors inhibit metastasis by restoring a tumor suppressive microRNA-150 in advanced cutaneous T-cell lymphoma

et al. 2016

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Tumor suppressive microRNA (miR)-150 inhibits metastasis by combining with the C-C chemokine receptor 6 (CCR6) “seed sequence” mRNA of the 3′-untranslated region (3′-UTR) in advanced cutaneous T-cell lymphoma (CTCL). Because the histone deacetylase inhibitor (HDACI) vorinostat showed excellent outcomes for treating advanced CTCL, HDACIs may reduce the metastasis of CTCL by targeting miR-150 and/ or CCR6. To examine whether these candidate molecules are essential HDACI targets in advanced CTCL, we used the My-La, HH, and HUT78 CTCL cell lines for functional analysis because we previously demonstrated that their xenografts in NOD/Shi-scid IL-2γnul mice (CTCL mice) induced multiple metastases. We found that pan- HDACIs (vorinostat and panobinostat) inhibited the migration of CTCL cells and downregulated CCR6. The miRNA microarray analysis against CTCL cell lines demonstrated that these pan-HDACIs commonly upregulated 161 miRNAs, including 34 known tumor suppressive miRNAs such as miR-150. Although 35 miRNAs possessing the CCR6 “seed sequence” were included in these 161 miRNAs, miR-150 and miR-185-5p were downregulated in CTCL cells compared to in normal CD4+ T-cells. The transduction of 12 candidate miRNAs against CTCL cells revealed that miR-150 most efficiently inhibited their migration capabilities and downregulated CCR6. Quantitative reverse transcriptase-polymerase chain reaction demonstrated that miR-150 was downregulated in advanced but not early CTCL primary cases. Finally, we injected miR-150 or siCCR6 into CTCL mice and found that mouse survival was significantly prolonged. These results indicate that miR-150 and its target, CCR6, are essential therapeutic targets of pan-HDACIs in advanced CTCL with metastatic potential.

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“…281 Another phase 2 trial (NCT00901147) of bortezomib and panobinostat showed an ORR of 43% (CR 22%) in relapsed or refractory PTCL patients. 282 Bortezomib in combination with other agents, such as ibrutinib in MCL (NCT02356458), dexamethasone in CTCL (NCT03487133), and chemotherapeutic regimens, such as gemcitabine, dexamethasone, and cisplatin (GDP) in DLBCL (NCT02542111) and CHOP in T-NHLs (NCT00374699), are currently ongoing. A randomized phase 3 trial (NCT00722137) compared the efficacy of R-CHOP with bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) in untreated MCL, showing an improved median PFS but increased hematologic toxicity.…”

Section: Nf-κbmentioning

confidence: 99%

Advances in targeted therapy for malignant lymphoma

Wang

Qin

Huo

et al. 2020

Sig Transduct Target Ther

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The incidence of lymphoma has gradually increased over previous decades, and it ranks among the ten most prevalent cancers worldwide. With the development of targeted therapeutic strategies, though a subset of lymphoma patients has become curable, the treatment of refractory and relapsed diseases remains challenging. Many efforts have been made to explore new targets and to develop corresponding therapies. In addition to novel antibodies targeting surface antigens and small molecular inhibitors targeting oncogenic signaling pathways and tumor suppressors, immune checkpoint inhibitors and chimeric antigen receptor T-cells have been rapidly developed to target the tumor microenvironment. Although these targeted agents have shown great success in treating lymphoma patients, adverse events should be noted. The selection of the most suitable candidates, optimal dosage, and effective combinations warrant further investigation. In this review, we systematically outlined the advances in targeted therapy for malignant lymphoma, providing a clinical rationale for mechanism-based lymphoma treatment in the era of precision medicine.Signal Transduction and Targeted Therapy (2020) 5:15; https://doi.

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Panobinostat in combination with bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma: an open-label, multicentre phase 2 trial

Cited by 53 publications

References 33 publications

Combinatorial ixazomib and belinostat therapy induces NFE2L2‐dependent apoptosis in Hodgkin and T‐cell lymphoma

Combinatorial ixazomib and belinostat therapy induces NFE2L2‐dependent apoptosis in Hodgkin and T‐cell lymphoma

Histone deacetylase inhibitors inhibit metastasis by restoring a tumor suppressive microRNA-150 in advanced cutaneous T-cell lymphoma

Advances in targeted therapy for malignant lymphoma

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