Combining carfilzomib and panobinostat to treat relapsed/refractory multiple myeloma: results of a Multiple Myeloma Research Consortium Phase I Study

Kaufman, Jonathan L.; Mina, Roberto; Jakubowiak, Andrzej; Zimmerman, Thomas; Wolf, Jeffrey; Gleason, Charise; Sharp, Cathy; Martin, Thomas G.; Heffner, Leonard T.; Nooka, Ajay K.; Harvey, R. Donald; Lonial, Sagar

doi:10.1038/s41408-018-0154-8

Cited by 44 publications

(44 citation statements)

References 24 publications

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“…358 Carfilzomib treatment can also cause adverse effects, such as cardiovascular complications (hypertension, heart failure), hematologic complications (thrombocytopenia, anemia), gastrointestinal complications (diarrhea, nausea/vomiting) and systemic symptoms (fever, fatigue). Therefore, its treatment should also be monitored carefully 359,360 As a new generation of PIs, oprozomib (ONX0912; PR-047) is designed as a tripeptide analog of carfilzomib (Table 1). 361 In contrast to intravenously administered bortezomib and carfilzomib, oprozomib has better oral bioavailability and is suitable for oral administration.…”

Section: Preclinical/researchmentioning

confidence: 99%

“…478 Panobinostat, an HDAC inhibitor, is also used with carfilzomib in MM patients and achieves a good response rate (ClinicalTrial.gov: NCT01549431). 359 In addition to combination treatment targeting UPS and other signaling pathways, combined inhibitors within the UPS also work in cancer treatment. In PI-resistant MM, inhibiting upstream components of UPS is a promising interest.…”

Section: Targeting E3 Enzymesmentioning

confidence: 99%

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The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

468

308

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Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" and "quality" of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI-219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.Signal Transduction and Targeted Therapy (2020) 5:11; https://doi.

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Section: Preclinical/researchmentioning

confidence: 99%

Section: Targeting E3 Enzymesmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

468

308

View full text Add to dashboard Cite

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“…Many common treatment-emergent AEs may be attributed to the overlapping toxicity profiles of the various classes of agents involved. Despite the relatively limited information regarding toxicity profile of the combination of carfilzomib and panobinostat, safety profile of carfilzomibpanobinostat combination, particularly regarding thrombocytopenia, neurotoxicity, fatigue, and gastrointestinal disorders, compares favorably with that of panobinostat and bortezomib [77,78]. Carfilzomib-panobinostat regimen necessitated less-frequent dose reductions due to toxicity, compared to established bortezomib-panobinostat-dexamethasone regimen.…”

Section: Safety Issues and Strategies Of Management Of Key Adverse Evmentioning

confidence: 99%

“…After a median follow-up of 17 months, the overall survival has not been reached rendering this combination an effective regimen in these heavily pretreated patients. Combination of panobinostat with carfilzomib was further explored in another phase I trial [78]. 32 patients with a median number of 4 previously administered therapies received a median of 8 treatment cycles with carfilzomib and panobinostat.…”

Section: Panobinostat and Carfilzomibmentioning

confidence: 99%

Efficacy of Panobinostat for the Treatment of Multiple Myeloma

Eleutherakis‐Papaiakovou

Kanellias

Kastritis

et al. 2020

Journal of Oncology

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Panobinostat represents a potent oral nonselective pan-histone deacetylase inhibitor (HDAC) with activity in myeloma patients. It has been approved by the FDA and EMA in combination with bortezomib and dexamethasone for the treatment of multiple myeloma, in patients who have received at least two prior regimens, including bortezomib and an immunomodulatory agent. In order to further explore its clinical potential, it is evaluated in different combinations in relapsed/refractory and newly diagnosed multiple myeloma. This review focuses on available data about panobinostat’s pharmacology and its role in clinical practice. This review will reveal panobinostat’s efficacy as antimyeloma treatment, describing drug evolution from preclinical experimental administration to administration in phase III trials, which established its role in current clinical practice. Based on the latest data, we will present its mechanism of action, its efficacy, and most important issues regarding its toxicity profile. We will further try to shed light on its role in current and future therapeutic landscape of myeloma patients. Panobinostat retains its role in therapy of multiple myeloma because of its manageable toxicity profile and its efficacy, mainly in heavily pretreated multiple myeloma patients. These characteristics make it valuable also for novel regimens in combination with second-generation proteasome inhibitors, IMiDs, and monoclonal antibodies. Results of ongoing trials are expected to shed light on drug introduction in different therapeutic combinations or even at an earlier level of disease course.

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“…The recommended expansion phase dose was PANO 20 mg plus CFZ 20/45 mg/m 2 . A phase I trial conducted by Kaufman et al, is investigating PANO 15–20 mg with CFZ-DEX in 26 RRMM patients, [196] who had received a median of 3 prior lines. The MTD was determined to be PANO 20 mg plus CFZ 20/36 mg/m 2 .…”

Section: Clinical Development Of Histone Deacetylase Inhibitorsmentioning

confidence: 99%

Novel Proteasome Inhibitors and Histone Deacetylase Inhibitors: Progress in Myeloma Therapeutics

Chhabra

2017

Pharmaceuticals

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The unfolded protein response is responsible for the detection of misfolded proteins and the coordination of their disposal and is necessary to maintain the cellular homoeostasis. Multiple myeloma cells secrete large amounts of immunoglobulins, proteins that need to be correctly folded by the chaperone system. If this process fails, the misfolded proteins have to be eliminated by the two main garbage-disposal systems of the cell: proteasome and aggresome. The blockade of either of these systems will result in accumulation of immunoglobulins and other toxic proteins in the cytoplasm and cell death. The simultaneous inhibition of the proteasome, by proteasome inhibitors (PIs) and the aggresome, by histone deacetylase inhibitors (HDACi) results in a synergistic increase in cytotoxicity in myeloma cell lines. This review provides an overview of mechanisms of action of second-generation PIs and HDACi in multiple myeloma (MM), the clinical results currently observed with these agents and assesses the potential therapeutic impact of the different agents in the two classes. The second-generation PIs offer benefits in terms of increased efficacy, reduced neurotoxicity as off-target effect and may overcome resistance to bortezomib because of their different chemical structure, mechanism of action and biological properties. HDACi with anti-myeloma activity in clinical development discussed in this review include vorinostat, panobinostat and selective HDAC6 inhibitor, ricolinostat.

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Combining carfilzomib and panobinostat to treat relapsed/refractory multiple myeloma: results of a Multiple Myeloma Research Consortium Phase I Study

Cited by 44 publications

References 24 publications

The role of ubiquitination in tumorigenesis and targeted drug discovery

The role of ubiquitination in tumorigenesis and targeted drug discovery

Efficacy of Panobinostat for the Treatment of Multiple Myeloma

Novel Proteasome Inhibitors and Histone Deacetylase Inhibitors: Progress in Myeloma Therapeutics

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