Phase I study of carfilzomib, lenalidomide, vorinostat, and dexamethasone in patients with relapsed and/or refractory multiple myeloma

Bilotti, Elizabeth; Richter, Joshua; McNeill, Ann; McBride, Laura; Raucci, Laura; Anand, Palka; Bednarz, Urszula; Ivanovski, Kristin; Smith, Judith E.; Batra, Veena; Aleman, Adolfo; Sims, Taliah; Guerrero, Laura; Mato, Anthony R.; Siegel, David S.

doi:10.1111/bjh.13517

Cited by 34 publications

(21 citation statements)

References 36 publications

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“…With the goal of translating our findings to the clinic, we focused on the pan-HDACi SAHA (vorinostat), an FDA-approved drug for the treatment of cutaneous T-cell lymphoma (20). SAHA, a hybrid polar compound (47) with a longer half-life, lower toxicity, and greater stability than earlier HDACi has demonstrated encouraging activity in patients with relapsed and/or refractory multiple myeloma in combination with novel (carfilzomib, lenalidomide) or conventional (dexamethasone) drugs (22,48,49). Molecular mechanisms underlying SAHA activity are diverse and not completely understood.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma

et al. 2016

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Epigenetic abnormalities are common in hematologic malignancies, including multiple myeloma, and their effects can be efficiently counteracted by a class of tumor suppressor miRNAs, named epi-miRNAs. Given the oncogenic role of histone deacetylases (HDAC) in multiple myeloma, we investigated whether their activity could be antagonized by miR-29b, a well-established epi-miRNA. We demonstrated here that miR-29b specifically targets HDAC4 and highlighted that both molecules are involved in a functional loop. In fact, silencing of HDAC4 by shRNAs inhibited multiple myeloma cell survival and migration and triggered apoptosis and autophagy, along with the induction of miR-29b expression by promoter hyperacetylation, leading to the downregulation of prosurvival miR-29b targets (SP1, MCL-1). Moreover, treatment with the pan-HDAC inhibitor SAHA upregulated miR-29b, overcoming the negative control exerted by HDAC4. Importantly, overexpression or inhibition of miR-29b, respectively, potentiated or antagonized SAHA activity on multiple myeloma cells, as also shown in vivo by a strong synergism between miR-29b synthetic mimics and SAHA in a murine xenograft model of human multiple myeloma. Altogether, our results shed light on a novel epigenetic circuitry regulating multiple myeloma cell growth and survival and open new avenues for miR-29b-based epi-therapeutic approaches in the treatment of this malignancy. Mol Cancer Ther; 15(6); 1-12. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma

et al. 2016

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“…In 2005, phase I clinical trials with CFZ began and the drug was successfully investigated in additional clinical trials [105,106]. This included phase III clinical trials where it was shown that CFZ was effective in patients with relapsed and BTZ-chemoresistant disease [202,203]. Owing to its more selective mechanisms of action, CFZ had fewer side effects as compared to BZT including less pronounced neuropathy.…”

Section: Carfilzomib: Second-in-class Proteasome Inhibitormentioning

confidence: 99%

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Zhang

Linder

Bazzaro

2020

Cancers

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Cancer cells are characterized by a higher rate of protein turnover and greater demand for protein homeostasis compared to normal cells. In this scenario, the ubiquitin-proteasome system (UPS), which is responsible for the degradation of over 80% of cellular proteins within mammalian cells, becomes vital to cancer cells, making the UPS a critical target for the discovery of novel cancer therapeutics. This review systematically categorizes all current reported small molecule inhibitors of the various essential components of the UPS, including ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), the 20S proteasome catalytic core particle (20S CP) and the 19S proteasome regulatory particles (19S RP), as well as their mechanism/s of action and limitations. We also discuss the immunoproteasome which is considered as a prospective therapeutic target of the next generation of proteasome inhibitors in cancer therapies.Cancers 2020, 12, 902 2 of 34 core component of the nucleosome, which is critical for transcription and cell cycle, is recognized and linked by Lysine Residue 48 (K48) and further degraded by the proteasome [17,18]; DbpB (also named Y-box protein 1), a transcription factor, is reported to selectively recognize the Y-box promoter element. Studies showed that its terminal 105-amino-acid-long fragment is removed after a specific proteolytic cleavage by the proteasome complex [19,20]; NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is located outside the nucleus and is reported to be involved in DNA transcription as well as cell survival [21,22]. The NF-κB p105 is the precursor of NF-κB p50. It is evident that NF-κB p105 is cleaved and selectively degraded at the C-terminus by proteasome, generating the active form of NF-κB p50 [23]. Products of UPS degradation can also be further degraded into single amino acids by aminopeptidases [24]. Aminopeptidases are the class of enzymes that catalyze the final steps in the ubiquitin-proteasome pathway by breaking down shorter peptides (<5 residues) into even smaller fragments [25]. Many, but not all, of aminopeptidases, are zinc metalloenzymes, such as leucine aminopeptidases (lAPs) and methionine aminopeptidases (metAPs) [26,27]. Studies showed that blocking the activity of the aminopeptidases by inhibitor of bestatin could generate a major accumulation of peptides which are ∼2-5 residues long [28].The 26S proteasome contains one/two 19S regulatory particles (19S RP) which mainly regulate the translocation of ubiquitinated proteins to the 20S CP and one 20S core particle (20S CP) in which proteolysis finally occurs [29,30]. In general, two main processes are associated with the process of degradation of proteins by the UPS: (1) tagging the to-be-degraded proteins by polyubiquitination (normally more than four ubiquitins), and (2) proteolytic degradation of the polyubiquitinated protein by the 26S proteasome complex [31,32]. Each step incorporates an intricate and complex spectrum of protein interaction...

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“…Recently developed quadruplet regimens have also been evaluated for managing multiple myeloma [37][38][39][40][41]. However, there are limited data on their relative efficacy and safety compared with triplets and doublets.…”

Section: Compared With Doublets Triplets or Quadruplets May Better Omentioning

confidence: 99%

Modern multiple myeloma therapy: deep, sustained treatment response and good clinical outcomes

2017

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Abstract. Landgren O, Iskander K (Memorial SloanKettering Cancer Center, New York, NY, USA; Amgen, Thousand Oaks, CA, USA). Modern multiple myeloma therapy: deep, sustained treatment response and good clinical outcomes. J Intern Med 2017; 281: 365-382.In the USA at the beginning of this century, the average overall survival in patients with multiple myeloma was about 3 years. Around that time, three drugs (bortezomib, lenalidomide and thalidomide) were introduced for the treatment of multiple myeloma and, in 2012, carfilzomib received accelerated approval by the US Food and Drug Administration (FDA). Driven by access to better drugs, median overall survival in younger patients (aged <50 years) was >10 years by 2014. The FDA approved 14 new drugs for the treatment of cancer in 2015; four of these were approved for the treatment of myeloma (panobinostat, daratumumab, elotuzumab and ixazomib). In 2015 and 2016, expanded label indications were approved by the FDA for lenalidomide and carfilzomib, respectively. The recent increase in approved, highly effective combination therapies for patients with multiple myeloma has led the way to redefining the goals of therapy. Here, we review and provide a clinical perspective on the treatment goals and management of multiple myeloma in the era of modern therapy. Recent meta-analyses show that minimal residual disease (MRD) negativity is associated with longer progression-free and overall survival in patients with multiple myeloma. With the use of modern combination therapy, large proportions (>60-70%) of newly diagnosed multiple myeloma patients achieve complete responses and MRD negativity. Modern combination therapies induce rapid, deep and sustainable responses (including MRD negativity), supporting a treatment paradigm shift away from palliative two-drug combinations towards the use of modern, potent, three-or four-drug combination regimens in early lines of therapy. Data support the use of modern therapy upfront rather than reserving it for later stages of the disease. As survival time increases with modern combination therapies, development of early reliable surrogate end-points for survival, such as MRD negativity, are needed for expedited read-out of future randomized clinical trials.

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Phase I study of carfilzomib, lenalidomide, vorinostat, and dexamethasone in patients with relapsed and/or refractory multiple myeloma

Cited by 34 publications

References 36 publications

Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma

Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Modern multiple myeloma therapy: deep, sustained treatment response and good clinical outcomes

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