The evolution of thalidomide and its IMiD derivatives as anticancer agents

Bartlett, J. Blake; Dredge, Keith; Dalgleish, Angus

doi:10.1038/nrc1323

Cited by 722 publications

(546 citation statements)

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“…28 Lenalidomide has many biologic activities, including the promotion of erythropoiesis, modulation of cytokine production, inhibition of 2 phosphatases on 5q (CDC25C, and PP2A) and the activation of Rac1 and RhoA. [28][29][30][31][32] RPS14 was identified as a 5qϪ syndrome gene in an RNA interference screen of each gene within the 5qϪ syndrome common deleted region. 3,33 In patients with the 5qϪ syndrome, 1 allele of RPS14 is deleted, 3 and haploinsufficient expression of RPS14 has been confirmed in patient samples.…”

Section: Q؊ Syndromementioning

confidence: 99%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

698

726

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Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, SchwachmanDiamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q؊ syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases. Identification of ribosomal abnormalities in human diseaseIn 1999, Draptchinskaia et al reported recurrent mutations in a ribosomal protein gene, RPS19, in patients with Diamond-Blackfan anemia (DBA), a rare congenital bone marrow failure syndrome with a striking erythroid defect. 1 Since that initial discovery, mutations in a number of ribosomal proteins have been identified in up to 50% of patients with DBA. Moreover, other congenital syndromes have been linked to defective ribosome biogenesis, including Schwachman-Diamond syndrome (SDS), X-linked dyskeratosis congenita (DKC), cartilage hair hypoplasia (CHH), and Treacher Collins syndrome (TCS). 2 In the 5qϪ syndrome, a subtype of adult myelodysplastic syndrome, acquired haploinsufficiency for RPS14 resulting from an interstitial chromosomal deletion causes a severe refractory anemia. 3 Each of these disorders is associated with specific defects in ribosome biogenesis, which cause distinct clinical phenotypes, most often involving bone marrow failure and/or craniofacial or other skeletal defects. The disorders of ribosome dysfunction have become collectively known as ribosomopathies. Overview of ribosome biogenesisThe eukaryotic ribosome is composed of 40S and 60S subunits, which associate to form the translationally active 80S ribosome. This process requires the coordinated synthesis of 4 ribosomal RNAs (rRNAs), approximately 80 core ribosomal proteins, more than 150 associated proteins, and approximately 70 small nucleolar RNAs (snoRNAs). 4,5 The 40S subunit contains 18S rRNA and the 60S subunit contains 28S, 5.8S, and 5S rRNAs. In eukaryotes, assembly of rRNA and ribosomal proteins, along with assoc...

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Section: Q؊ Syndromementioning

confidence: 99%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

698

726

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“…Pomalidomide is an immunomodulatory drug that is structurally related to both lenalidomide and thalidomide [1]. All three drugs display anti-angiogenic, anti-tumor necrosis factor-a, and T cell modulatory effect, but the precise mechanism of action in vivo is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Long‐term outcome of pomalidomide therapy in myelofibrosis

et al. 2011

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Ninety-four Mayo Clinic patients with myelofibrosis (MF) participated in two consecutive clinical trials of pomalidomide (0.5-3.5 mg/day), with or without prednisone. Overall anemia response was 27% and increased to 53% in JAK2V617F-positive patients with <10 cm palpable splenomegaly and <5% circulating blasts; response rate was 0% in mutation-negative patients with either 10 cm splenomegaly or 5% circulating blasts (P 5 0.0001). Median duration of anemia response was 16 months. Treatment effect on splenomegaly was negligible. To date, pomalidomide therapy has been discontinued in 86 (91%) patients at a rate of 68% at 1 year and 89% at 2 years. Grade 1 sensory neuropathy developed in 4 (13%) of 30 patients treated for 1 year. Risk-adjusted survival in pomalidomide-treated primary MF patients (n 5 72) was similar to their counterparts not exposed to the drug (n 5 471; P 5 0.19). Long-term follow-up of pomalidomide treatment in MF reveals palliative value for a select group of patients and treatment-emergent sensory neuropathy. Am. J. Hematol. 87:66-68, 2012. V V C 2011 Wiley Periodicals, Inc. IntroductionPomalidomide is an immunomodulatory drug that is structurally related to both lenalidomide and thalidomide [1]. All three drugs display anti-angiogenic, anti-tumor necrosis factor-a, and T cell modulatory effect, but the precise mechanism of action in vivo is poorly understood. Thalidomide [2], lenalidomide [3], and pomalidomide [4] have all been shown to have therapeutic activity in myelofibrosis (MF), including primary (PMF), post-polycythemia vera (post-PV MF), and post-essential thrombocythemia (post-ET MF). Higher doses (100-400 mg/day) of thalidomide were associated with an increased adverse drop-out rate whereas low-dose (50 mg/day) thalidomide, alone or in combination with prednisone, was better tolerated and alleviated anemia in approximately 20% of treated patients with MF [5][6][7]. Lenalidomide (5-10 mg/day), with or without prednisone, also alleviated anemia in a similar proportion of patients with MF [3,8,9], and was most useful in the presence of del(5q) [10]. Two recent studies reassessed treatment response using the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria [11]; one study reported up to 38% response rate for lenalidomide plus prednisone therapy [12] whereas the other study reported 28% response rate for thalidomide-based therapy [13]. However, in a prospective multi-center study [8], the combination of lenalidomide and prednisone resulted in only 19% anemia response and 23% overall response. Regardless, the use of thalidomide or lenalidomide in MF is limited by the respective occurrence of peripheral neuropathy [12] and moderate to severe myelosuppression [8], in the majority of treated patients.We have recently communicated the short-term results of two consecutive clinical trials using pomalidomide therapy for MF [4,14,15]. The maximum tolerated dose of pomalidomide in MF was 3 mg/day (dose-limiting toxicity was myelosuppression) but...

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“…Lenalidomide (Revlimid) and pomalidomide are IMiDs immunomodulatory compounds developed by Celgene Corp. that possess multiple cellular activities including direct inhibition of hematopoietic tumor growth, immunomodulation via T-cell and natural killer cell stimulation, enhancement of erythropoiesis, and microenvironmental effects such as antiangiogenic activity (1)(2)(3)(4)(5)(6). These compounds have negative effects on hematopoietic tumor cell proliferation and positive effects on CD34 + cell expansion (1)(2)(3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Pomalidomide and Lenalidomide Induce p21WAF-1 Expression in Both Lymphoma and Multiple Myeloma through a LSD1-Mediated Epigenetic Mechanism

Escoubet-Lozach¹,

Lin²,

Jensen-Pergakes³

et al. 2009

Cancer Research

159

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Lenalidomide and pomalidomide have both been evaluated clinically for their properties as anticancer agents, with lenalidomide being available commercially. We previously reported that both compounds cause cell cycle arrest in Burkitt's lymphoma and multiple myeloma cell lines by increasing the level of p21 WAF-1 expression. In the present study, we unravel the molecular mechanism responsible for p21 WAF-1 up-regulation using Namalwa cells as a human lymphoma model. We show that the increase of p21 WAF-1 expression is regulated at the transcriptional level through a mechanism independent of p53. Using a combination of approaches, we show that several GC-rich binding transcription factors are involved in pomalidomide-mediated upregulation of p21 WAF-1 . Furthermore, we report that p21 WAF-1 up-regulation is associated with a switch from methylated to acetylated histone H3 on p21 WAF-1 promoter. Interestingly, lysine-specific demethylase-1 (LSD1) silencing reduced both pomalidomide and lenalidomide up-regulation of p21 WAF-1 , suggesting that this histone demethylase is involved in the priming of the p21 WAF-1 promoter. Based on our findings, we propose a model in which pomalidomide and lenalidomide modify the chromatin structure of the p21 WAF-1 promoter through demethylation and acetylation of H3K9. This effect, mediated via LSD1, provides GC-rich binding transcription factors better access to DNA, followed by recruitment of RNA polymerase II and transcription activation. Taken together, our results provide new insights on the mechanism of action of pomalidomide and lenalidomide in the regulation of gene transcription, imply possible efficacy in p53 mutated and deleted cancer, and suggest new potential clinical uses as an epigenetic therapy.

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The evolution of thalidomide and its IMiD derivatives as anticancer agents

Cited by 722 publications

References 53 publications

Ribosomopathies: human disorders of ribosome dysfunction

Ribosomopathies: human disorders of ribosome dysfunction

Long‐term outcome of pomalidomide therapy in myelofibrosis

Pomalidomide and Lenalidomide Induce p21WAF-1 Expression in Both Lymphoma and Multiple Myeloma through a LSD1-Mediated Epigenetic Mechanism

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