A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia

Byrd, John C.; Marcucci, Guido; Parthun, Mark R.; Xiao, Jim; Klisovic, Rebecca B.; Moran, Mollie E.; Lin, Thomas S.; Liu, Shujun; Sklenar, Amy R.; Davis, Melanie E.; Lucas, David M.; Fischer, Beth; Shank, Roshini S.; Tejaswi, Sooraj; Binkley, Philip F.; Wright, John J.; Chan, Kenneth K.; Grever, Michael R.

doi:10.1182/blood-2004-05-1693

Cited by 388 publications

(261 citation statements)

References 50 publications

(59 reference statements)

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“…By contrast, DEP is a natural tetrapeptide HDAC inhibitor that is currently in phase I and II clinical trials for treating hematological malignancies and solid tumors (Piekarz et al, 2001;Marshall et al, 2002;Sandor et al, 2002;Piekarz and Bates, 2004;Byrd et al, 2005). DEP inhibits all the known Class I and Class II HDAC enzymes (Nakajima et al, 1998).…”

Section: Resultsmentioning

confidence: 99%

Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein

et al. 2006

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The t(8;21) chromosomal translocation that generates the fusion oncoprotein RUNX1-ETO predominates in leukemia patients of the French-American-British (FAB) class M2 subtype. The oncoprotein has the capacity to promote expansion of hematopoietic stem/progenitor cells and induces leukemia in association with other genetic alterations. Here, we show that RUNX1-ETO undergoes degradation in response to treatment with histone deacetylase inhibitors, one of which, depsipeptide (DEP), is currently undergoing phase II clinical testing in a variety of malignancies. These compounds induce turnover of RUNX1-ETO without affecting the stability of RUNX1-ETO partner proteins. In addition, RUNX1-ETO physically interacts with heat shock protein 90 (HSP90). DEP treatment interrupts the association of RUNX1-ETO with HSP90 and induces proteasomal degradation of RUNX1-ETO. DEP and the HSP90 antagonist 17-allylamino-geldanamycin (17-AAG) both triggered RUNX1-ETO degradation, but without any additive or cooperative effects. These findings may stimulate the development of more rational and effective approaches for treating t(8;21) patients using histone deacetylase inhibitors or HSP90 inhibitors.

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Section: Resultsmentioning

confidence: 99%

Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein

et al. 2006

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“…[31][32][33] The first clinical trials in solid tumors that used these agents were not successful, probably because the very high drug doses had cytotoxic effects. 34 To evaluate, in the lung cancer xenograft model, the potential therapeutic efficacy of drugs with epigenetic chromatin remodeling effects, we administered inhibitors of DNA methylation and histone deacetylation, singly or in combination, by i.p.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic modulation of endogenous tumor suppressor expression in lung cancer xenografts suppresses tumorigenicity

Cantor

Iliopoulos

Rao

et al. 2006

Intl Journal of Cancer

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Epigenetic changes involved in cancer development, unlike genetic changes, are reversible. DNA methyltransferase and histone deacetylase inhibitors show antiproliferative effects in vitro, through tumor suppressor reactivation and induction of apoptosis. Such inhibitors have shown activity in the treatment of hematologic disorders but there is little data concerning their effectiveness in treatment of solid tumors. FHIT, WWOX and other tumor suppressor genes are frequently epigenetically inactivated in lung cancers. Lung cancer cell clones carrying conditional FHIT or WWOX transgenes showed significant suppression of xenograft tumor growth after induction of expression of the FHIT or WWOX transgene, suggesting that treatments to restore endogenous Fhit and Wwox expression in lung cancers would result in decreased tumorigenicity. H1299 lung cancer cells, lacking Fhit, Wwox, p16 INK4a and Rassf1a expression due to epigenetic modifications, were used to assess efficacy of epigenetically targeted protocols in suppressing growth of lung tumors, by injection of 5-aza-2-deoxycytidine (AZA) and trichostatin A (TSA) in nude mice with established H1299 tumors. High doses of intraperitoneal AZA/TSA suppressed growth of small tumors but did not affect large tumors (200 mm 3 ); lower AZA doses, administered intraperitoneally or intratumorally, suppressed growth of small tumors without apparent toxicity. Responding tumors showed restoration of Fhit, Wwox, p16 INKa , Rassf1a expression, low mitotic activity, high apoptotic fraction and activation of caspase 3. These preclinical studies show the therapeutic potential of restoration of tumor suppressor expression through epigenetic modulation and the promise of re-expressed tumor suppressors as markers and effectors of the responses. ' 2006 Wiley-Liss, Inc.Key words: DNA methylation; tumor suppressor genes; 5-aza-2-deoxycytidine Lung cancer is the leading cause of cancer death in the western hemisphere for men and women, eclipsing the combined mortalities from breast, colon and prostate cancers. Genomic aberrations involving chromosome 3p are the most frequent and earliest genetic events in lung carcinogenesis. 1,2 In particular, the FHIT gene, spanning the human common fragile site, FRA3B, at chromosome 3p14.2, and the RASSF1A gene at 3p21 are frequently silenced in lung cancer and show hallmarks of tumor suppressor genes. 3 FHIT is altered in many other types of cancers, including breast, head and neck, cervical, bladder, esophageal, gastric, pancreatic and renal cancer and alterations occur in very early stages of preneoplasia in some organs. Fhit loss is associated with progression and outcome in cancers of various organs. 4 Similarly, the WWOX gene at FRA16D is frequently silenced in lung cancers, and has recently been shown to suppress growth of lung cancer cells in nude mice. [5][6][7] The RASSF1A promoter region is hypermethylated in a large fraction of lung and other cancers 8,9 and methylation of the RASSF1A regulatory region has been proposed as a biomarker of lung ca...

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“…Flavopiridol has shown toxicity for patients, although a new schedule of administration was recently used more successfully (18). HDAC inhibitors displayed strong adverse effects (19), and no objective responses were achieved with the proteasome inhibitor bortezomib (20). These data are not surprising because the targets of these drugs are not specific; transcription inhibition by flavopiridol affects a broad range of short-lived proteins (10).…”

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confidence: 89%

Development of Noxa-like BH3 Mimetics for Apoptosis-Based Therapeutic Strategy in Chronic Lymphocytic Leukemia

Billard

2012

Molecular Cancer Research

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A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia

Cited by 388 publications

References 50 publications

Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein

Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein

Epigenetic modulation of endogenous tumor suppressor expression in lung cancer xenografts suppresses tumorigenicity

Development of Noxa-like BH3 Mimetics for Apoptosis-Based Therapeutic Strategy in Chronic Lymphocytic Leukemia

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