We have studied the histone deacetylase inhibitors romidepsin and belinostat in both the clinic and in the laboratory. We originally became interested in romidepsin in the context of a Phase I clinical trial, when we made the serendipitous discovery that (then-named) depsipeptide was highly effective in subsets of T cell lymphoma. While we have continued to be interested in our original strategy of preventing the emergence of resistance to this agent, we first pursued the use of depsipeptide/romidepsin as an orphan drug in T cell lymphoma, using both laboratory and clinical strategies. We have extended this work into solid tumors with the hydroxamic acid derivative belinostat.Our multi-institutional clinical trial for cutaneous and peripheral T cell lymphoma (CTCL and PTCL) completed accrual at 131 patients in 6 cohorts. Papers detailing responses to romidepsin in both CTCL and PTCL are published. The responses to depsipeptide are at times dramatic and have been very durable. As an example, one patient received therapy continuously for over 6 years, remained in a partial remission off of therapy for 20 months and has now resumed therapy for CTCL. Another patient with CTCL remains in complete remission off of therapy for over 7 years, and another patient with PTCL remained in continuous complete remission for 5 years before relapse occurred. The major response rate in cutaneous T cell lymphoma in both our NCI trial and in the Gloucester registration trial was 34-35%. For PTCL, our response rate was 38%. It is important to note that durable responses were also obtained in both subsets of patients by extramural investigators who were participating in our Phase II trial among more than 9 multicenter sites included in the study. These sites included North Shore University Hospital in Manhasset, New York;City of Hope National Cancer Center in Duarte, California;and Peter MacCallum Cancer Center in Melbourne, Australia.Our NCI Phase II trial had a major second objective in addition to proving efficacy in the various histologies. That was confirmation of the safety of the agent. EKG abnormalities have been noted following treatment and a great deal of effort has gone into demonstrating the lack of myocardial damage associated with administration of this agent. We have analyzed over 4000 ECGs, and collected much ancillary cardiac safety data. A goal in the coming year is to report additional cardiac findings with romidepsin that help establish the safety of the agent, and parameters for using all HDIs in conjunction with electrolyte supplementation. The trial had a significant translational component that consumed a major fraction of my laboratory resources. We developed a quantitative immunoblot assay for detecting and quantitating histone acetylation in patient samples, principally peripheral mononuclear cells as a surrogate. Results from these assays were compared to pharmacokinetic data. We have also evaluated gene expression including CD25, p21, and MDR1 by RT-PCR, finding that only MDR1 expression is induced sufficiently following depsipeptide for routine assay in patient mononuclear cells. Our data suggest that the 24hr timepoint of histone acetylation in peripheal blood mononuclear cells is associated with pharmacokinetic parameters including clearance and area under the curve. In addition, our data suggest that this endpoint is associated with disease response. Taken together these data suggest that drug exposure may be important for romidepsin and potentially for the entire class of histone deacetylase inhibitors. I addition, samples were sent as per protocol to Dr. Louise Showe at University of Pennsylvania. These samples have been analyzed by cDNA array and the data are being prepared for publication.Additional studies included a Phase I trial of romidepsin on a day 1, 3, and 5 schedule to achieve a more continuous drug effect. Dr. Richard Piekarz was PI on this study. This study had a focus in thyroid cancer, evaluating radioactive iodine uptake, which was observed in experimental models. The Phase I trial was completed;our assessment was that the dose and schedule did not give optimal gene expression changes. The question of how best to increase radioiodine accumulation in thyroid cancer remains an important one.We have nearly completed a combination clinical trial with a novel histone deacetylase inhibitor, belinostat, evaluating a 48 hr continuous infusion in combination with cisplatin and etoposide. This trial is based on preclinical evidence of synergy between HDAC inhibitors and chemotherapeutics, when properly scheduled. This was carried out as a Phase I trial in an advanced disease population;we are currently refining a Phase II dose. The Phase II dose will be explored in the same trial design in the small cell lung cancer patient population. Laboratory studies supporting the clinical trial have been published this year.Finally, we have been interested for some time in mechanisms of HDI sensitivity and resistance. This led us to the generation of cell lines with non-Pgp mediated romidepsin resistance and we have begun to ask whether other mechanisms of resistance can be identified. We continue to be interested in the mechanism of action of the HDIs. At least 5 mechanisms have been cited for histone deacetylase inhibitors: induction of gene expression, acetylation of cytoplasmic proteins and altered function, increased degradation of cytoplasmic proteins due to impaired Hsp90 activity, altered angiogenesis, and mitotic effects. Exactly which mechanism is of critical importance will be the subject of continuing investigation. These studies have also been complemented by experiments aimed at identifying synergistic drug combinations. We have identified a two drug combination that has markedly increased the activity already observed in monotherapy in lymphoma and we hope will translate into activity in solid tumors. Animal studies supporting a protocol concept for the combination of romidepsin with an experimental agent are ongoing;we plan to open a Phase I study of this combination in the coming year.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010621-09
Application #
8552751
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2012
Total Cost
$837,032
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Noonan, Anne M; Eisch, Robin A; Liewehr, David J et al. (2013) Electrocardiographic studies of romidepsin demonstrate its safety and identify a potential role for K(ATP) channel. Clin Cancer Res 19:3095-104
Ierano, Caterina; Chakraborty, Arup R; Nicolae, Alina et al. (2013) Loss of the proteins Bak and Bax prevents apoptosis mediated by histone deacetylase inhibitors. Cell Cycle 12:2829-38
Ierano, Caterina; Basseville, Agnes; To, Kenneth K W et al. (2013) Histone deacetylase inhibitors induce CXCR4 mRNA but antagonize CXCR4 migration. Cancer Biol Ther 14:175-83
Chakraborty, Arup R; Robey, Robert W; Luchenko, Victoria L et al. (2013) MAPK pathway activation leads to Bim loss and histone deacetylase inhibitor resistance: rationale to combine romidepsin with an MEK inhibitor. Blood 121:4115-25
Sissung, Tristan M; Troutman, Sarah M; Campbell, Tessa J et al. (2012) Transporter pharmacogenetics: transporter polymorphisms affect normal physiology, diseases, and pharmacotherapy. Discov Med 13:19-34
Akilov, O E; Grant, C; Frye, R et al. (2012) Low-dose electron beam radiation and romidepsin therapy for symptomatic cutaneous T-cell lymphoma lesions. Br J Dermatol 167:194-7
Basseville, Agnes; Tamaki, Akina; Ierano, Caterina et al. (2012) Histone deacetylase inhibitors influence chemotherapy transport by modulating expression and trafficking of a common polymorphic variant of the ABCG2 efflux transporter. Cancer Res 72:3642-51
Harrison, Simon J; Bishton, Mark; Bates, Susan E et al. (2012) A focus on the preclinical development and clinical status of the histone deacetylase inhibitor, romidepsin (depsipeptide, Istodax(®)). Epigenomics 4:571-89
Wang, Chunxi; Liu, Zhihui; Woo, Chan-Wook et al. (2012) EZH2 Mediates epigenetic silencing of neuroblastoma suppressor genes CASZ1, CLU, RUNX3, and NGFR. Cancer Res 72:315-24
Frye, Robin; Myers, Mary; Axelrod, Karen C et al. (2012) Romidepsin: a new drug for the treatment of cutaneous T-cell lymphoma. Clin J Oncol Nurs 16:195-204

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