We have studied the histone deacetylase inhibitor depsipeptide (now known as romidepsin) in both the clinic and in the laboratory. We originally became interested in depsipeptide in the context of a clinical trial strategy seeking to identify agents that could overcome or circumvent multidrug resistance. My laboratory identified the histone deacetylase inhibitor depsipeptide as an agent in preclinical development and a substrate for Pgp-mediated efflux. Because depsipeptide is avidly transported by Pgp, and because it induces MDR-1 in the constellation of genes altered by histone acetylation, we planned to eventually develop depsipeptide in combination with a Pgp modulator. However, in the Phase I setting, we made the serendipitous discovery that 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 have pursued the use of depsipeptide/romidepsin as an orphan drug in T cell lymphoma, using both laboratory and clinical strategies. Futhermore, our biomarker data do not suggest that Pgp develops as a mechanism of drug resistance following exposure to this compound. Our multi-institutional clinical trial for cutaneous and peripheral T cell lymphoma (CTCL and PTCL) completed accrual at 134 patients in 6 cohorts. Cohort 1, patients with cutaneous T cell lymphoma with fewer than 2 systemic chemotherapy regimens, is complete and a manuscript is in preparation. 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 5 years, and another patient with PTCL remained in continuous complete remission for 5 years before relapse occurred. We have anecdotally coined the phrase """"""""there when you need it"""""""" for romidepsin, based on its activity in retreating patients who demonstrate disease progression while off of therapy. The major response rate for depsipeptide, now termed romidepsin, in cutaneous T cell lymphoma in both our NCI trial and in the Gloucester registration trial is 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. Gloucester Pharmaceuticals obtained Orphan Drug status from the FDA for development of this therapy for CTCL and PTCL. NCI CTEP and our Cancer Therapeutics Branch (now Medical Oncology Branch) largely pushed the development of this agent alone during a period in which Fujisawa Pharmaceuticals debated the relative merits of becoming involved in an oncology development platform. Our NCI Phase II trial had a major second objective in addition to proving efficacy in the various histologies. That is 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 reported in June of 2006 in Clinical Cancer Research, our review of 2,051 ECGs obtained in 42 patients treated with depsipeptide. A goal in the coming year is to continue to report 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. MDR1 is also analyzed in tumor samples before therapy is initiated and then at the time of disease progression. 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 assocated 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. 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 a new clinical trial of an histone deacetylase inhibitor ongoing, evaluating 48 hr continuous infusion belinostat in combination with cisplatin and etoposide. This trial is based on preclinical evidence of synergy between HDAC inhibitors and chemotherapeutics, when properly scheduled. This is being carried out as a Phase I trial in an advanced disease population and the Phase II dose established in Phase I will be studied in the same trial in the small cell lung cancer patient population. This patient population has been difficult to accrue. However, we are determined to complete the study - as our laboratory studies suggest exquisite sensitivity of small cell lung cancer cells to romidepsin. We have just completed a publication demonstrating synergy between cisplatin or etoposide and romidepsin. These studies support our clinical trial. Finally, we have been interested for some time in mechanisms of depsipeptide sensitivity and resistance. This led us to the generation of cell lines with non-Pgp mediated depsipeptide 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 depsipeptide. 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 hope to identify drug combinations that exploit the various mechanisms of drug action and in this way to translate the activity already observed in monotherapy in lymphoma into activity in solid tumors. Undoubtedly combination therapy will be required in that setting. At a minimum, studies examining the combination of romidepsin and radiation therapy should be conducted, given the strong in vitro synergy observed in our studies with DNA damaging agents and in the studies of others. A protocol concept for the combination of romidepsin with an experimental signal transduction inhibitor is under review.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010621-08
Application #
8349074
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2011
Total Cost
$708,140
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Amiri-Kordestani, Laleh; Luchenko, Victoria; Peer, Cody J et al. (2013) Phase I trial of a new schedule of romidepsin in patients with advanced cancers. Clin Cancer Res 19:4499-507
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
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
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
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
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

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