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Pharmacodynamic Effects of Seliciclib, an Orally Administered

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Pharmacodynamic Effects of Seliciclib, an Orally Administered Cancer Therapy: Clinical Pharmacodynamic Effects of Seliciclib, an Orally Administered Cell Cycle Modulator, in Undifferentiated Nasopharyngeal Cancer Wen-Son Hsieh,4 Ross Soo,1Bee-Keow Peh,2 Thomas Loh,4 Difeng Dong,3 Donny Soh,5 Lim-SoonWong,3,5 Simon Green,6 Judy Chiao,6 Chun-Ying Cui,1Yo k e -F o n g L a i , 4 Soo-Chin Lee,1Benjamin Mow,1 Richie Soong,2 Manuel Salto-Tellez,2 and Boon-Cher Goh1, 2 Abstract Purpose: Cell cycle dysregulation resulting in expression of antiapoptotic genes and uncontrolled proliferation is a feature of undifferentiated nasopharyngeal carcinoma. The pharmacodynamic effects of seliciclib, a cyclin-dependent kinase (CDK) inhibitor, were studied in patients with nasopharyngeal carcinoma. Experimental Design: Patients with treatment-naI«ve locally advanced nasopharyngeal carci- noma received seliciclib at 800 mg or 400 mg twice daily on days1 to 3 and 8 to12.Paired tumor samples obtained at baseline and on day 13 were assessed by light microscopy, immunohisto- chemistry, and transcriptionalprofiling using real-time PCR low-density array consisting of apanel of 380 genes related to cell cycle inhibition, apoptosis, signal transduction, and cell proliferation. Results: At 800 mg bd, one patient experienced grade 3 liver toxicity and another had grade 2 vomiting; no significant toxicities were experienced in 13 patients treated at 400 mg bd. Seven of fourteen evaluable patients had clinical evidence of tumor reduction. Some of these responses were associated with increased tumor apoptosis, necrosis, and decreases in plasma EBV DNA posttreatment. Reduced protein expression of Mcl-1, cyclin D1, phosphorylated retinoblastoma protein pRB (T821), and significant transcriptional down-regulation of genes related to cellular proliferation and survival were shown in some patients posttreatment, indicative of cell cycle modulation by seliciclib, more specifically inhibition of cdk2/cyclin E, cdk7/cyclin H, and cdk9/cyclinT. Conclusions: Brief treatment with this regimen of seliciclib in patients with nasopharyngeal carcinoma is tolerable at 400 mg bd and associated with tumor pharmacodynamic changes consistent with cdk inhibition, and warrants further efficacy studies in this tumor. A common feature of cancer is dysregulated cell cycle control inhibitors like p16INK4A, p27kip1, loss of activity of p53, or that allows uncontrolled cell cycle progression through events excessive activity of cdk4/6. Whereas cdk4 and 6 and cdk2 that promote global gene transcription (1). These defects could when associated with their cyclins are known to activate be a result of activation of cyclin-dependent kinases (cdk) 4 and S-phase DNA replication through retinoblastoma protein 6 or their regulatory D-type cyclins, loss of function of cdk phosphorylation and consequent unbridled transcriptional effects of E2F, CDK7/9 are able to maintain gene transcription by activating RNA polymerase II (1–3). It is known that cancer cells require continuous expression of antiapoptotic genes for 1 Authors’ Affiliations: Department of Hematology-Oncology, National University maintenance of their transformed state (4). Therefore, down- Hospital, 2Oncology Research Institute, 3School of Computing, and 4Department of Head and Neck Surgery, National University of Singapore, and 5Institute for regulation of gene transcription through inhibition of CDK2, Infocomm Research, Singapore; and 6Cyclacel Pharmaceuticals Inc., Dundee, CDK7/9 would result in apoptosis. Cell cycle inhibitors exploit United Kingdom this mechanism as potential anticancer drugs. Received 7/8/08; revised 10/7/08; accepted 10/7/08. Seliciclib (Cyclacel Ltd.; CYC202; R-roscovitine), an orally Grant support: Biomedical Research Council of Singapore (BMRC 01/1/26/18/ 060), SCS-PN0022, CN0079 and NHGRISE 07003. administered small molecule inhibitor of the serine/threonine The costs of publication of this article were defrayed in part by the payment of page kinases CDKs, through competition with ATP for binding, can charges. This article must therefore be hereby marked advertisement in accordance induce apoptosis in several human tumor cell lines, including with 18 U.S.C. Section 1734 solely to indicate this fact. nasopharyngeal carcinoma, through inhibition of retinoblasto- Note: Supplementary data for this article are available at Clinical Cancer Research ma and RNA polymerase II carboxy terminal domain phos- Online (http://clincancerres.aacrjournals.org/). This study was presented in part at the 18th EORTC-NCI-AACR Symposium on phorylation, leading to a reduction in levels of key ‘‘Molecular Targets and Cancer Therapeutics’’ held in Prague, Czech Republic on antiapoptotic proteins like Mcl-1 and XIAP, and cell cycle November 7-10, 2006. regulators such as cyclin D1 (5–7). The IC50 of seliciclib for the Requests for reprints: Boon-Cher Goh, Department of Hematology-Oncology, various cdks are in similar ranges [cdk2/cyclin E (0.1 Amol/L), National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074. Phone: A A 65-67724621;Fax: 65-7775545; E-mail: [email protected]. cdk7/cyclin H (0.36 mol/L), and cdk9/cyclin T (0.8 mol/L); F 2009 American Association for Cancer Research. ref. 8]. Seliciclib is currently in phase II clinical trials in doi:10.1158/1078-0432.CCR-08-1748 combination with chemotherapy in breast and non–small cell www.aacrjournals.org 14 3 5 Clin Cancer Res 2009;15(4) February 15, 2009 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2009 American Association for Cancer Research. Cancer Therapy: Clinical Cooperative Oncology Group performance status of 0 or 1, and adequate bone marrow, renal, and hepatic function. Patients were Translational Relevance excluded if they were on alternative medications, had uncontrolled Cell cycle inhibitors have not been shown previously to major medical conditions, were pregnant or lactating, had evidence of malabsorption, had other malignancies within 5 y, or were known induce molecular changes in vivo in solid cancers. Using a carriers of hepatitis B or C or HIV. The protocol was approved by the window design clinical study, we showed that seliciclib local institutional review board and all patients gave written informed down-regulated transcription of genes relevant to EBV- consent prior to participation. mediated tumorigenesis and control of apoptosis through Treatment, procedures, and methodology. Baseline history, physical activation of signaling pathways that included mitogen- examination, performance status, biochemical profile, and complete activated protein kinase, c-Jun NH2-terminal kinase, p38, blood count were done within 7 d before starting treatment. Patients Janus kinase/signal transducer and activator of transcrip- had endoscopic assessment of tumor with tumor biopsy within 72 h tion, nuclear factor nB, phosphoinositide 3-kinase/protein prior to commencing seliciclib and on day 13 of treatment. Seliciclib was supplied by Cyclacel Ltd in 200-mg capsules. Previous phase I kinase B, and RhoGTPases in nasopharyngeal cancer, 2 where EBV-mediated transformation and expression of studies have established that 800 mg/m twice daily for 7 d is associated with dose-limiting toxicities; 5 d continuous dosing seemed to be latent membrane protein 1 has been associated with tolerable (14). Therefore, patients were orally administered a starting carcinogenicity. In addition, nasopharyngeal carcinoma is dose of 800 mg bd at least 2 h postprandial on days 1 to 3 and 8 to 12 characterized by dysregulation of the cell cycle, particularly for a single 14-day cycle. Treatment of three patients was planned at this through overexpression of cyclin D1 and silencing of dose level 1 with an additional three patients to be treated if one patient INK4A p16 , promoting gene transcription. Therefore, inhibi- had dose-limiting toxicities. Further enrollment at level 1 would tion of these pathways potentially restores cell cycle continue if no more than two of six patients had dose-limiting regulatory events. This proof of principle provides the toxicities. Reduction to dose level 2 was mandated if more than one of evidence required for a formal evaluation of cell cycle the first three patients exhibited dose-limiting toxicities. Patients were inhibitors in nasopharyngeal cancer, and represents a seen on days 8 and 12 for repeat laboratory testing, assessment of significant advance in the application of novel molecular- treatment compliance, and toxicity according to National Cancer targeted agents to therapy of this cancer. Institute Common Toxicity Criteria version 2. Tumor measurements and assessments. Bidimensional tumor meas- urements were done on all palpable cervical lymph nodes at pretreatment and on days 8 and 12 using skin calipers. The sum of lung cancer, but its pharmacodynamic effects of cdk inhibition the products of the pretreatment measurements was subtracted from the by itself in solid tumors in vivo have not been shown. In sum of the product of the posttreatment measurements and divided by chronic lymphocytic leukemia cells in vitro, seliciclib has been the sum of the product of the pretreatment measurements. Patients with shown to induce apoptosis through the down-regulation of >25% decrease in the sum of the product of the posttreatment genes, and a similar mechanism of apoptosis has been measurements were considered to show clinical response. Computed described with another cdk inhibitor flavopiridol (9). tomography scans of the nasopharynx and neck were done within 2 wk of starting seliciclib
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