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Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy

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Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy pISSN 1598-2998, eISSN 2005-9256 Cancer Res Treat. 2017;49(2):374-386 https://doi.org/10.4143/crt.2016.080 Original Article Open Access Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy Erta Kalanxhi, PhD1,2 Purpose Karianne Risberg, PhD1,2 When integrating molecularly targeted compounds in radiotherapy, synergistic effects of the systemic agent and radiation may extend the limits of patient tolerance, increasing the Imon S. Barua2,3 demand for understanding the pathophysiological mechanisms of treatment toxicity. In this MD, PhD4 Svein Dueland, Pelvic Radiation and Vorinostat (PRAVO) study, we investigated mechanisms of adverse 5 Stein Waagene, MSc effects in response to the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide 3,6 Solveig Norheim Andersen, MD, PhD hydroxamic acid, SAHA) when administered as a potential radiosensitiser. Solveig J. Pettersen, MSc5 Materials and Methods Jessica M. Lindvall, PhD2 This phase I study for advanced gastrointestinal carcinoma was conducted in sequential PhD1 Kathrine Røe Redalen, patient cohorts exposed to escalating doses of vorinostat combined with standard-fraction- 3,5,7 Kjersti Flatmark, MD, PhD ated palliative radiotherapy to pelvic target volumes. Gene expression microarray analysis 1,3 Anne Hansen Ree, MD, PhD of the study patient peripheral blood mononuclear cells (PBMC) was followed by functional validation in cultured cell lines and mice treated with SAHA. 1Department of Oncology, Akershus University Hospital, Lørenskog, Results 2Institute of Clinical Molecular Biology, PBMC transcriptional responses to vorinostat, including induction of apoptosis, were con- Akershus University Hospital, Lørenskog, fined to the patient cohort reporting dose-limiting intestinal toxicities. At relevant SAHA con- 3Institute of Clinical Medicine, centrations, apoptotic features (annexin V staining and caspase 3/7 activation, but not University of Oslo, Oslo, Departments of poly-(ADP-ribose)-polymerase cleavage) were observed in cultured intestinal epithelial cells. 4Oncology and 5Tumour Biology, Oslo University Hospital, Oslo, Moreover, SAHA-treated mice displayed significant weight loss. 6 Department of Pathology, Conclusion Akershus University Hospital, Lørenskog, 7Department of Gastroenterological Surgery, The PRAVO study design implemented a strategy to explore treatment toxicity caused by an Oslo University Hospital, Oslo, Norway HDAC inhibitor when combined with radiotherapy and enabled the identification of apoptosis as a potential mechanism responsible for the dose-limiting effects of vorinostat. To the best + C +o r +re s+p o +n d +e n +c e :+ A +n n +e H +a n+s e +n R+e e+, M + D +, P +h D + + of our knowledge, this is the first report deciphering mechanisms of normal tissue adverse + D +e p +a r +tm +en +t o +f O +n c +o l o+g y +, + + + + + + + + + effects in response to an HDAC inhibitor within a combined-modality treatment regimen. + + + + + + + + + + + + + + + + + + + + + A +k e+r s h+u s+ U +n i +ve r+s i t+y H+ o +sp i+ta l+, P +.O .+ B o+x +10 0+0 ,+ + + 1 +4 7 8+ L +ø r e+n s+k o +g , +N o+r w +a y+ + + + + + + + + + + T +e l :+ 4 7 +-6 7+9 - +69 4+1 1+ + + + + + + + + + + + + + F +a x +: 4 7+- 6 +79 -+6 8 +86 1+ + + + + + + + + + + + + + E +-m +a i l+: a +.h .r+e e +@ m+ e d+i s+in .+u i o+. n +o + + + + + + + Key words + + + + + + + + + + + + + + + + + + + + Histone deacetylase inhibitors, + R +e c +ei v +e d + F +eb r+u a+r y + 2 1 +, 2 +01 6+ + + + + + + + + Drug-related side effects and adverse reactions, Apoptosis, + A +c c +ep +te d + J u+n +e 2 +8, 2+0 1+6 + + + + + + + + + + Radiotherapy, Phase I Clinical Trials + P +u b +li s +h e d+ O +n l+in e+ J +u l y+ 2 8+, 2+0 1 +6 + + + + + + + + + + + + + + + + + + + + + + + + + + + Introduction (HDAC) inhibitors. Inhibition of HDAC enzymes increases histone acetylation, leading to modification of chromatin structure and changes in gene expression [2,3]. However, the Combined-modality therapies comprise the future of can- exact mechanisms by which this class of drugs enhances ther- cer medicine, and recent developments in radiobiology have apeutic DNA-damaging effects, including those from radia- made integration of molecularly targeted therapeutics in tion, remain to be understood. Nevertheless, it is assumed clinical radiotherapy increasingly conceivable [1]. One exam- that they comprise cell cycle arrest, DNA damage repair and ple is the combination of radiation with histone deacetylase apoptosis [4-6]. Adding to the complexity of HDAC inhibitor 374 Copyright ⓒ 2017 by the Korean Cancer Association │ http://www.e-crt.org │ This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Erta Kalanxhi, Apoptosis in Intestinal Treatment Toxicity mechanisms is the fact that they are not solely targeting his- both normal and CRC cell lines, and further functional end- tones, but also other signalling proteins [7]. While histone points were examined in an in vivo mouse model. In partic- acetylation occurs in both normal and tumour cells, it has ular, the use of intestinal epithelial cells was considered been contended that HDAC inhibitors selectively affect the essential in the light of the reported intestinal events [12,18]. latter [8-10]. Within the context of combined-modality therapy, the enhanced efficacy of radiation combined with a radiosensi- tising agent may reflect a therapeutic dose at the brink of Materials and Methods patient tolerance. Furthermore, evaluating the treatment tox- icity that arises from the systemic component (e.g., the radiosensitiser) is challenging, especially if its toxicity profile 1. Ethics, consent, and permissions is indistinguishable from normal tissue effects in the radio- therapy target volume [11]. In this context, sampling of a This PRAVO study (ClinicalTrials.gov NCT00455351) was non-irradiated surrogate tissue may enable investigation of approved by the Institutional Review Board and the the targeted agent’s mechanism-of-action which is both sep- Regional Committee for Medical and Health Research Ethics arate from radiation-induced molecular perturbations and (reference number REK S-06289) and performed in accor- representative of normal tissue responses to the particular dance with the Helsinki Declaration. Written informed con- compound. sent was required for participation. Housing and all pro- The Pelvic Radiation and Vorinostat (PRAVO) study for cedures involving research animals were developed accord- symptom palliation in advanced gastrointestinal cancer was ing to protocols approved by the Animal Care and Use Com- first to evaluate the therapeutic use of an HDAC inhibitor in mittee at the Department of Comparative Medicine, Oslo clinical radiotherapy [12]. This phase I study evolved from a University Hospital (reference number 885-2616-2919-2928- preclinical investigation of tumour radiosensitisation by 3688), in compliance with the National Committee for Ani- HDAC inhibitors in experimental colorectal carcinoma mal Experiments’ guidelines on animal welfare. (CRC) models [13-16]. Sequential patient cohorts were exposed to escalating doses of vorinostat combined with 2. Patients and study objectives fractionated radiotherapy to pelvic target volumes. Because common side effects of vorinostat single-agent therapy The principal eligibility criterion was histologically con- include intestinal toxicities [17], the primary objective of this firmed pelvic carcinoma scheduled to receive palliative study was to determine tolerability to vorinostat in combi- radiation to 30 Gy in 3-Gy daily fractions. Other details nation with pelvic radiation [12,18]. In addition, the periph- regarding eligibility are given in the initial report [12]. This eral blood mononuclear cells (PBMC) of patients were dose-escalation study adopted a phase I conventional 3+3 sampled before and after vorinostat administration to expansion cohort design in which patients with advanced explore molecular markers of vorinostat action through gastrointestinal carcinoma were enrolled onto four sequen- PBMC gene expression analysis. We previously showed that tial dose levels of vorinostat (Merck & Co., Inc., Whitehouse the expression kinetics of several genes encoding DNA dam- Station, NJ), starting at a daily dose of 100 mg with dose age response factors involved in clinical radiation sensitivity escalation in increments of 100 mg, given 3 hours (at 9 AM) [19] reflected the appropriate timing of vorinostat adminis- before the daily radiotherapy fraction (at 12 PM) [20]. The pri- tration in the fractionated radiotherapy protocol [20]. mary objective was to determine the tolerability to vorinos- To better understand mechanisms of normal tissue adverse tat, defined by the DLT and maximum-tolerated dose, when events, the PBMC gene expression profiles were reanalyzed administered concomitantly with palliative radiation to with respect to vorinostat dose and reported toxicities within pelvic target volumes. Amongst secondary objectives was the study protocol as assessed by the Common Terminology the identification of possible biomarkers of treatment toxic- Criteria for Adverse Events (CTCAE) scoring. Vorinostat- ity. The study data describing patient treatment tolerability, specific dose-limiting
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