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Giving Another Chance to Mifepristone in Pharmacotherapy for Aggressive Meningiomas—A Likely Synergism with Hydroxyurea?

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Giving Another Chance to Mifepristone in Pharmacotherapy for Aggressive Meningiomas—A Likely Synergism with Hydroxyurea? Curr Probl Cancer 40 (2016) 229–243 Contents lists available at ScienceDirect Curr Probl Cancer journal homepage: www.elsevier.com/locate/cpcancer Giving another chance to mifepristone in pharmacotherapy for aggressive meningiomas—A likely synergism with hydroxyurea? İlhan Elmaci, MDa, Meric A. Altinoz, MDb,*, Aydin Sav, MDc, Zeliha Yazici, PhDd, Aysel Ozpinar, PhDe Introduction Meningiomas: An underestimated health problem Meningiomas are the most frequently reported intracranial tumors, accounting for approx- imately one-fourth of all reported primary brain neoplasms.1 They are benign in approximately 90% of the cases and the remaining cases are either borderline or atypical (World Health Organization [WHO] grade II) or malignant (WHO grade III).1 In the United States, the incidence rates with similar age standardization estimated from figures provided by the Central Brain Tumor Registrywere1.8formenand4.2per100,000forwomenin2006.1 Increasing incidence rates of meningiomas have been reported from several industrialized countries since the early 1980s. But recent studies revealed that real meningioma incidence is even higher.1 As meningiomas are mostly benign, they are not covered by most cancer registries.1 Nevertheless, in Finland, as in other Nordic countries, all surgeons and pathologists are obliged to report all tumors of the central nervous system, both malignant and benign, to the cancer registry.1 To reveal the real incidence of Grant/Financial Support: none. This is original work and is not under consideration for publication elsewhere. This submission is for the special issue being compiled by Beata Holkova on the topic Amylodosis. a Department of Neurosurgery, Memorial Hospital, Istanbul, Turkey b Department of Immunology, Experimental Medical Research Institute/DETAE, Istanbul University, Istanbul, Turkey c Nisantasi Neuropathology Group, Istanbul, Turkey d Department of Pharmacology, Cerrahpasa Faculty of Medicine, Istanbul University, Turkey e Department of Biochemistry, Acibadem University, Istanbul, Turkey * Corresponding author: Meric A. Altinoz, MD, Guven Sk, Kagithane, Yildirim Apt. No: 5 D: 6, İstanbul. Tel.: +90 536 201 8327. E-mail address: [email protected] (M.A. Altinoz). http://dx.doi.org/10.1016/j.currproblcancer.2016.05.001 0147-0272/& 2016 Elsevier Inc. All rights reserved. 230 İ. Elmaci et al. / Curr Probl Cancer 40 (2016) 229–243 meningiomas, a comprehensive material was investigated by compiling hospital sources with the Finnish Cancer Registry database.1 The corrected age-standardized meningioma incidence rate was 2.9 per 100,000 for men and 13.0 per 100,000 for women, a third higher than the cancer registry figures.1 The researchers underlined that even these incidences may be lower than the real values, as only operated cases were included to the study. Furthermore, there exist studies that showed incidental meningiomas in 1% of asymptomatic volunteers.1 If we exclude incidental cases or asymptomatic meningiomas being followed clinically, a projection based on Finnish results would reveal that approximately 51,400 patients with meningioma are operated in the United States each year including 5140 patients having atypical or malignant tumors. High-grade meningiomas frequently recur despite surgery and radiotherapy and are therefore associated with poor overall survival.2 Anaplastic meningiomas (WHO grade III, 2007 WHO Classification) are particularly aggressive with a median overall survival time of 15 months.3 At present, guidelines recognize the following 3 medical therapies for inoperable and radiation-refractory meningiomas: hydroxyurea (HU), interferon alfa, and Sandostatin LAR, a somatostatin analogue.4 As would be discussed below, targeting angiogenesis is also suggested as a novel approach in the management of high-grade meningioma. But before that, we would give a short description regarding the sex difference and complex endocrinology of meningiomas. Sex difference and endocrinological complexity of meningiomas As would be discussed in detail, pregnancy is an accelerating factor for the growth of meningiomas, yet nonpregnant women also develop meningiomas with higher incidences than men. The exact mechanism of this difference is unknown. However, there exist some clues. Clinical complaints of women patients with meningioma may also increase during menstruation, and several authors have reported an association between meningioma and breast cancer.5 Therefore, estrogen may be blamed as a stimulating factor for meningioma growth and as the responsible factor for sex difference. Indeed, regression of meningiomas with antiestrogen mepitiostane has been reported.5 But here, one should also admit that some investigators showed that 40% of meningiomas also express androgen receptor, and androgen receptor antagonists may also slower meningioma growth.5 Some groups also suggested that progesterone and androgen receptor expression in meningiomas did not change with sex and hence sex steroid receptor expression does not associate with the sex difference.5 So what could be the exact reason for the women preponderance in meningiomas? When sex steroid receptors including estrogen, androgen, and progesterone receptors (PRs) were compared with Ki-67 proliferation index (PI) in 443 meningioma samples, it was revealed that only the estrogen receptor correlated with cell proliferationinboththesexes.5 Furthermore, it shall also be kept in mind that the rate of the androgen receptor expression in whole meningiomas is about the half of PRs.5 Cytosolic receptors of the sex steroids belong to the steroid-thyroid receptor superfamily, and these receptors are not 100% specific for each sex steroid. Hence, it is very likely that not a single sex steroid receptor, rather the sum effects of steroid receptors and the ratio of their ligands modify the meningioma cell response to sex steroids and determine the sex difference. As estrogen receptor is the predominant proliferating receptor among other sex steroid receptors, a high estrogen-to- androgen ratio may explain a strong stimulus of estrogen in women. On the contrary, despite androgen receptors may also act as proliferative agents, they are expressed approximately half the ratios of PRs, and estrogen receptors are not additionally saturated with estrogen in men.5 As would be mentioned below, such a sum effect may also explain why the PR expression does not highly correlate with the meningioma response to the PR antagonist, mifepristone. Higher angiogenesis in high-grade meningiomas Microvessel density (MVD) correlates with enhanced tumor cell proliferation and tumor grade in human meningioma.6 Vascular endothelial growth factor (VEGF) is highly produced in İ. Elmaci et al. / Curr Probl Cancer 40 (2016) 229–243 231 Fig. A schematic representation of antitumor pathways activated by mifepristone and HU. The possibility of likely synergisms at multiple levels was suggested. (Color version of figure is available online.) malignant meningiomas, and a significant regression of a recurring anaplastic meningioma was reported following bevacizumab (VEGF-A antagonist) treatment.5 VEGF receptor 2 messenger ribonucleic acid exists in 75% of recurring meningiomas vs none of those which did not recur (P ¼ 0.007).7 MVD and PI are positively correlated and time to recurrence is also shorter in patients with high MVD (P ¼ 0.027).7 Treatment with bevacizumab in 15 patients with atypical (WHO grade II) or anaplastic (WHO grade III) meningioma was well tolerated with a median progression-free survival (PFS) of 26 weeks and with a 6-month PFS rate of 43.8%.8 Hence, in patients who have exhausted radiation and surgical options, antiangiogenic drugs may be considered including HU and mifepristone, as both exert antiangiogenic activities (Fig). Role of hydroxyurea in recurring and high-grade meningiomas The HU blocks DNA synthesis by decreasing deoxyribonucleotide production via inhibiting the R2 subunit of ribonucleotide reductase (RRM2).9 Ribonucleotide reductase, consisting of 2 subunits (RRM1 and RRM2), is a rate-limiting enzyme in deoxynucleotide production for DNA synthesis and it plays an important role in cell proliferation and tumorigenicity. Reduction of intracellular deoxyribonucleotides also block DNA excision repair,10 leading to tumor radiosensitization with HU.9 Despite being synthesized very early in 1869, HU is still in use for the treatment of myeloproliferative diseases and chronic myeloid leukemia.10,11 HU is generally administered orally with excellent absorption from the gastrointestinal tract and with a very good oral bioavailability ranging from 80%-100%. At tissue level, HU easily enters both brain and cerebrospinal fluid.12 In many studies, the oral dosage given was 20-30 mg/kg/d (1.4-2.1 g/70 kg normal-weight patient) or 1 g/m2/d (average body surface areas of normal women and men are 1.6 and 1.9 m2, respectively, corresponding to approximate doses of between 1.6 and 1.9 g/d).12 HU was first tested in 1997 in 4 patients with inoperable meningiomas invading the cavernous sinus. Tumor shrinkage occurred in 3 patients and stabilization occurred in all patients.12 After5yearsofthisstudy,35patientswithWHOgradeII(n ¼ 22) or III (n ¼ 13) meningioma were reported who were treated with HU following disease progression after surgery and radiotherapy.13 HU was given at a dose of 1 g/m2 orally twice a day (3.2- 232 İ. Elmaci et al. / Curr Probl Cancer 40 (2016) 229–243 3.8 g in total) and 1 cycle was defined as 4 weeks of daily HU. Patients received 0.5-7 cycles (median
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