Fabio Barra

Investigational drugs for the treatment of cervical cancer

ABSTRACT Introduction: Cervical cancer (CC) is currently the fourth most common malignant disease of women worldwide. Although the incidence and the mortality rates have been decreasing with screening detection and new treatment strategies, a significant number of metastatic or recurrent disease is still diagnosed. For those patients not amenable to curative treatments, such as surgery and radiation, palliative chemotherapy remains the standard of care. As chemotherapy regimens have limited activity, research is focalized on investigating novel pharmacologic strategies. Areas covered: This paper aims to give a complete and updated overview on investigated therapies for the treatment of CC. The authors review the results of clinical studies and highlight the ongoing trials. Expert opinion: Agents targeting various molecular pathways including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), poly ADP-ribose polymerase (PARP), epigenetics and other biological mechanisms represent interesting investigational opportunities. Amongst such drugs, bevacizumab, an anti-VEGF monoclonal antibody, was the first targeted drug recently approved by the FDA for the treatment of patients with metastatic, recurrent, or persistent CC. Another interesting experimental approach is represented by immunotherapy, which is leading to promising results with to the development of therapeutic vaccines and immune checkpoints inhibitors.

Current understanding on pharmacokinetics, clinical efficacy and safety of progestins for treating pain associated to endometriosis

ABSTRACT Introduction: Endometriosis is a chronic estrogen and progestogen responsive inflammatory disease associated with pain symptoms and infertility. The medical therapy of endometriosis aims to induce decidualization within the hormonally dependent ectopic endometrium, and it is often administered to ameliorate women’ pain symptoms or to prevent post-surgical disease recurrence. A variety of progestins have been used in monotherapy for the medical management of women with endometriosis. Areas covered: This review aims to offer the reader a complete overview of pharmacokinetic (PK) and clinical efficacy of progestins for the treatment of endometriosis. Expert opinion: Each progestin has a distinct PK parameters and pharmacodynamics affinity not only for progesterone receptor, but also for other steroid receptors, such as estrogen, androgen, and glucocorticoid. Moreover, progestins can also be delivered in different formulations. All these characteristics influence their final biological effect. Randomized, controlled, non-blinded studies support the use of oral progestin-only treatment for pelvic pain associated with endometriosis. Currently, the only two progestins approved by Food and Drug Administration (FDA) for the treatment of endometriosis are norethindrone acetate (NETA) and depot medroxyprogesterone acetate (DMPA).

Current and emerging treatment options for endometriosis

ABSTRACT Introduction: Pharmacotherapy has a pivotal role in the management of endometriosis with long-term treatments balancing clinical efficacy (control of pain symptoms and prevention of recurrence of the disease after surgery) with an acceptable safety profile. Treatment choice is based on several factors including age and patient preference, reproductive plans, intensity of pain, severity of disease and incidence of adverse effects. Areas covered: The aim of this review is to provide the reader with a complete overview of drugs that are currently available or are under investigation for the treatment of endometriosis highlighting on-going clinical trials. Expert opinion: Almost all of the available treatment options for endometriosis suppress ovarian function and are not curative. Combined oral contraceptives and progestins are commonly administered to these patients in order to ameliorate pain symptoms. Gonadotropin-releasing hormone-agonists are prescribed when first-line therapies are ineffective, not tolerated or contraindicated. Aromatase inhibitors should be reserved only for women who are refractory to other treatments. Amongst the drugs under development, gonadotropin-releasing hormone antagonists have shown the most promising results. Presently, are a number of potential therapies currently in pre-clinical or early clinical studies which may alter treatment strategies in the future although further studies are necessary.

Pharmacokinetic drug evaluation of ulipristal acetate for the treatment of uterine fibroids

ABSTRACT Introduction: Uterine fibroids are the most common form of benign gynecological tumors in women of reproductive ages. Although surgery is the main option to treat them, alternative pharmacological approaches are being investigated to control their symptoms. Among them, ulipristal acetate (UPA) has been the first selective progesterone-receptor modulator (SPRM) approved for the pre-operative and long-term treatment of uterine fibroids. Areas covered: The aim of this article is to review the literature on the pharmacodynamics, pharmacokinetics (PK), clinical efficacy and safety of UPA for the treatment of uterine fibroids. Expert opinion: UPA has both agonistic and antagonistic activity on progesterone receptor. Results from PK studies have shown that it has good oral bioavailability, and that it is extensively metabolized in the liver by cytochrome (CYP) 3A4. The PEARL I-II showed that the preoperative treatment with UPA decreases uterine bleeding, uterine volume and fibroid size in women with symptomatic uterine leiomyomas. The PEARL III and IV trials demonstrated the efficacy and safety of long-term intermittent treatment with UPA for the control of fibroid-related symptoms.

Investigational drugs for the treatment of endometriosis, an update on recent developments

ABSTRACT Introduction: Endometriosis is a hormone-dependent benign chronic disease that requires a chronic medical therapy. Although currently available drugs are efficacious in treating endometriosis-related pain, some women experience partial or no improvement. Moreover, the recurrence of symptoms is expected after discontinuation of the therapies. Currently, new drugs are under intense clinical investigation for the treatment of endometriosis. Areas covered: This review aims to offer the reader a complete and updated overview on new investigational drugs and early molecular targets for the treatment of endometriosis. The authors describe the pre-clinical and clinical development of these agents. Expert opinion: Among the drugs under investigation, late clinical trials on gonadotropin-releasing hormone antagonists (GnRH-ant) showed the most promising results for the treatment of endometriosis. Aromatase inhibitors (AIs) are efficacious in treating endometriosis related pain symptoms but they cause significant adverse effects that limit their long-term use. New targets have been identified to produce drugs for the treatment of endometriosis, but the majority of these new compounds have only been investigated in laboratory studies or early clinical trials. Thus, further clinical research is required in order to elucidate their efficacy and safety in human.

The use of retinoic acid for the treatment of endometriosis

We read with great interest the article of Lu et al. [1] entitled ‘Retinoic acid regulates endometriotic stromal cell growth through the upregulation of Beclin1’ published in your journal. The authors demonstrated that the treatment with retinoic acid induced autophagy in endometriotic stromal cells (ESC) obtained from women with endometriosis who underwent previous hysterectomy. In particular, they reported that this drug succeeded in inducing Beclin1, a fundamental protein involved in autophagosome formation, and observed an inverse correlation between the expression of Beclin1 and a higher clinical grade of endometriosis. Retinoic acid has several and partly known mechanisms of action. The rational of this study is based on the evidence of its role in gene expression and hormonal regulation of eutopic and ectopic endometrium [2], and supported by two previous pre-clinical studies in rodens [3, 4], in which the authors showed that the administration of retinoic acid decreased the volume of endometriotic implants. Although Lu et al. [1] should be congratulated for their laboratory findings, we would like to discuss some points of the study. The authors did not precisely report from which site ESC were obtained, and in particular, whether they originated from nodules of endometriosis or adenomyosis. In fact, it would be of particular interest to know if acid retinoic had different effects to induce cell apoptosis in nodules originating from these two distinguished diseases that has probably different pathogenesis. Moreover, we think that retinoic acid induced-apoptosis might have different efficacy in treating peritoneal endometriotic nodules, ovarian endometriomas (OE) or nodules of deep infiltrating endometriosis (DIE), as controversy exists on a single versus diverse origin of the three lesion types [5]. Previously, Yagamata et al. [6] investigated mRNA expression levels after the treatment with retinoic acid of ESC obtained from OE, showing a reduction in enzymes involved in estradiol production. In particular, we hypothesize that also large nodules of DIE, mainly composed of fibromuscular tissue, may be responsive to retinoic acid that has not only anti-fibrotic effects, but also the ability to modulate collagen metabolism. Moreover, we would like to raise a concern on the potential administration of retinoic acid in women affected by endometriosis, who need a long-term therapy that balances clinical efficacy (preventing recurrence, controlling pain symptoms) with acceptable toxicity [7]. The main limiting factors of retinoic acid use are the development of not negligible adverse effects, such as mucocutaneous alterations, myalgia and release of transaminases, and nonetheless the teratogenicity. For this reason, it seems unlikely that the chronic administration of retinoic acid may have a relevant role in the future treatment of women with endometriosis where the aim is improving the quality of life.

Epigenetic Drugs in the Treatment of Endometriosis

We read with great interest the study by Seo et al entitled “Trichostatin A induces NAG-1 expression and apoptosis in human endometriotic stromal cells” published in your journal. The authors investigated the use of trichostatin A (TPA), a histone deacetylase inhibitor (HDACI), for inducing growth arrest and apoptosis of human endometriotic stromal cells (HESCs) obtained from 15 women with ovarian endometriomas who underwent previous cystectomy. In particular, TPA was effective in enhancing the expression of nonsteroidal antiinflammatory drug-activated gene 1 (NAG-1), a critical proapoptotic gene, which has been demonstrated in patients with endometriosis. The rational of this study is based on the evidence that epigenetic aberrations may underlie the pathogenesis of endometriosis and that the use of HDACIs can modulate the histone acetylation/deacetylation and, thus, protein transcription. These drugs have demonstrated to inhibit proliferation and to stimulate apoptosis of various cell types, including HESCs. Furthermore, their administration has been supported by previous studies on animal model with endometriosis, resulting efficacious in decreasing size and number of implants and in reducing disease-related hyperalgesia. The authors should be congratulated for their laboratory findings; anyway, we would like to raise a concern on the administration of TPA. Currently, although this drug is under investigation, especially in oncologic setting, TPA has not yet been tested in human. Thus, in the absence of solid preclinical data on its pharmacokinetics parameters and safety profile, the development of early clinical trials and thus its introduction in clinical practice appear far to be realized. Among HDACIs investigated, we would turn also the attention on the results of valproic acid (VPA). This drug is widely used to treat epilepsy; it is considered safe and cost-effective. Preclinical studies reported its efficacy for inducing HESCs apoptosis and for reducing size of endometriotic implants of mice. Exploring its mechanism of action, VPA not only caused inhibition of the transcription of CYP19 gene, which encodes P450 aromatase, responsible for implants estrogen production, but also induced that of p21, a proapoptotic protein. Interestingly, a pilot study demonstrated that the administration of VPA in 12 patients with confirmed adenomyosis, who complained of dysmenorrhea and had enlarged uterus, caused complete resolution of symptoms as well as an average reduction in uterine size by 26% after 6 months of therapy. Currently, to the best of our knowledge, no clinical trials on VPA for the treatment of women with endometriosis have been never reported. Although these 2 conditions are very much different, having probably 2 distinct pathogenesis, in the near future it would be rational to evaluate also VPA for treating women with endometriosis. Thus, among HDACIs, the planning of future clinical trials on VPA seems to be most realistic. In conclusion, patients with endometriosis need a long-term therapy that balances clinical efficacy (preventing recurrence, controlling pain symptoms) with acceptable toxicity. As accumulating evidence suggests that various epigenetic aberrations might play critical roles in the development of this benign chronic disease, the preclinical results obtained by HDACIs, such as TPA or VPA, are promising. Anyway, only a minority of these tested drugs may be considered for future studies and we think that the safety profile of these agents may be the turning point for their clinical use. Further data are expected to draw a conclusion on the role of epigenetic drugs for treating endometriosis.

Cardiovascular effects of antimuscarinic agents and beta3-adrenergic receptor agonist for the treatment of overactive bladder

ABSTRACT Introduction: Overactive bladder (OAB) syndrome is common in the general population, particularly in elderly patients. Antimuscarinic drugs (AMs) are considered the mainstay pharmaceutical treatment of OAB whereas β3-adrenoceptor agonists, such as mirabegron, represent a good alternative. Owing to the important role of muscarinic and β3 receptors in cardiovascular (CV) tissue and to the fact that OAB patients often have CV comorbidities, the safety-profile of these drugs constitute an important challenge. Area covered: The aim of this review is to evaluate the CV effects of AMs and mirabegron in OAB. A systematic literature search from inception until December 2017 was performed on PubMed and Medline. Expert opinion: AMs are generally considered to have good CV safety profile but, however, they may cause undesirable adverse events, such as dry mouth, constipation. CV AEs are rare but noteworthy, the most common CV consequences related to the use of these drugs are constituted by an increase in HR and QT interval. Mirabegron has similar efficacy and tolerability to AMs but causes less adverse events, with either modest hypertension and modest increase in HR (<5 bpm) being the most commonly reported.

Inhibition of PI3K/AKT/mTOR pathway for the treatment of endometriosis

We read with great interest the article by Matsuzaki et al. (2018) entitled ‘In vitro and in vivo effects of MK2206 and chloroquine combination therapy on endometriosis: autophagymay be required for regrowth of endometriosis’ recently published in the British Journal of Pharmacology. The authors showed the efficacy of MK2206, an Akt inhibitor, in combination with chloroquine for inducing autophagy of endometriotic stromal and epithelial cells. Moreover, in their study, this double regimen succeeded in reducing the size of endometriotic implants in a xenograft mouse model of endometriosis. The rationale of this study is based on evidence of the important role displayed by PI3K/Akt/mTOR pathway in the pathogenesis of endometriosis. In fact, it has been suggested that this pathway may significantly modulate survival, proliferation of endometriotic cells and angiogenesis in endometriotic implants and that it may also be involved in resistance to progestins. To confirm its importance, some studies reported the overexpression of this pathway in women with endometriosis (Lee and Kim, 2014). The positive results of the study by Matsuzaki et al. (2018) are in line with the previous studies on temsirolimus and everolimus, two rapamycin-analogues that specifically inhibit mTORC1. In two preclinical studies on rats, these drugs were able to cause significant reduction of endometriosis implants growth (Kacan et al., 2017; Lee and Kim, 2014). Although Matsuzaki et al. (2018) should be congratulated for their laboratory findings, we would like to raise some concerns on the administration of PI3K/Akt/mTOR inhibitors and, in particular MK2206, in the clinical treatment of endometriosis. Currently, in oncology, several agents inhibiting key components of this pathway are being tested, such as mTOR (e.g. rapamycin analogues), PI3K (e.g. LY294002), PI3K/mTOR (e.g. BEZ235; dactolisib) or Akt inhibitors (e.g. MK2206). Specifically, MK2206 is being investigated for the treatment of patients with breast, non-small lung and pancreatic cancers (Janku et al., 2018). Although, in an oncological setting, patients with specific mutations (i.e. PIK3CA and PTEN) tend to have higher benefit receiving these inhibitors, a first non-negligible problem is that there are no validated predictive biomarkers for the selection of patients and for monitoring drug efficacy (Janku et al., 2018). More importantly, as the majority of these inhibitors are in early clinical development, there is a lack of solid clinical data on their efficacy and toxicity. However, a not negligible incidence of drug-related adverse events and treatment discontinuation has been reported, in patients receiving these compounds in clinical trials for advanced cancer. Their metabolic, haematological, respiratory, renal and dermatological related toxicities may be partly due to a broad activity profile and crossover inhibition of other ubiquitous lipid and protein kinases. Although some of these adverse events, such as oral stomatitis (30–60% of patients treated) or rash (30–40%), seem to increase with the dosage of the drug, they are often idiosyncratic and unpredictable, potentially occurring from days to years after the beginning of the therapy (Janku et al., 2018). Moreover, evaluating the double regimen administered in the study (Matsuzaki et al., 2018), it should be stated that also chloroquine itself is not free from gastrointestinal (12%), dermatological (3%) and less frequently ophthalmological adverse events (Rainsford et al., 2015). In conclusion, the administration of MK2206, eventually combined with chloroquine, may be acceptable for cancer therapy, in which the primary endpoints are represented by disease-free survival and overall survival. By contrast, it appears less reasonable to use them in youngwomenwith endometriosis where the goal is improving the quality of life. In fact, endometriosis needs a long-term therapy combining clinical efficacy, such as prevention of implants recurrence or control of disease-related pain, with acceptable costs and, more importantly, tolerability. Given this background, it seems unlikely that in the near future, MK2206 or its British Journal of Pharmacology British Journal of Pharmacology (2018) 175 3626–3627 3626

Influence of adenomyosis on pregnancy and perinatal outcomes in women with endometriosis

Several studies have investigated the correlation between endometriosis and adverse pregnancy and perinatal outcomes. However, the role of adenomyosis as a risk factor for adverse perinatal outcome in women with endometriosis has yet to be established. The aim of this study was to explore if fetal and maternal outcomes, in particular the incidence of a small‐for‐gestational‐age (SGA) infant, are different in pregnant women with endometriosis only from in those with the concomitant presence of diffuse or focal adenomyosis.