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Congenital Adrenal Hyperplasia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Biochemical pathways of adrenal steroidogenesis consist of three major routes that all start with cholesterol: mineralocorticoids (end product: aldosterone), glucocorticoids (end product: cortisol), and sex steroids (end product: testosterone) (Figure 52.1). Multiple proteins/enzymes are required for these biochemical pathways, including steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage (CYP11A1), 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2), 17α-hydroxylase/17,20-lyase (CYP17A1), cytochrome b5 (CYB5A), 21-hydroxylase (CYP21A2), 11β-hydroxylase (CYP11B1), aldosterone synthase (CYP11B2), and 17β-hydroxysteroid dehydrogenase type 5 (AKR1C3) (Figure 52.1). Although mutations in the underlying genes encoding any of these proteins/enzymes may cause disruptions in steroidogenesis, potentially leading to CAH, those affecting 21 hydroxylase (P450c21), 11ß hydroxylase (P450c11β) and 17α-hydroxylase/17,20-lyase (P450c17), stand out most (Table 52.1). In fact, mutations in the CYP21A2 (6p21.3), CYP11B1 (8q24.3), and CYP17A1 (10q21-q22) genes encoding P450c21, P450c11β, and P450c17 account for approximately 90%, 5%, and 5% of CAH cases, respectively (Table 52.1) [7–10].
Genetic Engineering of Clostridial Strains for Cancer Therapy
Published in Ananda M. Chakrabarty, Arsénio M. Fialho, Microbial Infections and Cancer Therapy, 2019
Maria Zygouropoulou, Aleksandra Kubiak, Adam V. Patterson, Nigel P. Minton
Nevertheless, the lack of an optimal NTR/prodrug combination was compounded when safety concerns around the use of CB1954 in humans were brought to light; a phase I study in cancer patients revealed dose-limiting diarrhea and hepatotoxicity, with subsequent toxicological studies confirming metabolism of the prodrug by endogenous human liver enzymes [80, 87]. Naturally, research also branched toward the identification of novel prodrugs that are either safer or a better match with candidate NTRs; these include dinitrobenzamide mustards, oxazino-acrinides, nitrobenzyl, and nitroheterocyclic carbamate prodrugs [78, 79]. A subset of these compounds has indeed demonstrated better binding and cytotoxic properties than CB1954 in combination with nfsB or other NTRs, as well as a more pronounced bystander effect. Most notable and clinically advanced among those is PR-104, a dinitrobenzamide mustard initially developed as a hypoxia-activated prodrug. PR-104 is also the only prodrug apart from CB1954 that has been tested in combination with an NTR-expressing clostridial strain; in fact, Liu et al. demonstrated that PR-104 in combination with an sNTR-expressing C. sporogenes strain was more efficient than CB1954 in generating a sustained tumor reduction in mice with SiHa xenografts, even at comparatively lower administered doses [40]. Unfortunately, findings from phase I/II clinical trials employing PR-104 have cast doubts on the clinical utility of this prodrug; dose-limiting myelotoxicity attributed to prodrug metabolism by the human aldo-keto reductase 1C3 (AKR1C3) as well as high levels of clearance were common shortcomings responsible for stalling the clinical implementation of PR-104, inside or outside CDEPT [82].
Adapting to hormone-therapy resistance for adopting the right therapeutic strategy in advanced prostate cancer
Published in Expert Review of Anticancer Therapy, 2023
Giacomo Nuvola, Matteo Santoni, Mimma Rizzo, Matteo Rosellini, Veronica Mollica, Alessandro Rizzo, Andrea Marchetti, Nicola Battelli, Francesco Massari
In the absence of circulating androgens produced by the testes, an alternative mechanism to activate AR signaling is the conversion of cholesterol and adrenal androgen precursors to testosterone and DHT directly in PCa cells (Figure 1). The production of androgen precursors, such as dehydroepiandrosterone (DHEA) and androstenedione, is blocked by androgen biosynthesis inhibitors through inhibition of the enzymatic activity of the CYP17A1 enzyme. Studies in animal models showed that tumor recurrence with abiraterone was associated with upregulation of intratumoral CYP17A1 and other key genes involved in intratumoral androgen synthesis, such as CYP11A1, AKR1C3, and HSD17B3 [17]. A gain-of-function mutation (N367T) has been shown to produce ubiquitination-resistant 3 beta-hydroxysteroid dehydrogenase type 1, which results in the accumulation of this enzyme responsible for DHT synthesis during abiraterone treatment [18]. DHT can also be synthesized from 5-alphaandrostenedione through the activity of the enzyme AKR1C3 which is overexpressed in CRPC. AKR1C3 is also overexpressed in enzalutamide-resistant PC cells and this overexpression confers resistance to enzalutamide [8].
Future directions in endometriosis treatment: discovery and development of novel inhibitors of estrogen biosynthesis
Published in Expert Opinion on Investigational Drugs, 2019
Fabio Barra, Andrea Romano, Giovanni Grandi, Fabio Facchinetti, Simone Ferrero
The aldo/keto reductase (AKR) superfamily includes the enzyme AKR1C3 (also known as 17β-HSD-5): this enzyme can catalyze the reduction of estrone to estradiol, of androstenedione to testosterone and can act as prostaglandin F2α (PGF2α) synthase as well, and it has a broad substrate specificity [22]. Because of the possibility to inhibit multiple signalings relevant to endometriosis, 17β-HSD-5 attracted considerable attention as a novel drug target, although the expression and function of AKR1C3 mRNA within the different endometriotic phenotypes or the eutopic endometrium of women affected by endometriosis are not completely clear [20,23]. Inhibitors of AKR1C3 have been developed for clinical indications such as breast cancer and prostate cancer [24], and, in particular, an AKR1C3 inhibitor (BAY 1,128,688) has been developed and tested for the treatment of patients with endometriosis. After the end of a promising randomized, placebo-controlled, double-blind, dose–response study on different oral doses of BAY 1,128,688 (NCT03373422, definitive results not yet available), a recent phase II clinical trial preliminary ended due to the development of drug-related hepatotoxicity (NCT03373422).
A comprehensive review of hormonal and biological therapies for endometriosis: latest developments
Published in Expert Opinion on Biological Therapy, 2019
Fabio Barra, Giovanni Grandi, Matteo Tantari, Carolina Scala, Fabio Facchinetti, Simone Ferrero
In the latest years, new targets, which may significantly contribute to the development of endometriosis, have been investigated. Among them, AKR1C3 encodes a member of the aldo/keto reductase superfamily, which, importantly, catalyzes the reduction and the oxidation of several PGs (PG-D2, PG-H2, and 9-α,11-β-PG-F2, respectively) [164]. Its expression seems to be reduced by the use of progestins [165]. An ongoing randomized, placebo-controlled, double-blind, the dose-response study is evaluating the efficacy and safety of different oral doses of BAY1128688 for treating patients with symptomatic disease over a 12-week treatment period (NCT03373422).