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Studies on the Mechanism Regulating Reproductive Function in Puberty and the Application of Kisspeptin Analogs for the Treatment of Prostate Cancer

田中, 晃 筑波大学 DOI:10.15068/00160448

2020.07.22

概要

Prostate cancer has high prevalence rate in men worldwide and there is no curable treatment established. Androgen deprivation therapy (ADT) is a gold standard therapy for advanced prostate cancer, however, eventually the cancer will be recurred by transforming to castration-resistant prostate cancer. Therefore, there is still an unmet medical need for a better treatment which can prolong or prevent the recurrence of prostate cancer. Thus, this study was aimed to develop a novel ADT agent which leads to better therapeutic outcome in the treatment of prostate cancer based on the better understanding of the mechanism regulating reproductive function in puberty.

In chapter 1, I studied on the mechanism regulating reproductive function in puberty focusing on how estrogen regulates gonadotropin releasing hormone (GnRH)/luteinizing hormone (LH) secretion in puberty in female rats. Reproductive function in mammalian species is centrally regulated by GnRH through the hypothalamus–pituitary–gonadal (HPG) axis. Puberty is a key process in the maturation of reproductive function in mammalian species, which can be defined as the initiation of GnRH/LH secretion. Previous study showed that estrogen strongly suppresses GnRH/LH secretion in prepubertal female rats, and its effectiveness is declined during pubertal period, however, the precise mechanism remained elusive. Kisspeptin is the endogenous ligand for human G-protein coupled receptor GPR54. With numerous efforts since two independent research groups reported that loss-of-function mutation of GPR54 are responsible for pubertal failure in patients with hypogonadotropic hypogonadism, it has been suggested that kisspeptin-GPR54 signaling might be involved in the pubertal initiation of GnRH/LH secretion. In my study, I firstly identified that at least two distinct hypothalamic regions, medial preoptic area (mPOA) and arcuate nucleus (ARC), are the action sites of estrogen for prepubertal restraint of GnRH/LH secretion in female rats in estradiol microimplant study in prepubertal and postpubertal ovariectomized (OVX) rats. I also determined that the attenuation of estrogen responsiveness observed in puberty is not due to the reduction of estrogen receptor expression in the mPOA and ARC in immunohistochemistry and gene expression analysis. Furthermore, I demonstrated that multiple rat kisspeptin analog rKp-10 or GnRH subcutaneous injections induce significant LH secretion in prepubertal OVX rats treated with systemic estradiol replacement. These findings suggest that a neural complex including estrogen-responsive neurons in the mPOA and ARC regulates GnRH/LH secretion in puberty possibly through modulating kisspeptin signals.

In chapter 2, I studied on the application of kisspeptin analogs for the treatment of prostate cancer. There are two different pharmacological approaches that can be considered to block kisspeptin-GPR54 signaling. One is the receptor antagonization and another is the receptor desensitization with the chronic treatment of agonist. Prior to my study, my team succeeded to synthesize Kiss-001 and Kiss-002 which are investigational kisspeptin analogs that have improved pharmacological stability with maintained potent agonistic activity for GPR54. In my study, I developed the one-month sustained release depot of Kiss-001 and Kiss-002, Kiss-001-SR(1M) and Kiss-002-SR(1M), and characterized their pharmacokinetics (PK), pharmacodynamics (PD) and efficacy profiles in animal models. Single subcutaneous injection of Kiss-001-SR(1M) and Kiss-002- SR(1M) maintained plasma Kiss-001 and Kiss-002 concentrations at certain levels for at least 4 weeks, before clearance from the circulation in intact male rats. Accompanying these PK profiles, Kiss-001-SR(1M) and Kiss-002-SR(1M) showed favorable PD responses. Both Kiss-001-SR(1M) and Kiss-002-SR(1M) demonstrated more rapid and profound suppression of plasma testosterone levels than TAP-144-SR(1M), a GnRH agonist which is currently used in the treatment of prostate cancer, in intact male rats. These profound suppressive effects were maintained in dose-dependent manners, before recovery toward normal levels. In the JDCaP xenograft model, both Kiss-001-SR(1M) and Kiss-002-SR(1M) showed better prostate-specific antigen (PSA) control than TAP144-SR(1M), although all treatment groups eventually experienced PSA recurrence and tumor regrowth. These study results indicate that both Kiss-001-SR(1M) and Kiss-002- SR(1M) have desirable and better PK/PD profiles than TAP-144-SR(1M) in rats, which could potentially provide better clinical outcomes in the treatment of androgen-dependent prostate cancer.

In conclusion, my study demonstrates that estrogen-responsive neurons located in the mPOA and ARC play important role in estrogen-dependent pubertal change of GnRH/LH secretion in female rats, and contributes better understanding on the mechanism regulating reproductive function in puberty. Also, my study indicates that kisspeptin analogs are applicable for the treatment of prostate cancer and Kiss-001- SR(1M) and Kiss-002-SR(1M) are the promising clinical candidates to be tested in patients with prostate cancer.

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