Insights into immuno-oncology drug development landscape with focus on bone metastasis.

Bone is among the main sites of metastasis in breast, prostate and other major cancers. Bone metastases remain incurable causing high mortality, severe skeletal-related effects and decreased quality of life. Despite the success of immunotherapies in oncology, no immunotherapies are approved for bone metastasis and no clear benefit has been observed with approved immunotherapies in treatment of bone metastatic disease.

The Translational Role of Animal Models for Estrogen-Related Functional Bladder Outlet Obstruction and Prostatic Inflammation.

The prevalence of LUTS and prostatic diseases increases with age both in humans and companion animals, suggesting that a common underlying cause of these conditions may be age-associated alterations in the balance of sex hormones. The symptoms are present with different and variable micturition dysfunctions and can be assigned to different clinical conditions including bladder outlet obstruction (BOO). LUTS may also be linked to chronic non-bacterial prostatitis/chronic pelvic pain syndrome (CP/CPPS), but the relationship between these conditions is unknown.

Osteoimmuno-Oncology: Therapeutic Opportunities for Targeting Immune Cells in Bone Metastasis.

Immunotherapies provide a potential treatment option for currently incurable bone metastases. Bone marrow is an important secondary lymphoid organ with a unique immune contexture. Even at non-disease state immune cells and bone cells interact with each other, bone cells supporting the development of immune cells and immune cells regulating bone turnover.

Immunotherapies and Metastatic Cancers: Understanding Utility and Predictivity of Human Immune Cell Engrafted Mice in Preclinical Drug Development.

Metastases cause high mortality in several cancers and immunotherapies are expected to be effective in the prevention and treatment of metastatic disease. However, only a minority of patients benefit from immunotherapies. This creates a need for novel therapies that are efficacious regardless of the cancer types and metastatic environments they are growing in.

Human Immune System Increases Breast Cancer-Induced Osteoblastic Bone Growth in a Humanized Mouse Model without Affecting Normal Bone.

Bone metastases are prevalent in many common cancers such as breast, prostate, and lung cancers, and novel therapies for treating bone metastases are needed. Human immune system-engrafted models are used in immuno-oncology (IO) studies for subcutaneous cancer cell or patient-derived xenograft implantations that mimic primary tumor growth. Novel efficacy models for IO compounds on bone metastases need to be established.

Characterization a model of prostatic diseases and obstructive voiding induced by sex hormone imbalance in the Wistar and Noble rats.

Background: Chronic nonbacterial prostatitis associated with lower urinary tract symptoms (LUTS) is a prevalent condition in men. One potential pathophysiological factor is change in sex hormone, testosterone and estrogen, balance. Inflammation, cancer and obstructive voiding has been induced in the Noble rat strain by altering levels of sex hormones.

Chronic nonbacterial prostate inflammation in a rat model is associated with changes of gut microbiota that can be modified with a galactoglucomannan-rich hemicellulose extract in the diet.

Objectives: To investigate dietary effects on the gut microbiota composition in a rat model of nonbacterial chronic prostate inflammation (CPI).

Materials And Methods: Nonbacterial CPI was induced in the Wistar rat strain with subcutaneous testosterone and 17β-oestradiol (E ) hormone pellets for 18 weeks. Rats with placebo pellets served as healthy controls.

Antitumor Activity of Novel Bone-seeking, α-emitting Ra-solution in a Breast Cancer Skeletal Metastases Model.

Background/aim: Bone metastases are associated with increased morbidity and poor prognosis in a variety of cancers. The present study investigated the effects of targeted radionuclide therapy with α-emitting, bone-seeking radium-224 (Ra) on osteolytic bone metastasis of MDA-MB-231(SA)-GFP human breast cancer cells injected intracardially into nude mice.

Materials And Methods: Vehicle, ethylenediamine tetra (methylene phosphonic acid) (EDTMP) and Ra-solution (45, 91 or 179 kBq/kg) with EDTMP were intravenously administered to mice two days after cell injection.

Galactoglucomannan-rich hemicellulose extract from Norway spruce (Picea abies) exerts beneficial effects on chronic prostatic inflammation and lower urinary tract symptoms in vivo.

Galactoglucomannan (GGM) is the main hemicellulose class in wood of coniferous trees and could be potentially utilized as a possible health-promoting substance for food and pharmaceutical industry. Our aim was to evaluate effects of orally administered GGM-rich extract from Norway spruce in a rat model of chronic prostatitis associated with lower urinary tract symptoms (LUTS). Prostatic inflammation and LUTS was induced in male rats using testosterone and 17β-estradiol exposure for 18 weeks.

Intravesical treatment with cis-urocanic acid improves bladder function in rat model of acute bladder inflammation.

Aims: The aim was to study the effect of intravesically instilled cis-urocanic acid (cis-UCA) on bladder function in an experimental rat model of acute bladder inflammation. Hyaluronic acid (HA) was used as a comparator compound.

Methods: Bladder irritation was induced in female rats by intravesical hydrochloric acid (HCl) infusion.

Inflammation and epithelial alterations in rat prostate: impact of the androgen to oestrogen ratio.

Chronic non-bacterial prostatitis may offer new insights into the pathogenesis of human benign prostatic hyperplasia and prostate cancer and the strategies for their treatment and prevention. The potential significance of androgen replacement therapy in terms of the reversal of oestradiol (E(2))-induced inflammatory reaction was studied in the dorsolateral prostate (DLP) of the Noble rat. Castrated Noble rats were treated with E(2) and different doses of androgens [dihydrotestosterone (DHT) and testosterone (T)] to achieve an elevated concentration of E(2) and a wide range of the androgen-to-oestradiol ratios in serum.

Fispemifene [Z-2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)-phenoxy]ethoxy}-ethanol], a novel selective estrogen receptor modulator, attenuates glandular inflammation in an animal model of chronic nonbacterial prostatitis.

The anti-inflammatory and antiestrogenic action of fispemifene [Z-2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}-ethanol], a novel selective estrogen receptor modulator (SERM), was tested on the Noble rat model of chronic nonbacterial prostatic inflammation with cellular composition and inflammation patterns similar to those described in human prostatitis. Inflammation was assessed by counting perivascular and stromal infiltrates and the number of inflamed acini. Furthermore, the aggressiveness of inflammation was assessed on the basis of the relation of lymphocytes to the acinar epithelium.

Prostatic inflammation and obstructive voiding in the adult Noble rat: impact of the testosterone to estradiol ratio in serum.

Background: The age-related decline of the testosterone to estradiol (T-to-E(2)) ratio in serum is associated with the increased prevalence of prostatic inflammation and lower urinary tract symptoms suggesting obstructive voiding. The impact of the T-to-E(2) ratio on the development and reversal of non-bacterial prostatic inflammation and obstructive voiding was tested in adult Noble rats.

Methods: Adult male Noble rats (n = 16) were treated with estradiol (83 microg/day) and two different doses (280 and 830 microg/day) of testosterone to cause hypoandrogenic and hyperandrogenic states with elevated estrogen.

Histopathological evidence for an association of inflammation with ductal pin-like lesions but not with ductal adenocarcinoma in the prostate of the noble rat.

Background: Chronic inflammation may contribute to the development of prostate cancer. The goal of this study was to determine the possible association of prostatic inflammation, prostatic intraepithelial neoplasia (PIN)-like lesion, and prostate cancer, and to assess the androgen and estrogen dependency of the early steps of carcinogenesis.

Methods: Noble rats were treated with testosterone and estradiol implants for 13, 18, or 26 weeks.

The soy effect in the disease models of nonbacterial prostatitis and obstructive voiding.

The goal of this study was to improve the understanding of the potential significance of dietary soy for human health by investigating its effects in the animal models of nonbacterial prostatitis and urethral obstruction. Nonbacterial prostatitis was induced in adult Noble rats with the combined treatment of testosterone and 17beta-estradiol. The inflammatory foci categorized into three forms were counted and correlated with expression of an estrogen-responsive gene, progesterone receptor (PR), in the dorsolateral lobes of the rats on soy (+) and soy (-) diets.

Urodynamic changes in a noble rat model for nonbacterial prostatic inflammation.

Background: Chronic nonbacterial prostatitis (CP) associated with voiding dysfunction is a poorly understood clinical phenomenon. The goal of the present study was to induce prostatic inflammation with estrogen and androgen treatment and to record associated urodynamic changes in Noble rats.

Methods: Rats were treated with estradiol and testosterone implants to increase estradiol concentration in serum while testosterone concentration was maintained at or slightly above the control level.

Activation of NF-kappaB in association with prostate carcinogenesis in noble rats.

There is an increasing interest in the role of chronic nonbacterial prostatitis in the development of prostate cancer. The aim of the study was to explore the role of NF-kappaB in the prostate of Noble rats treated with testosterone (T) and 17beta-estradiol (E(2)), a widely used model for prostate carcinogenesis. NF-kappaB-positive epithelial cells appeared in both inflamed and noninflamed glands and ducts at 13 weeks after hormone implantation in hypoandrogenemic, hyperestrogenemic rats.