Conventional Hormone Therapy Research Articles

Assessing the predictive value of intraductal carcinoma of the prostate (IDC-P) in determining abiraterone efficacy for metastatic hormone-sensitive prostate cancer (mHSPC) patients.

This study explored the value of intraductal carcinoma of the prostate (IDC-P) in predicting the efficacy of abiraterone treatment in metastatic hormone-sensitive prostate cancer (mHSPC) patients. A retrospective study of 925 patients who underwent prostate biopsies to detect IDC-P was conducted, with participants divided into two cohorts. The first cohort of 165 mHSPC patients receiving abiraterone treatment was analyzed to compare therapeutic effectiveness between IDC-P positive and negative cases. Utilizing propensity score matching (PSM) to reduce bias, outcomes such as PSA response, progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival were assessed. Additionally, the second cohort of 760 mHSPC patients compared the efficacy of abiraterone with conventional hormone therapy, focusing on differences between IDC-P positive and negative individuals. After PSM, our first cohort included 108 patients with similar baseline characteristics. Among them, 50% (54/108) were diagnosed with IDC-P, with 22.2% (12/54) having IDC-P pattern 1 and 77.8% (42/54) with IDC-P pattern 2. While no notable difference was seen in PSA responses between IDC-P positive and negative patients, IDC-P presence linked to worse clinical outcomes (PSA-PFS: 18.6 months vs. not reached [NR], p = 0.009; rPFS: 23.6 months vs. NR, p = 0.020). Further analysis showed comparable outcomes for IDC-P pattern 1 but significantly worse prognosis for IDC-P pattern 2 (PSA-PFS: 18.6 months vs. NR, p = 0.002; rPFS: 22.4 months vs. NR, p = 0.010). Subgroup analysis revealed IDC-P pattern 2 consistently predicted poorer outcomes across patient subgroups. Remarkably, both IDC-P positive and negative patients gained more from androgen deprivation therapy with abiraterone than conventional treatment, with IDC-P negative patients showing a more significant survival advantage, supported by better hazard ratios (0.47 and 0.66). This study found that IDC-P, especially pattern 2, predicts poor prognosis in mHSPC patients on abiraterone therapy. Also, abiraterone's advantage over hormone therapy is reduced in cases with IDC-P compared to those without.

An Overview of Cardiovascular Risk in Pituitary Disorders.

Cardiovascular comorbidities owing to hormonal excess or deficiency are the main cause of mortality in patients with pituitary disorders. In patients with Cushing's Disease, there is an increased prevalence of cardiovascular diseases and/or risk factors including visceral obesity, insulin resistance, atherosclerosis, arterial hypertension, dyslipidaemia, hypercoagulability as well as structural and functional changes in the heart, like cardiac hypertrophy and left ventricle (LV) dysfunction. Notably, these demonstrate limited reversibility even after remission. Furthermore, patients with acromegaly may manifest insulin resistance but also structural and functional heart changes, also known as "acromegalic cardiomyopathy". Patients with prolactinomas demonstrate an aggravation of metabolic parameters, obesity, dysregulation of glucose and lipid metabolism as well as endothelial dysfunction. Hypopituitarism and conventional hormonal replacement therapy may also contribute to an unhealthy metabolic status, which promotes atherosclerosis and may lead to premature mortality. This review discusses the literature on cardiovascular risk in patients with pituitary disorders to increase physician awareness regarding this aspect of management in patients with pituitary disorders.

Cardiovascular Events and Androgen Receptor Signaling Inhibitors in Advanced Prostate Cancer

Cardiovascular (CV) events remain a substantial cause of mortality among men with advanced and metastatic prostate cancer (PCa). The introduction of novel androgen receptor signaling inhibitors (ARSI) has transformed the treatment landscape of PCa in recent years; however, their associated CV toxic effects remains unclear. To assess the incidence of CV events with addition of ARSI to standard of care (SOC) in locally advanced (M0) and metastatic (M1) PCa. Systematic searches of PubMed, Scopus, Web of Science, EMBASE, and ClinicalTrials.gov were performed from inception up to May 2023. Randomized clinical trials of ARSI agents (abiraterone, apalutamide, darolutamide, enzalutamide) that reported CV events among individuals with M0 and M1, hormone-sensitive prostate cancer (HSPC) and castration-resistant prostate cancer (CRPC). A systematic review was performed in accordance with PRISMA guidance. Two authors screened and independently evaluated studies eligible for inclusion. Data extraction and bias assessment was subsequently performed. A random-effects meta-analysis was performed to estimate risk ratios for the incidence of all grade and grade 3 or higher CV events (primary outcomes), in addition to hypertension, acute coronary syndrome (ACS), cardiac dysrhythmia, CV death, cerebrovascular event, and venous thromboembolism (secondary outcomes). Sources of heterogeneity were explored using meta-regression. There were 24 studies (n = 22 166 patients; median age range, 63-77 years; median follow-up time range, 3.9-96 months) eligible for inclusion. ARSI therapy was associated with increased risk of all grade CV event (risk ratio [RR], 1.75; 95% CI, 1.50-2.04; P < .001) and grade 3 or higher CV events (RR, 2.10; 95%, 1.72-2.55; P < .001). ARSI therapy also was associated with increased risk for grade 3 or higher events for hypertension (RR, 2.25; 95% CI, 1.74-2.90; P < .001), ACS (RR, 1.93; 95% CI, 1.43-1.60; P < .01), cardiac dysrhythmia (RR, 1.64; 95% CI, 1.23-2.17; P < .001), cerebrovascular events (RR, 1.86; 95% CI, 1.34-2.59; P < .001) and for CV-related death (RR, 2.02; 95% CI, 1.32-3.10; P = .001). Subgroup analysis demonstrated increased risk of all CV events across the disease spectrum (M0 HSPC: RR, 2.26; 95% CI, 1.36-3.75; P = .002; M1 HSPC: RR, 1.85; 95% CI, 1.47-2.31; P < .001; M0 CRPC: RR, 1.79; 95% CI, 1.13-2.81; P = .01; M1 CRPC: RR, 1.46; 95% CI, 1.16-1.83; P = .001). This systematic review and meta-analysis found that the addition of ARSIs to traditional ADT was associated with increased risk of CV events across the prostate cancer disease spectrum. These results suggest that patients with prostate cancer should be advised about and monitored for the potential of increased risk of CV events with initiation of ARSI therapy alongside conventional hormonal therapy.

Homologous Recombination Repair Gene Mutations in Prostate Cancer: Prevalence and Clinical Value.

Despite advances in our understanding of the molecular landscape of prostate cancer and the development of novel biomarker-driven therapies, the prognosis of patients with metastatic prostate cancer that is resistant to conventional hormonal therapy remains poor. Data suggest that a significant proportion of patients with metastatic castration-resistant prostate cancer (mCRPC) have mutations in homologous recombination repair (HRR) genes and may benefit from poly(ADP-ribose) polymerase (PARP) inhibitors. However, the adoption of HRR gene mutation testing in prostate cancer remains low, meaning there is a missed opportunity to identify patients who may benefit from targeted therapy with PARP inhibition, with or without novel hormonal agents. Here, we review the current knowledge regarding the clinical significance of HRR gene mutations in prostate cancer and discuss the efficacy of PARP inhibition in patients with mCRPC. This comprehensive overview aims to increase the clinical implementation of HRR gene mutation testing and inform future efforts in personalized treatment of prostate cancer.

Deep Infiltrating Endometriosis in Adolescence: Early Diagnosis and Possible Prevention of Disease Progression.

Endometriosis has a prevalence of 10% worldwide in premenopausal women. Probably, endometriosis begins early in the life of young girls, and it is commonly diagnosed later in life. The prevalence of deep infiltrating endometriosis (DIE) in adolescence is currently unknown due to diagnostic limits and underestimation of clinical symptoms. Dysmenorrhea is a common symptom in adolescents affected by DIE, often accompanied by dyspareunia and chronic acyclic pelvic pain. Ultrasonography-either performed transabdominal, transvaginal or transrectal-should be considered the first-line imaging technique despite the potential for missed diagnosis due to early-stage disease. Magnetic resonance imaging should be preferred in the case of virgo patients or when ultrasonographic exam is not accepted. Diagnostic laparoscopy is deemed acceptable in the case of suspected DIE not responding to conventional hormonal therapy. An early medical and/or surgical treatment may reduce disease progression with an immediate improvement in quality of life and fertility, but at the same time, painful symptoms may persist or even recur due to the surgery itself. The aim of this narrative review is to report the prevalence of DIE in adolescents, describe the pathogenetic theories and discuss the management in adolescent women, including the challenging road to diagnosis and the treatment alternatives.

Androgen Receptor in Hormone Receptor-Positive Breast Cancer.

Breast cancer subtypes expressing hormone receptors (HR+ BCa) have a good prognosis and respond to first-line endocrine therapy (ET). However, the majority of HR+ BCa patients exhibit intrinsic or acquired ET resistance (ET-R) and rapid onset of incurable metastatic BCa. With the failure of conventional ET, limited targeted therapy exists for ET-R HR+ BCa patients. The androgen receptor (AR) in HR-negative BCa subtypes is emerging as an attractive alternative target for therapy. The AR drives Luminal AR (LAR) triple-negative breast cancer progression, and LAR patients consistently exhibit positive clinical benefits with AR antagonists in clinical trials. In contrast, the function of the AR in HR+ BCa is more conflicting. AR in HR+ BCa correlates with a favorable prognosis, and yet, the AR supports the development of ET-R BCa. While AR antagonists were ineffective, ongoing clinical trials with a selective AR modulator have shown promise for HR+ BCa patients. To understand the incongruent actions of ARs in HR+ BCa, the current review discusses how the structure and post-translational modification impact AR function. Additionally, completed and ongoing clinical trials with FDA-approved AR-targeting agents for BCa are presented. Finally, we identify promising investigational small molecules and chimera drugs for future HR+ BCa therapy.

Correlation of Expression of Androgen Receptors and P16 in Triple Negative Breast Carcinoma - A Five Years Retrospective and Prospective Study

AIM AND OBJECTIVE Triple negative breast carcinoma (TNBC) is an aggressive breast carcinoma, lacking estrogen receptor (ER),progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2neu receptor) amplification, thereby, unresponsive to conventional hormonal therapy. The aim of present study is to examine androgen receptor (AR) and p16 expression in TNBC cases and explore its clinical significance in view of potential AR and p16 targeted TNBC therapy. MATERIAL AND METHOD A total 94 TNBC patients were included in this 5 years (3 years retrospective and 2 years prospective) study, conducted at Department of Pathology, JNMCH, Aligarh. Immunohistochemical stains for AR and p16 were performed and their relationship with TNBC clinicopathological data were analyzed. Positive AR expression was defined as ≥1% nuclear staining wheras positive p16 expression was defined as score of ≥1which in turn calculated as product of intensity score and extent of positivity score of cytoplasmic and nuclear stained cells. RESULT Out of 94 TNBC patients, 92 cases were of invasive carcinoma (NST) and 2 cases were invasive lobular carcinoma.AR was expressed in 38/94 (40.4%) cases, all of which were of invasive carcinoma (NST) type. We observed higher expression rate in postmenopausal women i.e.43.2% (16/37) cases and in patients with age ≥60 years i.e. 66.7% (8/12) cases. Statistical analysis showed significant association of AR + TNBC cases with larger tumor size (p= 0.017412) and lymph node metastases (p= 0.033119). Higher expression rate was found in lower grade and stage III, however statistically insignificant.p16 protein was positively expressed in 72.3% (68/94) of the total TNBC cases. We observed higher expression rate in premenopausal women i.e.78.9%(48/57) cases and in patients with age 40-49 years i.e. 84.4% (27/32) . Significantly higher p16 expression rate was found in grade II (90%) followed by grade I (66.7%) and grade III (65%) (p= 0.04). CONCLUSION TNBC was more common in older age group and had a higher propensity for lymph node metastases. AR positive and p16 positive TNBC cases may represent a breast cancer subtype with unique features that may be amenable to treatment with alternative targeted therapy.

Targeting Triple-Negative Breast Cancer by the Phytopolyphenol Carnosol: ROS-Dependent Mechanisms.

Triple-negative breast cancer (TNBC), which lacks the expression of the three hormone receptors (i.e., estrogen receptor, progesterone receptor, and human epidermal growth factor receptor), is characterized by a high proliferative index, high invasiveness, poor prognosis, early relapse, and a tendency to be present in advanced stages. These characteristics rank TNBC among the most aggressive and lethal forms of breast cancer. The lack of the three receptors renders conventional hormonal therapy ineffective against TNBC. Moreover, there are no clinically approved therapies that specifically target TNBC, and the currently used chemotherapeutic agents, such as cisplatin, taxanes, and other platinum compounds, have a limited clinical effect and develop chemoresistance over time. Phytochemicals have shown efficacy against several types of cancer, including TNBC, by targeting several pathways involved in cancer development and progression. In this review, we focus on one phytochemical carnosol, a natural polyphenolic terpenoid with strong anti-TNBC effects and its ROS-dependent molecular mechanisms of action. We discuss how carnosol targets key pathways and proteins regulating the cell cycle, growth, epigenetic regulators, invasion, and metastasis of TNBC. This review identifies carnosol as a potential novel targeting protein degradation molecule.

Structure-guided identification of novel dual-targeting estrogen receptor α degraders with aromatase inhibitory activity for the treatment of endocrine-resistant breast cancer

Drug resistance is a major challenge in conventional endocrine therapy for estrogen receptor (ER) positive breast cancer (BC). BC is a multifactorial disease, in which simultaneous aromatase (ARO) inhibition and ERα degradation may effectively inhibit the signal transduction of both proteins, thus potentially overcoming drug resistance caused by overexpression or mutation of target proteins. In this study, guided by the X-ray structure of a hit compound 30a in complex with ER-Y537S, a structure-based optimization was performed to get a series of multiacting inhibitors targeting both ERα and ARO, and finally a novel class of potent selective estrogen receptor degraders (SERDs) based on a three-dimensional oxabicycloheptene sulfonamide (OBHSA) scaffold equipped with aromatase inhibitor (AI) activity were identified. Of these dual-targeting SERD-AI hybrids, compound 31q incorporating a 1H-1,2,4-triazole moiety showed excellent ERα degradation activity, ARO inhibitory activity and remarkable antiproliferative activity against BC resistant cells. Furthermore, 31q manifested efficient tumor suppression in MCF-7 tumor xenograft models. Taken together, our study reported for the first time the highly efficient dual-targeting SERD-AI hybrid compounds, which may lay the foundation of translational research for improved treatment of endocrine-resistant BC.

Efficacy of tumor necrosis factor inhibitor combined with intra-articular injection of triamcinolone acetonide in the treatment of refractory rheumatoid arthritis synovitis: a retrospective study.

To investigate whether there is a difference in the efficacy of intra-articular injection of tumor necrosis factor (TNF) inhibitor and triamcinolone acetonide (HA) in rheumatoid arthritis (RA) patients with recurrent synovitis after the first intra-articular injection of HA. RA patients who relapsed 12weeks after the first HA treatment were enrolled in this study. After joint cavity extraction, recombinant human TNF receptor-antibody fusion protein (TNFR:FC) (25mg or 12.5mg) or HA (1ml or 0.5ml) was injected then. The changes in the visual analog scale (VAS), joint swelling index, and joint tenderness index before and 12weeks after reinjection were compared and analyzed. The changes in synovial thickness, synovial blood flow, and fluid dark zone depth before and after reinjection were observed by ultrasound. Forty-two RA patients were enrolled, including 11 males and 31 females, with an average age of 46.79 ± 12.61years and an average disease duration of 7.76 ± 5.44years. After 12weeks of intra-articular injection of HA or TNFR:FC, the VAS scores were significantly lower than those before treatment (P < 0.01). After 12weeks of injection, the scores of the joint swelling index and tenderness index in both groups were significantly decreased compared with those before treatment. There was no significant difference in synovial thickness under ultrasound in the HA group before and after injection, while the synovial thickness in the TNFR:FC group was significantly improved after 12weeks (P < 0.01). After 12weeks of injection, the grade of synovial blood flow signal in both groups decreased significantly compared with that before treatment, especially in the TNFR:FC group. After 12weeks of injection, the depth of the liquid dark area under ultrasound decreased significantly in the HA group and TNFR:FC group compared with that before treatment (P < 0.01). Intra-articular injection of a TNF inhibitor is an effective method for the treatment of recurrent synovitis after conventional hormone therapy. Compared with HA treatment, it can reduce synovial thickness. Key Points • Intra-articular injection of a TNF inhibitor is an effective method for the treatment of recurrent synovitis after conventional hormone therapy. • Compared with HA treatment, intra-articular injection of biological agents combined with glucocorticoids can not only relieve joint pain but also significantly inhibit joint swelling. • Compared with HA treatment, intra-articular injection of biological agents combined with glucocorticoids cannot only improve synovial inflammation but also inhibit synovial proliferation. • For the treatment of refractory RA synovitis, biological agents combined with glucocorticoid injection are an effective and safe option.

Phytocannabinoids in Triple Negative Breast Cancer Treatment: Current Knowledge and Future Insights.

Triple negative breast cancer (TNBC) represents an aggressive subtype of breast cancer, which is deficient in estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Thus, TNBC cells are unable to respond to the conventional hormonal therapies, making chemotherapy the only therapeutic choice. Patients with TNBC develop metastasis and recurrence over time and have reduced survival compared to patients with other subtypes of breast cancer. Therefore, there is a need for innovative therapies. Data emerged from pre-clinical studies, highlighted various antitumor activities of plant-derived Cannabis sativa and synthetic cannabinoids (CBs), including delta-9-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD). On the contrary, some studies indicated that CBs might also promote tumor progression. At present, clinical studies on the effects of CBs from Cannabis sativa in cancer patients are few. In the present study, we reviewed known and possible interactions between cannabinoids and TNBC therapies.

Fe-curcumin nanozyme-mediated immunosuppression and anti-inflammation in experimental autoimmune uveitis

BackgroundEAU is an inflammatory disease usually characterized by autoinflammation and autoimmunity and is aggravated by excessive generation of ROS. Conventional hormone therapy often has more adverse effects. It is urgent to find a therapeutic drug with higher efficiency and fewer adverse effects.MethodsWe developed an Fe-curcumin nanozyme in which natural antioxidants coordinate with Fe3+ to form nanoparticles with excellent solubility for directing anti-inflammatory and ROS scavenging effects to treat EAU. Several experiments were used to detect the characteristics of nanozymes. EAU model rats were used to detect the abilities of decreasing autoinflammation and autoimmunity. PBMCs were used to detect the ability to inhibit cell proliferation.ResultsFree radical scavenging experiments showed that nanozymes decreased the level of free radicals at low concentrations. In vitro and in vivo experiments revealed that the group treated with Fe-curcumin nanozymes had lower inflammatory reactions and ROS levels than the control group, as reflected by the downregulated levels of several critical inflammatory cytokines, such as IFN-γ, IL-17, and TNF-α; decreased H2O2 release; inhibited proliferation of Th1 and Th17 cells; and alleviated pathological changes in the eye. Importantly, the Fe-curcumin nanozyme was detected in the retina using Prussian blue staining. Additionally, Fe-curcumin nanozyme is noncytotoxic when directing these biological activities.ConclusionThis study has demonstrated the feasibility of using the Fe-curcumin nanozyme as a nanodrug to inhibit inflammatory reactions and scavenge ROS in the treatment of EAU, indicating that it may serve as a promising therapeutic agent in clinical treatment.Graphical

Hydrogen sulfide alleviates hypothyroidism-induced myocardial fibrosis in rats through stimulating autophagy and inhibiting TGF-β1/Smad2 pathway.

Hypothyroidism alone can lead to myocardial fibrosis and result in heart failure, but traditional hormone replacement therapy does not improve the fibrotic situation. Hydrogen sulfide (H2S), a new gas signaling molecule, possesses anti-inflammatory, antioxidant, and anti-fibrotic capabilities. Whether H2S could improve hypothyroidism-induced myocardial fibrosis are not yet studied. In our study, H2S could decrease collagen deposition in the myocardial tissue of rats caused by hypothyroidism. Furthermore, in hypothyroidism-induced rats, we found that H2S could enhance cystathionine-gamma-lyase (CSE), not cystathionine β-synthase (CBS), protein expressions. Finally, we noticed that H2S could elevate autophagy levels and inhibit the transforming growth factor-β1 (TGF-β1) signal transduction pathway. In conclusion, our experiments not only suggest that H2S could alleviate hypothyroidism-induced myocardial fibrosis by activating autophagy and suppressing TGF-β1/SMAD family member 2 (Smad 2) signal transduction pathway, but also show that it can be used as a complementary treatment to conventional hormone therapy.

Estrogen Receptor-α Targeting: PROTACs, SNIPERs, Peptide-PROTACs, Antibody Conjugated PROTACs and SNIPERs.

Targeting selective estrogen subtype receptors through typical medicinal chemistry approaches is based on occupancy-driven pharmacology. In occupancy-driven pharmacology, molecules are developed in order to inhibit the protein of interest (POI), and their popularity is based on their virtue of faster kinetics. However, such approaches have intrinsic flaws, such as pico-to-nanomolar range binding affinity and continuous dosage after a time interval for sustained inhibition of POI. These shortcomings were addressed by event-driven pharmacology-based approaches, which degrade the POI rather than inhibit it. One such example is PROTACs (Proteolysis targeting chimeras), which has become one of the highly successful strategies of event-driven pharmacology (pharmacology that does the degradation of POI and diminishes its functions). The selective targeting of estrogen receptor subtypes is always challenging for chemical biologists and medicinal chemists. Specifically, estrogen receptor α (ER-α) is expressed in nearly 70% of breast cancer and commonly overexpressed in ovarian, prostate, colon, and endometrial cancer. Therefore, conventional hormonal therapies are most prescribed to patients with ER + cancers. However, on prolonged use, resistance commonly developed against these therapies, which led to selective estrogen receptor degrader (SERD) becoming the first-line drug for metastatic ER + breast cancer. The SERD success shows that removing cellular ER-α is a promising approach to overcoming endocrine resistance. Depending on the mechanism of degradation of ER-α, various types of strategies of developed.

A Case Report on the Impact of a Lean Poly Cystic Ovarian Syndrome on Fertility and Potential Benefit of Ayurveda Regime

Despite of advances in Artificial Reproductive Techniques (ART), female infertility is the predominant health issue faced by approximate 15% couples globally.Out of the ovarian factors responsible for infertility, PCOS is a burning issue worldwide affecting female fertility and creating endocrine level disturbances. Case presentation: We are reporting a case of primary infertility presenting with Lean phenotypical features and USG findings of PCOS. She underwent conventional Hormonal therapy for two years and single cycle of IVF which resulted in failure. On evaluating the parameters in view of Ayurveda, a diagnosis of Anapatya Vandhya with Artavakshaya and Karshya was made. Intervention: Therapeutic strategy included Shamana therapy for three months followed by Shodhana Therapy involving Uttarabasti (Intrauterine instillation of drug), Ksheerabasti and Nasya Karma. Outcome: Following treatment, 4 kg gain in body weight, moderate relief in acne and substantial improvement in duration and flow of menstruation was observed and the patient conceived in the 4th month of treatment course. Conclusion: This case report presents a successful outcome of Ayurveda regime planned on the basis of Ayurveda diagnosis in a rare case of Primary infertility associated with Lean PCOS

Lipid nanoparticles to silence androgen receptor variants for prostate cancer therapy.

Advanced-stage prostate cancer remains an incurable disease with poor patient prognosis. There is an unmet clinical need to target androgen receptor (AR) splice variants, which are key drivers of the disease. Some AR splice variants are insensitive to conventional hormonal or androgen deprivation therapy due to loss of the androgen ligand binding domain at the C-terminus and are constitutively active. Here we explore the use of RNA interference (RNAi) to target a universally conserved region of all AR splice variants for cleavage and degradation, thereby eliminating protein level resistance mechanisms. To this end, we tested five siRNA sequences designed against exon 1 of the AR mRNA and identified several that induced potent knockdown of full-length and truncated variant ARs in the 22Rv1 human prostate cancer cell line. We then demonstrated that 2'O methyl modification of the top candidate siRNA (siARvm) enhanced AR and AR-V7 mRNA silencing potency in both 22Rv1 and LNCaP cells, which represent two different prostate cancer models. For downstream in vivo delivery, we formulated siARvm-LNPs and functionally validated these in vitro by demonstrating knockdown of AR and AR-V7 mRNA in prostate cancer cells and loss of AR-mediated transcriptional activation of the PSA gene in both cell lines following treatment. We also observed that siARvm-LNP induced cell viability inhibition was more potent compared to LNP containing siRNA targeting full-length AR mRNA (siARfl-LNP) in 22Rv1 cells as their proliferation is more dependent on AR splice variants than LNCaP and PC3 cells. The in vivo biodistribution of siARvm-LNPs was determined in 22Rv1 tumor-bearing mice by incorporating 14C-radiolabelled DSPC in LNP formulation, and we observed a 4.4% ID/g tumor accumulation following intravenous administration. Finally, treatment of 22Rv1 tumor bearing mice with siARvm-LNP resulted in significant tumor growth inhibition and survival benefit compared to siARfl-LNP or the siLUC-LNP control. To best of our knowledge, this is the first report demonstrating therapeutic effects of LNP-siRNA targeting AR splice variants in prostate cancer.

Diverse role of androgen action in human breast cancer.

Breast cancer is a hormone-dependent cancer, and sex steroids play a pivotal role in breast cancer progression. Estrogens are strongly associated with breast cancers, and the estrogen receptor (estrogen receptor α; ERα) is expressed in 70-80% of human breast carcinoma tissues. Although antiestrogen therapies (endocrine therapies) have significantly improved clinical outcomes in ERα-positive breast cancer patients, some patients experience recurrence after treatment. In addition, patients with breast carcinoma lacking ERα expression do not benefit from endocrine therapy. The androgen receptor (AR) is also expressed in >70% of breast carcinoma tissues. Growing evidence supports this novel therapeutic target for the treatment of triple-negative breast cancers that lack ERα, progesterone receptor, and human EGF receptor 2, and ERα-positive breast cancers, which are resistant to conventional endocrine therapy. However, the clinical significance of AR expression is still controversial and the biological function of androgens in breast cancers is unclear. In this review, we focus on the recent findings concerning androgen action in breast cancers and the contributions of androgens to improved breast cancer therapy.

Androgen receptor axis-targeted agents are not superior to conventional hormonal therapy for treatment of metastatic prostate cancer.

The present study aimed to use real-world Japanese data to compare the treatment outcome of conventional hormonal therapy to that of using androgen receptor axis-targeted (ARAT) agents for patients with metastatic castration-resistant prostate cancer. The overall survival between the conventional hormonal therapy group and the ARAT agent therapy group was compared using a group of 75 Japanese patients who were treated for metastatic castration-resistant prostate cancer. A subgroup analysis was carried out and the risk factors that affected overall survival (OS) were determined. The median OS from the time of prostate-specific antigen recurrence was 73.1 months in the ARAT group and 45.2 months in the conventional treatment group (P=0.414). Although OS tended to be slightly longer in the ARAT group, the difference between the groups was not significant. Subgroup analysis suggested that the therapeutic outcome of using ARAT agents tended to be less beneficial in patients who were older, and in those with a higher tumor volume or low Gleason grade. In conclusion, use of ARAT agents did not impart a significant survival benefit to patients with metastatic castration-resistant prostate cancer when compared with survival rates in response to conventional therapy. However, there was some clinical benefit when ARAT agents were used after patients developed castration-resistant prostate cancer. These findings suggest that up-front therapy using ARAT agents at the time of the initial hormone therapy can impart clinical benefit in Japanese patients with metastatic prostate cancer.

The Divergent Effects of Ovarian Steroid Hormones in the MCF-7 Model for Luminal A Breast Cancer: Mechanistic Leads for Therapy.

The growth modulating effects of the ovarian steroid hormones 17β-estradiol (E2) and progesterone (PRG) on endocrine-responsive target tissues are well established. In hormone-receptor-positive breast cancer, E2 functions as a potent growth promoter, while the function of PRG is less defined. In the hormone-receptor-positive Luminal A and Luminal B molecular subtypes of clinical breast cancer, conventional endocrine therapy predominantly targets estrogen receptor function and estrogen biosynthesis and/or growth factor receptors. These therapeutic options are associated with systemic toxicity, acquired tumor resistance, and the emergence of drug-resistant cancer stem cells, facilitating the progression of therapy-resistant disease. The limitations of targeted endocrine therapy emphasize the identification of nontoxic testable alternatives. In the human breast, carcinoma-derived hormone-receptor-positive MCF-7 model treatment with E2 within the physiological concentration range of 1 nM to 20 nM induces progressive growth, upregulated cell cycle progression, and downregulated cellular apoptosis. In contrast, treatment with PRG at the equimolar concentration range exhibits dose-dependent growth inhibition, downregulated cell-cycle progression, and upregulated cellular apoptosis. Nontoxic nutritional herbs at their respective maximum cytostatic concentrations (IC90) effectively increase the E2 metabolite ratio in favor of the anti-proliferative metabolite. The long-term exposure to the selective estrogen-receptor modulator tamoxifen selects a drug-resistant phenotype, exhibiting increased expressions of stem cell markers. The present review discusses the published evidence relevant to hormone metabolism, growth modulation by hormone metabolites, drug-resistant stem cells, and growth-inhibitory efficacy of nutritional herbs. Collectively, this evidence provides proof of the concept for future research directions that are focused on novel therapeutic options for endocrine therapy-resistant breast cancer that may operate via E2- and/or PRG-mediated growth regulation.

Abstract P2-10-07: Prediction of menstruation recovery timing in premenopausal breast cancer patients taking tamoxifen after chemotherapy: An ASTRRA substudy

Abstract Introduction Addition of ovarian function suppression to conventional endocrine therapy alone in premenopausal women provides a survival benefit with moderate to high risk hormone-receptor positive breast cancer, especially who received chemotherapy Prediction of menstruation recovery after chemotherapy is important for deciding subsequent endocrine treatment and addressing fertility issues. Methods In the adding OFS after chemotherapy trial (ASTRRA), patients who resumed ovarian function up to 2 years after chemotherapy were randomized to receive either 5 years of tamoxifen or adding 2 years of OFS with tamoxifen. With these 1383 patients, we developed a model that predicts when patients recover menstruation within 3 years after chemotherapy using several variables including age, BMI, chemotherapy regimen and duration, serum E2 and FSH level. Results A total of 1017 patients data were used to develop prediction model and 366 patients data were used for external validation. In development group, 546 (53.6%) patients resumed menstruation during follow up period of 5 years. In multivariable analysis, younger age and AC based regimen without taxane were strong predictive factor for menstruation recovery. However predictive value of chemotherapy regimen was not constant over time. Therefore, we conducted another model with patients (n= 624) who did not recover menstruation within one year. In this patient group, predictive factors for menstruation recovery was age and serum E2 level at 6 months after chemotherapy. We also conducted a simplified scoring system to estimate change of recovery by using risk factors mentioned above. Conclusion Younger age is an important persisting factor predicting menstrual recovery after chemotherapy. Although chemotherapy regimen predicts shor-term menstrual recovery, over time, patient factors have more predictive influence on recovery. Recovery of serum E2 level would be important to predict subsequent menstruation recovery. Citation Format: Young Joo Lee, Woo C Noh, Seok J Nam, Byeong-Woo Park, Eun S Lee, Seock A Im, Yong S Jung, Jung H Yoon, Sung S Kang, Kyong H Park, Soo-Jung Lee, Min H Lee, Joon Jeong, Sung Y Kim, Hyun-Ah Kim, Se-Hwan Han, Wonshik Han, Min H Hur, Seonok Kim, Sei-hyun Ahn, Hee J Kim. Prediction of menstruation recovery timing in premenopausal breast cancer patients taking tamoxifen after chemotherapy: An ASTRRA substudy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-10-07.