Androgen Receptor Modulators Research Articles

Ligandrol Ameliorates High-Fat Diet- and Streptozotocin-Induced Type 2 Diabetes Mellitus and Prevents Pancreatic Islets Degeneration.

Androgen therapy has been shown to alleviate type 2 diabetes mellitus (T2DM) but is also associated with severe side effects such as prostate cancer. The present study aims to identify the best hit selective androgen receptor (AR) modulator by in silico studies and then investigates its antidiabetic effects in high-fat diet- and streptozotocin (STZ)-induced T2DM male rat model. Molecular docking and molecular dynamics (MD) studies were carried out using Maestro 13.1 and Desmond (2023-2024). Cytotoxicity and insulin secretion were measured in MIN6 cell lines. T2DM was induced using high-fat diet (HFD) for 4 weeks, followed by single STZ (40 mg/kg, intraperitoneally). OneTouch Ultra glucometer was used to measure fasting blood glucose. Gene expression was determined using reverse transcription polymerase chain reaction. Histopathology was carried out using hematoxylin and eosin stain. Through molecular docking, we identify ligandrol as a potential hit. Ligandrol showed a good binding affinity (-10.74 kcal/mol). MD showed that ligandrol is stable during the 100 ns simulation. Ligandrol increases insulin secretion in a dose-dependent manner in vitro in 2 h. Ligandrol (0.3 and 1 mg/kg, orally) significantly decreased the body weight and fasting blood glucose levels compared with the HFD and STZ group. Gene expression showed that ligandrol significantly increased the AR-targeted gene, neurogenic differentiation 1, compared with the HFD and STZ group. Histopathological staining studies showed that ligandrol prevents pancreatic islet degeneration compared with the HFD and STZ group. Our findings suggest that ligandrol's protective effect on pancreatic islets leading to its antidiabetic effect occurs through the activation of AR.

79 (PB067): Identification of biomarkers of response and the mechanism of action of a selective androgen receptor modulator in estrogen receptorpositive breast cancer patient-derived xenografts

79 (PB067): Identification of biomarkers of response and the mechanism of action of a selective androgen receptor modulator in estrogen receptorpositive breast cancer patient-derived xenografts

Neurological Aspects of Sarcopenia: A Comprehensive Update on Pathophysiology, Diagnosis, and Therapeutic Advances

Sarcopenia is an age-related disorder characterized by progressive and generalized loss of skeletal muscle tissue. This condition affects approximately 9.9-40.4% of older adults, 2-34% of outpatients, and about 56% of hospitalized patients. Sarcopenia is classified into primary and secondary types, with primary sarcopenia resulting from the natural aging process and secondary sarcopenia caused by various factors such as sedentary lifestyle, disease, and nutrition. The pathophysiology of sarcopenia involves cellular mechanisms, including genetic alterations, telomere erosion, and proteostasis disruption. Mitochondrial dysfunction, epigenetic modifications, and metabolic factors also contribute to the condition. Neurological aspects, such as motor neuron loss and sodium channel dysfunction, play a crucial role in the development of sarcopenia. Prevention and treatment strategies include exercise interventions, nutritional strategies, and pharmacological interventions. Vitamin D supplementation, testosterone replacement therapy, and selective androgen receptor modulators (SARMs) are among the treatments explored. However, these treatments come with potential

Sarcopenia in the era of precision health: Toward personalized interventions for healthy longevity.

Sarcopenia, characterized by the progressive loss of skeletal muscle mass and function, significantly impacts health outcomes in older adults. This review explores the evolving landscape of sarcopenia research, with a particular focus on its unique characteristics in Asian populations and emerging pharmaceutical interventions. Recent studies have revealed distinct patterns of muscle mass decline in Asian adults, particularly in women, challenging the universal application of global sarcopenia diagnostic criteria. The Asian Working Group for Sarcopenia has proposed region-specific diagnostic criteria, acknowledging these ethnic variations. Prevalence estimates of sarcopenia vary widely, ranging from 10% to 40% in community-dwelling older adults. For specific chronic conditions, the prevalence of sarcopenia is notably higher, reaching 35% for cardiovascular diseases and 24.5% for chronic kidney disease. Sarcopenia is strongly associated with various chronic conditions, increasing the risk of falls by 1.5 to 3 times and significantly increasing mortality risk by 29% to 51%. Current management strategies primarily involve resistance exercise and nutritional interventions, with a recommended daily protein intake of at least 1.2 g/kg to maintain muscle health. Pharmaceutical development has gained significant momentum, with over 20 compounds in various stages of clinical trials. These include myostatin inhibitors, selective androgen receptor modulators, ghrelin receptor agonists, mesenchymal stem cell therapy, and follistatin gene therapy. However, the unique dietary patterns, cultural contexts, and potentially distinct drug responses in Asian populations necessitate tailored interventions and Asia-specific clinical trials. Future directions include refining Asian-specific diagnostic criteria, conducting large-scale epidemiological studies across multiple Asian countries, developing culturally appropriate interventions, integrating sarcopenia management into chronic disease care, and advancing pharmaceutical research with a focus on Asian populations. In conclusion, sarcopenia emerges as a critical nexus in the aging process, intricately linked with multiple organ systems and chronic conditions, underscoring the imperative for its recognition as a cornerstone in person-centered care and the holistic management of age-related health challenges.

MED12 and CDK8/19 Modulate Androgen Receptor Activity and Enzalutamide Response in Prostate Cancer.

Prostate cancer progression is driven by androgen receptor (AR) activity, which is a target for therapeutic approaches. Enzalutamide is an AR inhibitor that prolongs the survival of patients with advanced prostate cancer. However, resistance mechanisms arise and impair its efficacy. One of these mechanisms is the expression of AR-V7, a constitutively active AR splice variant. The Mediator complex is a multisubunit protein that modulates gene expression on a genome-wide scale. MED12 and cyclin-dependent kinase (CDK)8, or its paralog CDK19, are components of the kinase module that regulates the proliferation of prostate cancer cells. In this study, we investigated how MED12 and CDK8/19 influence cancer-driven processes in prostate cancer cell lines, focusing on AR activity and the enzalutamide response. We inhibited MED12 expression and CDK8/19 activity in LNCaP (AR+, enzalutamide-sensitive), 22Rv1 (AR-V7+, enzalutamide-resistant), and PC3 (AR-, enzalutamide-insensitive) cells. Both MED12 and CDK8/19 inhibition reduced cell proliferation in all cell lines, and MED12 inhibition reduced proliferation in the respective 3D spheroids. MED12 knockdown significantly inhibited c-Myc protein expression and signaling pathways. In 22Rv1 cells, it consistently inhibited the AR response, prostate-specific antigen (PSA) secretion, AR target genes, and AR-V7 expression. Combined with enzalutamide, MED12 inhibition additively decreased the AR activity in both LNCaP and 22Rv1 cells. CDK8/19 inhibition significantly decreased PSA secretion in LNCaP and 22Rv1 cells and, when combined with enzalutamide, additively reduced proliferation in 22Rv1 cells. Our study revealed that MED12 and CDK8/19 regulate AR activity and that their inhibition may modulate response to enzalutamide in prostate cancer.

A comprehensive gas chromatography electron ionization high resolution mass spectrometry study of a new steroidal selective androgen receptor modulator (SARM) compound S42.

The synthetic 20-keto-steroid S42 (1) demonstrated selective androgen receptor modulator (SARM) properties in preclinical studies and, consequently, received growing attention also in the context of sports drug testing programs. Fundamental understanding of the behavior of S42 (1) and of relevant derivatives in gas chromatography-electron ionization MS experiments at high resolution (GC-EI-HRMS) is indispensable to develop a reliable qualitative and quantitative doping control method for S42 (1) and its metabolites in body fluid matrices. We present important fundamental mechanistic data on the EI fragmentation behavior of S42 (1) and of silyl ether derivatives as well as of stable isotope-labelled reference material.

Aryl Hydrocarbon Receptor Signaling in Prostate Cancer Therapy: A Review of Implications for Anti-androgen Treatment Strategies and Resistance.

Prostate cancer is a leading cause of cancer-related morbidity and mortality in men, frequently exhibiting resistance to conventional anti-androgen therapies. This review investigates the emerging significance of the aryl hydrocarbon receptor (AhR) in prostate cancer, focusing on its role in modulating androgen receptor (AR) signaling and its potential as a therapeutic target. AhR, traditionally known for detoxifying harmful compounds, has been increasingly recognized for its dual capacity to either enhance or inhibit AR activity based on cellular context and specific coactivators. Furthermore, AhR influences tumor progression independently of AR by regulating genes involved in cell cycle control and apoptosis. This narrative review synthesizes current research on AhR's multifaceted roles in prostate cancer, evaluates its potential as a biomarker, and discusses the therapeutic implications of targeting AhR, particularly for hormone-refractory prostate cancer. Our findings underscore the necessity for personalized AhR-targeted therapies and advocate for continued clinical research to fully leverage AhR's therapeutic potential.

Effect of selective androgen receptor modulator RAD140 on prostate and testosterone levels in Wistar strain rats with bilateral orchidectomy

BACKGROUND Selective androgen receptor modulators (SARMs) have been investigated as a potential treatment for hypogonadism, a condition characterized by low testosterone levels in men. The idea is to provide therapeutic benefits similar to traditional testosterone replacement therapy. However, research in this area is still in its early stages, and more extensive studies are needed to establish the efficacy of SARM. This study aimed to determine the impact of SARM RAD140 on testosterone levels, fibromuscular stroma, and prostate mass in rats undergoing bilateral orchidectomy. METHODS This was an in vivo study using posttest-only control group design in rats (Rattus norvegicus). The positive and negative control groups consisted of rats with and without bilateral orchidectomy, respectively. The treatment groups were rats given SARM RAD140 with and without orchidectomy. Testosterone levels, histopathology, and prostate mass were examined at the end of week 6, and the quantitative data were analyzed using one-way ANOVA. RESULTS This study found no difference in prostate mass (0.598 [0.05] g versus 0.590 [0.07] g, p = 0.984), fibromuscular stroma ratio (0.483 [0.094] versus 0.463 [0.057], p = 0.984), and testosterone level (0.006 [0.005] ng/dl versus 0.014 [0.004] ng/dl, p = 0.098) compared to positive control with orchidectomy and SARM RAD140 administration 6 weeks after treatment. CONCLUSIONS There were no differences in testosterone levels, prostate mass, or the ratio of fibromuscular stroma to epithelium area in rats undergoing bilateral orchidectomy and placebo surgery with the administration of SARM RAD140.

In Vitro and In Vivo Human Metabolism of Ostarine, a Selective Androgen Receptor Modulator and Doping Agent.

Ostarine (enobasarm) is a selective androgen receptor modulator with great therapeutic potential. However, it is also used by athletes to promote muscle growth and enhance performances without the typical adverse effects of anabolic steroids. Ostarine popularity increased in recent years, and it is currently the most abused "other anabolic agent" (subclass S1.2. of the "anabolic agents" class S1) from the World Anti-Doping Agency's (WADA) prohibited list. Several cases of liver toxicity were recently reported in regular users. Detecting ostarine or markers of intake in biological matrices is essential to document ostarine use in doping. Therefore, we sought to investigate ostarine metabolism to identify optimal markers of consumption. The substance was incubated with human hepatocytes, and urine samples from six ostarine-positive cases were screened. Analyses were performed via liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS) and software-assisted data mining, with in silico metabolite predictions. Ten metabolites were identified with hydroxylation, ether cleavage, dealkylation, O-glucuronidation, and/or sulfation. The production of cyanophenol-sulfate might participate in the mechanism of ostarine liver toxicity. We suggest ostarine-glucuronide (C25H22O9N3F3, diagnostic fragments at m/z 118, 185, and 269) and hydroxybenzonitrile-ostarine-glucuronide (C25H22O10N3F3, diagnostic fragments at m/z 134, 185, and 269) in non-hydrolyzed urine and ostarine and hydroxybenzonitrile-ostarine (C19H14O4N3F3, diagnostic fragments at m/z 134, 185, and 269) in hydrolyzed urine as markers to document ostarine intake in doping.

Detection of nonsteroidal and steroidal selective androgen receptor modulators in equine hair after oral administrations.

This paper describes the detections of nonsteroidal and steroidal selective androgen receptor modulators (SARMs), namely, RAD140 and YK-11, in mane hair collected from horses having been orally administered with the respective drugs. SARMs are potent anabolic agents with a high potential of misuse in horseracing and equestrian sports, and the misuses of RAD140 and YK-11 in human sports have been reported. To better control the misuse of RAD140 and YK-11 in horses, two separate oral administration studies of RAD140 (0.3mg/kg daily for 3days) and YK-11 (0.2mg/kg daily for 3days) were previously conducted to investigate their metabolism and to identify target analyte(s) with the longest detection time in urine and plasma for doping control. In this work, segmental analyses of post-administration hair samples have revealed that (i) RAD140 and YK-11 could be detected in horse mane after oral administration and (ii) internal incorporation of RAD140 into hair via bloodstream and external incorporation through sweat or sebum were both observed, whereas YK-11 was primarily incorporated into hair via sweat or sebum.

Exploring the potentials of S4, a selective androgen receptor modulator, in glioblastoma multiforme therapy

Glioblastoma multiforme (GBM) ranks among the prevalent neoplastic diseases globally, presenting challenges in therapeutic management. Traditional modalities have yielded suboptimal response rates due to its intrinsic pathological resistance. This underscores the imperative for identifying novel molecular targets to enhance therapeutic efficacy. Literature indicates a notable correlation between androgen receptor (AR) signaling and GBM pathogenesis. To mitigate the adverse effects associated with androgenic modulation of AR, scientists have pivoted towards the synthesis of non-steroidal anabolic agents, selective androgen receptor modulators (SARMs). Among these, S4, used as a supplement by the bodybuilders to efficiently grow muscle mass with favourable oral bioavailability has emerged as a candidate of interest. This investigation substantiates the anti-oncogenic potential of S4 in temozolomide-responsive and -resistant GBM cells through cellular and molecular evaluations. We observed restriction in GBM cell growth, and motility, coupled with an induction of apoptosis, reactive oxygen species (ROS) generation, and cellular senescence. S4 exposure precipitated the upregulation of genes associated with apoptosis, cell-cycle arrest, DNA damage response, and senescence, while concurrently downregulating those involved in cellular proliferation. Future research endeavours are warranted to delineate the mechanisms underpinning S4's actions, assess its antineoplastic effects in-vivo, and its ability to penetrate the blood-brain barrier.

Detection of the selective androgen receptor modulator S-23 and its metabolites in equine urine and plasma following oral administration.

S-23 is an arylpropionamide selective androgen receptor modulator that has been investigated in animal models for use as a male hormonal contraceptive but is not yet available therapeutically. S-23 is available alongside other selective androgen receptor modulators (SARMs) to purchase online via uncontrolled sites, sold as supplement products. It has been detected in several human doping cases, highlighting the importance of identifying the best analytical targets for equine doping control. The purpose of this study was to investigate the detection of S-23 and its phase I metabolites in equine urine and plasma following a multiple dose oral administration to two Thoroughbred racehorses. Liquid chromatography-high resolution mass spectrometry was used for metabolite identification, and liquid chromatography-tandem mass spectrometry was used for full sample analysis and generation of urine and plasma profiles. S-23 and seven phase I metabolites were observed in urine following enzyme hydrolysis and solvolysis. The most abundant analyte detected was the hydroxylated 4-amino-2-(trifluoromethyl)benzonitrile metabolite, which also allowed the longest duration of detection in urine from both horses, for up to 360 h following administration. The data suggest that this metabolite was likely to be highly conjugated with both sulphate and glucuronide moieties. In plasma, S-23 and two phase I metabolites were observed. S-23 was the most abundant analyte detected for both horses, allowing detection for up to 143 h post-administration. To the best of the authors' knowledge, this is the first report of S-23 and metabolites in equine urine and plasma samples.

Harnessing androgen receptor: Revolutionizing diabetes treatment in men with selective androgen receptor modulators

Diabetes is a chronic metabolic disorder. Among different types, type 2 diabetes mellitus (T2DM) is the most prevalent accounting for 90 % to 95 % of all reported cases. T2DM is more prevalent in men compared to women. According to several literature reports, men with low testosterone levels and/or decreased androgen receptor (AR) expression are prone to T2DM. Consistently, androgen therapy was effective in treating T2DM in several preclinical and clinical studies. Activation of AR has been shown to induce the gene expression of NGN3 and NEUROD1 which helps in pancreatic β-cell differentiation, regeneration, and proliferation. AR activation can also increase the gene expression of glucose transporter (GLUT4) in the hepatocytes, skeletal muscle fibers, and adipocytes. An increase in GLUT4 expression could augment the activity of insulin and could help to reduce the insulin dose. However, testosterone therapy even for the short term was found to produce significant adverse effects. The rate-limiting being the increase in the hematocrit value. Hence, to minimize or avoid the serious adverse effects associated with androgen therapy, selective androgen receptor modulators (SARMs) could be employed to harness the goodness of the AR. A preliminary study based on the network analysis of the genes associated with T2DM has also pointed towards the importance of AR in T2DM.

Ambient ionization mass spectrometry provides screening of selective androgen receptor modulators

Ambient ionization mass spectrometry allows for analysis of samples in their natural state, i.e., with no sample pre-treatment. It can be viewed as a fast, simple, and economical analysis, but its main disadvantages include a lower analytical performance due to the presence of complex sample matrix and the lack of chromatographic separation prior to the introduction of the sample into the mass spectrometer. Here we present an application of two ambient ionization mass spectrometry techniques, i.e., Desorption Atmospheric Pressure Photoionization and Dielectric Barrier Discharge Ionization, for the analysis of known Selective Androgen Receptor Modulators, which represent common compounds of abuse in professional and semiprofessional sport. Eight real samples of illegal food supplements, seized by the local law enforcement, were used to test the performance of the ambient mass spectrometry and the results were validated against a newly developed targeted LC-UV-MS/MS method performed in multiple reaction monitoring mode with an external calibration for each analyte. In order to decide whether or not the compound can be declared as present, we proposed a system of rules for the interpretation of the obtained spectra. The criteria are based on mass spectrum matching (5–10 ppm accuracy from the theoretical exact mass and a correct isotopic pattern), duration of the mass signal (three or five consecutive scans, depending on the instrumentation used), and intensity above the background noise (threefold increase in intensity and absolute intensity above 5E4 or 1E5, depending on the instrumentation). When applying these criteria, good agreement was found between the tested methods. Ambient ionization techniques were effective at detecting SARMs at pharmacologically relevant doses, i.e., approximately above 1 mg per capsule, although they may fail to detect lower levels or isomeric species. It is demonstrated that when adhering to a set of clear and consistent rules, ambient mass spectrometry can be employed as a qualitative technique for the screening of illegal SARMs with sufficient confidence and without the necessity to perform a regular LC-MS analysis.

Selective androgen receptor modulator abuse-induced heart failure: catastrophic effects of RAD-140 (Testolone).

Selective androgen receptor modulator abuse-induced heart failure: catastrophic effects of RAD-140 (Testolone).

Advances in SARMs anti-doping analysis.

Selective androgen receptor modulators (SARMs) are performance-enhancing drugs (PEDs) that stimulate anabolism, increase muscle mass and strength and promote recovery from exercise. The use of SARMs in sports is considered doping and is strictly prohibited by the World Anti-Doping Agency (WADA) and the International Federation of Horseracing Authorities (IFHA). To monitor the abuse of SARMs in sports, it is essential to develop advanced, selective and sensitive analytical methods that provide reliable results. This review evaluates the advances in this area, with a focus on the identification of target analytes related to SARMs, such as SARMs, their metabolites or markers. The aim is to identify targets that could extend the detection windows of SARMs, provide scientific support for results management and/or offer an indirect biomarker-based approach to doping control. This review also aims to evaluate the current liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) methods developed for the monitoring of SARMs in different biological matrices, including traditional matrices such as urine and serum/plasma samples, as well as alternative matrices such as dried blood spots, hair and nail samples.

Abstract PO3-05-06: Targeting PAM50 HER2-Enriched intrinsic subtype with enzalutamide in hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer: results of the SOLTI-1502 ARIANNA trial

Abstract Background Pre-clinical evidence and retrospective studies suggest that PAM50 HER2-Enriched (HER2-E), HR+/HER2- tumors have estrogen receptor (ER) independence and poor prognosis but seem to have androgen receptor (AR)-addiction. Enzalutamide (ENZ) is a potent inhibitor of AR signaling. We hypothesized that ENZ may induce a significant proliferative arrest in PAM50 HER2-E, HR+/HER2-negative advanced breast cancer (ABC), leading to clinical benefit in this poor prognosis population. Methods Eligible patients (pts), males or pre/post-menopausal women with advanced HR+/HER2- ABC resistant to endocrine therapy, received ENZ 160 mg/day until disease progression. Pts were assigned to different cohorts according to PAM50 intrinsic subtypes identified in the pre-treatment tumor biopsy: Cohort A included pts with HER2-E and Cohort B pts with Luminal A/B tumors. Centralized molecular assessment of pre-treatment and C1D15 tumor biopsies were required for the primary endpoint evaluation. After C1D15 biopsy, exemestane 50mg QD could be added to ENZ at physician’s discretion. Tumor assessments were performed every 8 weeks. Primary efficacy endpoint was the relative change in the PAM50 11-gene proliferation-related signature in Cohort A. Secondary objectives included anti-proliferative effect of ENZ in Cohort B, overall response rate (ORR), Clinical benefit rate (CBR; partial response [PR] + stable disease ≥ 24 weeks) progression-free survival (PFS), and safety. Results From June 2020 to October 2022, 47 tumors were screened, and 6 PAM50 HER2-E tumors were identified (13%). A total of 34 pts were enrolled: 6 pts in Cohort A and 28 pts in Cohort B. Among them, 4 pts from Cohort A received ENZ plus exemestane and 23 pts in Cohort B. Mean age was 59 (range 39-76), 89% of pts were postmenopausal, 74% had liver disease, and 59% received (neo)adjuvant treatment. The median number of lines for ABC was 4 (1-8). Mean Ki67 (central assessment) in Cohort A was 37% (5%-70%), while in Cohort B it was 30% (3%-90%). Mean central AR in Cohort A was 66% (30-100), while in Cohort B it was 55% (1-100). The mean suppression of PAM50 11-gene proliferation-signature after 2 weeks of treatment with ENZ was 3.7% (p=0.848) in Cohort A and 1.2% (p=0.909) in Cohort B. The median change in Ki67 levels in Cohort A was -0.43% (p=0.812), while in Cohort B it was +3.86% (p=0.081). No statistically significant differentially expressed genes or changes in intrinsic subtypes were observed. Overall, the median PFS was 1.8 months (95% CI 1.6-1.8). In Cohort A, median PFS was 1.6 months (95% CI 1.0-1.9), and in Cohort B, it was 1.8 months (95% CI 1.6-1.8). CBR was 0% and 11% (n=3, 95% CI 2.8-25.9%) in Cohorts A and B, respectively. A PR with 16 months duration in cohort B was observed in a patient with an AR-mutated tumor (AR c. 689C >T). Regarding safety, grade 1-2 and 3-4 toxicities occurred in 94.1% and 35.3% of patients, respectively. ENZ dose reduction and discontinuation occurred in 2 (5.9%) and 3 (8.8%) pts, respectively. The most common toxicities related to ENZ were nausea (n=8, 24%), decreased appetite (n=8, 24%), AST increase (n=6, 18%) and vomiting (n=6, 18%). Conclusions The hypothesis that ENZ could induce proliferation arrest in HR+/HER2-, PAM50 HER2-E tumors was not confirmed, and ARIANNA was prematurely closed due to the lack of efficacy. Additional research is needed to explore if ENZ may benefit specific populations of pts with breast cancer (e.g. AR-mut tumors) and whether alternative AR modulators are more effective in blocking AR signaling in HR+/HER2-, PAM50 HER2-E tumors Citation Format: Mafalda Oliveira, Tomás Pascual, Sonia Pernas, Mireia Margelí, Salvador Blanch, Barbara Adamo, Francisco Javier Salvador Bofill, Xavier Gonzalez-Farré, Samyukta Chillara, Patricia Galván, Esther Sanfeliu, Paula Blasco, Valeria Sirenko, Alejandra Espinosa, Charles M Perou, Aleix Prat, Luis Manso. Targeting PAM50 HER2-Enriched intrinsic subtype with enzalutamide in hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer: results of the SOLTI-1502 ARIANNA trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-05-06.

Qualitative interviews of patients with COPD and muscle weakness enrolled in a clinical trial evaluating a new anabolic treatment: patient perspectives of disease experience, trial participation and outcome assessments

BackgroundChronic obstructive pulmonary disease (COPD) and muscle weakness can cause impaired physical function, significantly impacting patients’ health-related quality of life (HRQoL). Loss of muscle strength is usually assessed through clinical and performance outcome (PerfO) assessments, which consists of tasks performed in a standardized manner, providing evidence of a patient’s functional ability. However, evidence documenting the patient experience of COPD and muscle weakness is limited.MethodsThis two-stage qualitative study used semi-structured interviews in patients aged 45–80 years with COPD (post-bronchodilator forced expiratory volume in 1s [FEV1]/forced vital capacity ratio < 0.70, and FEV1% predicted of 30–80%) and muscle weakness. In Stage 1, 30-minute concept elicitation interviews were conducted with participants recruited across three US sites to explore impacts on physical functioning and activities of daily living. In Stage 2, interviews were performed with participants exiting a Phase IIa trial investigating the efficacy of a selective androgen receptor modulator (GSK2881078) on leg strength, whereby PerfOs were used to evaluate strength and physical functioning endpoints. These participants completed either 60-minute in-depth (n = 32) or 15-minute confirmatory (n = 35) interviews exploring trial experience, completion of outcome measures, disease experience and treatment satisfaction.ResultsIn Stage 1 (n = 20), most participants described their muscles as weak (83.3%). Difficulties with walking (100%) and lifting heavy objects (90%) were reported. In Stage 2, 60-minute interviews, all participants (n = 32) reported a positive trial experience. Most participants reported that the home exercise program was easy to fit into daily life (77.8%), the PROactive daily diary was easy to complete (100%) and wearable sensors were easy to use (65.6%). However, technical issues were reported (71%), and few participants (19.4%) found physical assessments easy to complete. Improvements in muscle strength and functional limitations were reported by most participants. The shorter 15-minute confirmatory interviews (n = 35) supported the in-depth interview results.ConclusionThe qualitative interviews generated in-depth evidence of key concepts relevant to patients with COPD and muscle weakness and support the assessments of patient strength and physical function as outcome measures in this population in future studies.Trial numberGSK Stage 1: 206869; Stage 2: 200182, NCT03359473; Registered December 2, 2017, https://clinicaltrials.gov/ct2/show/NCT03359473.

An Extracellular Matrix Overlay Model for Bioluminescence Microscopy to Measure Single-Cell Heterogeneous Responses to Antiandrogens in Prostate Cancer Cells.

Prostate cancer (PCa) displays diverse intra-tumoral traits, impacting its progression and treatment outcomes. This study aimed to refine PCa cell culture conditions for dynamic monitoring of androgen receptor (AR) activity at the single-cell level. We introduced an extracellular matrix-Matrigel (ECM-M) culture model, enhancing cellular tracking during bioluminescence single-cell imaging while improving cell viability. ECM-M notably tripled the traceability of poorly adherent PCa cells, facilitating robust single-cell tracking, without impeding substrate permeability or AR response. This model effectively monitored AR modulation by antiandrogens across various PCa cell lines. Single-cell imaging unveiled heterogeneous antiandrogen responses within populations, correlating non-responsive cell proportions with drug IC50 values. Integrating ECM-M culture with the PSEBC-TSTA biosensor enabled precise characterization of ARi responsiveness within diverse cell populations. Our ECM-M model stands as a promising tool to assess heterogeneous single-cell treatment responses in cancer, offering insights to link drug responses to intracellular signaling dynamics. This approach enhances our comprehension of the nuanced and dynamic nature of PCa treatment responses.

Illegal products containing selective androgen receptor modulators purchased online from Italy: health risks for consumers.

Selective androgen receptor modulators (SARMs) are small synthetic drug molecules that are still not approved as medicine in Europe or the United States but are sold on illegal websites to improve sport performance, particularly bodybuilding. To address the quality issues of illegal SARM products and their increasing diffusion in Italy with their potential health risks for consumers. Web-based tools were used to investigate retail websites, trending searches, and information exchange via social media. Thirteen SARM products, purchased on retail websites accessible from Italy, were subject to visual inspection and chemical analysis by mass spectrometry and quantitative nuclear magnetic resonance. The primary outcome was demonstration of additional health risks due to the illicit presence of other active ingredients, contamination, and misdosage in SARM products sold on the internet. The secondary outcome was to show the increasing trend of interest in Italy for these products. Most websites reported misleading information; specifically, the statement "for research only" was reported notwithstanding indications on dosage and training phases. The trending search showed that interest toward SARMs increased in Italy in the last years. The use of these products is clearly encouraged by the emerging phenomenon of "broscience" as revealed in socials. Visual inspection evidenced nonconform labeling. Qualitative analysis confirmed the presence of the stated SARM in about 70% of samples. In 23% of samples, the expected SARM was not detected but a different one instead, and in 1 sample, no SARMs were detected. Other undeclared pharmaceutical substances (tamoxifen, clomifene, testosterone, epimethandienone, tadalafil) were measured in 30% of samples. The copresence of >1 active substance was observed in >60% of samples. Quantitative nuclear magnetic resonance data showed nonuniform content ranging from 30% to 90% of the label claim. The use of SARMs, in the presence of unexpected life-threatening reactions in persons using the products to increase sport performance, should be assessed. This investigation involved an integrated approach to study SARM products and related sociologic aspects. The main shortcomings are the limited number of samples and retail websites in the clear web investigated. SARMs sold online as food supplement-like products represent a health hazard due to the presence of unapproved and undeclared active substances. The presence of contaminants clearly indicates the absence of good manufacturing practices in the production, which increases the health risks.