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County-Level Factors and Mortality Among Pacific Islander Compared With Asian American Adults.
No full textIMPORTANCE: Interactions between race and county-level factors associated with mortality, such as employment, education, income, and population density, are understudied among Asian American and Pacific Islander populations. OBJECTIVE: To compare all-cause, cancer, and heart disease mortality rates between Pacific Islander and Asian American adults across county-level factors. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study examined National Center for Health Statistics death certificate data on non-Hispanic Asian American and Pacific Islander adults (aged 20-84 years) between January 1, 2018, and December 31, 2020. County-level socioeconomic data were obtained from the American Community Survey, and population density was determined using Rural-Urban Continuum Codes. Analyses were conducted between August 1, 2023, and September 4, 2024. EXPOSURES: County-level unemployment, educational attainment, median household income, and population density. MAIN OUTCOMES AND MEASURES: Age-standardized all-cause, cancer, and heart disease mortality rates and mortality rate ratios (MRRs), comparing Pacific Islander with Asian American individuals by sex and age. Interactions between race and county-level factors associated with MRRs were evaluated using P value for trend across county-level factors. RESULTS: During 2018 to 2020, 43 221 696 Asian American and 1 281 221 Pacific Islander adults resided in the US. A total of 148 939 Asian American individuals (16.7% aged 20-54 years, 17.2% aged 55-64 years, and 66.1% aged ≥65 years; 57.5% male) and 9628 Pacific Islander individuals (29.9% aged 20-54 years, 23.0% aged 55-64 years, and 47.1% aged ≥65 years; 57.2% male) died of any cause. Across all county-level factors, Pacific Islander adults had elevated all-cause, cancer, and heart disease mortality rates compared with Asian American adults (female: MRR range from 1.82 [95% CI, 1.67-1.98] for population 1 000 000 population, 2.13 [95% CI, 1.95-2.32]). The largest heart disease MRRs for Pacific Islander compared with Asian American individuals occurred among those younger than 65 years, with the greatest relative mortality among those aged 20 to 54 years in counties with the lowest unemployment (female: MRR, 14.21 [95% CI, 9.89-20.04]; male: MRR, 5.75 [95% CI, 4.58-7.15]) and highest educational attainment (female: MRR, 13.69 [95% CI, 9.68-18.94]; male: MRR, 6.17 [95% CI, 5.00-7.54]), median household income (female: MRR, 11.97 [95% CI, 9.55-14.91]; male: MRR, 5.16 [95% CI, 4.49-5.91]), and population density (female: MRR, 11.77 [95% CI, 9.39-14.62]; male: MRR, 5.48 [95% CI, 4.76-6.29]). CONCLUSIONS AND RELEVANCE: In this cross-sectional study, all-cause mortality disparities between Asian American and Pacific Islander populations worsened in counties with higher socioeconomic status and greater population density. Historical aggregation of Pacific Islander with Asian American individuals may have misled health improvement efforts, especially for Pacific Islander adults who lived in high socioeconomic and more populated areas
Mendelian randomisation analysis to discover plasma metabolites mediating the effect of obesity on cancer risk.
No full textBACKGROUND: Obesity is a risk factor for several cancers, but the mechanistic basis is poorly understood. We sought to identify circulating metabolites mediating the effect of obesity on the risk of eight common cancers. METHODS: Using European ancestry data, we applied two-sample Mendelian randomisation (2S-MR) to screen 856 plasma metabolites for associations with body mass index (BMI) and waist-hip ratio (WHR). Metabolite GWAS data were sourced from INTERVAL, and obesity traits from the GIANT consortium and UK Biobank. We assessed the impact of obesity-associated metabolites on cancer risk (384,738 cases across eight cancer types and 799,908 controls) and conducted mediation analyses to identify potential mediators of obesity-driven cancer risk. RESULTS: MR analysis yielded 107 BMI-driven metabolites and 126 WHR-driven metabolites. The strongest relationships with cancer risk were between levels of obesity-driven 1-linoleoyl-GPC, 2-linoleoyl-GPC, 1,2-dilinoleoyl-GPC, 1-arachidonoyl-GPA, and 1-pentadecanoyl-2-linoleoyl-GPC and colorectal cancer (CRC). Additional associations were found between obesity-driven metabolites and breast cancer risk. Mediation analysis implicated multiple metabolites as potential mediators of obesity-driven CRC and breast cancer risk. CONCLUSIONS: As well as these findings highlighting how obesity-related metabolic changes influence cancer risk, our observations suggest potential interventional targets
Epigenetic Heritability of Cell Plasticity Drives Cancer Drug Resistance through a One-to-Many Genotype-to-Phenotype Paradigm.
No full textUNLABELLED: Cancer drug resistance is multifactorial, driven by heritable (epi)genetic changes but also by phenotypic plasticity. In this study, we dissected the drivers of resistance by perturbing organoids derived from patients with colorectal cancer longitudinally with drugs in sequence. Combined longitudinal lineage tracking, single-cell multiomics analysis, evolutionary modeling, and machine learning revealed that different targeted drugs select for distinct subclones, supporting rationally designed drug sequences. The cellular memory of drug resistance was encoded as a heritable epigenetic configuration from which multiple transcriptional programs could run, supporting a one-to-many (epi)genotype-to-phenotype map that explains how clonal expansions and plasticity manifest together. This epigenetic landscape may ensure drug-resistant subclones can exhibit distinct phenotypes in changing environments while still preserving the cellular memory encoding for their selective advantage. Chemotherapy resistance was instead entirely driven by transient phenotypic plasticity rather than stable clonal selection. Inducing further chromosomal instability before drug application changed clonal evolution but not convergent transcriptional programs. Collectively, these data show how genetic and epigenetic alterations are selected to engender a "permissive epigenome" that enables phenotypic plasticity. SIGNIFICANCE: Drug resistance is driven by genetic-epigenetic memory that enables cancer cells to adopt multiple phenotypic states depending on environmental conditions, supporting integration of evolutionary principles into biomarker discovery and personalized treatment strategies. This article is part of a special series: Driving Cancer Discoveries with Computational Research, Data Science, and Machine Learning/AI
Target Engagement Assays in Early Drug Discovery.
No full textIn target-based drug discovery, quantification of target engagement is required to build structure-activity relationships and develop a potent clinical candidate. Target engagement data also provides evidence of a drug's mechanism of action (MoA) which although is not required for approval, can increase the chance of a successful clinical outcome. Consequently, a plethora of assays has been developed to provide information about target engagement on isolated proteins and in cells. These techniques monitor changes in stability, structure, optical properties or mass difference between proteins and their complexes with ligands. They also provide characterization of the compound with thermodynamic, kinetic and structural binding parameters. The diversity of approaches reflects the challenges faced when drugging different protein classes, with each method having advantages, trade-offs and target specificity
ARID1A stabilizes non-homologous end joining factors at DNA breaks induced by the G4 ligand pyridostatin.
No full textARID1A, a subunit of the BAF chromatin remodeler, is frequently mutated in cancer. Predicting how ARID1A loss impacts cancer therapy response is challenging because it influences many cellular pathways. G quadruplex (G4) binding ligands, such as pyridostatin, show anticancer effects, but the genetic determinants influencing the response to G4 ligands are not fully understood. Here, we show that ARID1A-deficient cells are selectively sensitive to pyridostatin compared to isogenic controls. This was apparent in ovarian and colorectal cancer cell line models, and in vivo studies suggest that G4 ligands hold promise for ARID1A-deficient cancers. While ARID1A modulates pyridostatin-induced transcriptional responses, we show that toxicity in ARID1A-deficient cells arises from the defective repair of topoisomerase-induced breaks. Notably, these cells fail to efficiently accumulate non-homologous end joining proteins on chromatin following pyridostatin exposure. These data uncover a role for ARID1A in the cellular response to G4 ligands, linking remodeling to G4 ligand-induced responses
Xevinapant or Placebo Plus Platinum-Based Chemoradiotherapy in Unresected Locally Advanced Squamous Cell Carcinoma of the Head and Neck (TrilynX): A Randomized, Phase III Study.
No full textPURPOSE: TrilynX was a randomized, double-blind, phase III study evaluating the addition of xevinapant (an inhibitor of apoptosis proteins inhibitor) or placebo to chemoradiotherapy (CRT) in patients with unresected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). METHODS: Patients with unresected LA SCCHN (oropharynx [p16-negative only], hypopharynx, or larynx) were randomly assigned 1:1 to six cycles of oral xevinapant 200 mg/day or matched placebo (once daily on Days 1-14 of a 21-day cycle) plus CRT for the first three cycles (cisplatin [100 mg/m2 once on Day 2 of every cycle] plus intensity-modulated radiotherapy [70 Gy; 35 fractions of 2 Gy/day, 5 days/week]). The primary end point was event-free survival (EFS) assessed by the blinded independent review committee. Progression-free survival, overall survival (OS), and safety were secondary end points. RESULTS: Between September 20, 2020, and February 27, 2023, 730 patients were randomly assigned to xevinapant plus CRT (n = 364) or placebo plus CRT (n = 366). The median (95% CI) EFS was 19.4 months (14.5 to not estimable) with xevinapant and 33.1 months (21.0 to not estimable) with placebo (hazard ratio [HR], 1.33 [95% CI, 1.05 to 1.67]; P = .9919). OS was worse in the xevinapant arm (HR, 1.39 [95% CI, 1.04 to 1.86]). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 320 (87.9%; xevinapant) and 286 (80.3%; placebo) patients; anemia (78 [21.4%] v 51 [14.3%]) and neutropenia (71 [19.5%] v 69 [19.4%]) were the most common. Serious TEAEs occurred in 194 (53.3%; xevinapant) and 129 (36.2%; placebo) patients. TEAEs leading to death occurred in 22 (6.0%; xevinapant) and 13 (3.7%; placebo) patients. CONCLUSION: Xevinapant plus CRT did not improve EFS (EFS was shorter with xevinapant v placebo) and demonstrated an unfavorable safety profile versus placebo plus CRT in patients with unresected LA SCCHN
Acute myeloid leukaemia cells express high levels of androgen receptor but do not depend on androgen signaling for survival.
No full textMale sex is associated with worse outcome in acute myeloid leukemia (AML) in many studies. We analyzed the survival of 4281 patients treated with intensive chemotherapy in the AML17 and AML19 trials based on sex. Men had a significantly lower remission rate than women. Men had a higher incidence of adverse cytogenetic features and a lower incidence of the relatively favorable NPM1 mutation. However, male sex was an independent risk factor for survival in multi-variate analysis. We hypothesized that androgen signaling in men could worsen outcomes by protecting AML cells from chemotherapy. We demonstrated high levels of androgen receptor (AR) expression in AML across cytogenetic risk groups. We showed the AR expression was induced by IL-6 signaling in vitro and correlates with poor overall survival. Androgens had no effect on survival of primary AML cells in vitro, nor did they impact gene expression. Androgens did not protect AML cells against chemotherapy either in vitro or in vivo. Similar results were observed with estrogen signaling through estrogen receptor in vitro in AML cells. In conclusion, targeting the androgen pathway may not be a promising clinical strategy and sex hormone signaling in AML cells does not explain the poorer outcomes of men
Impact of Population Pharmacogenomics on Cisplatin-Induced Neurotoxicities in Testicular Cancer Survivors.
No full textBACKGROUND: Cisplatin is a commonly used chemotherapeutic across numerous cancer types that can cause neurotoxicities in patients, including peripheral sensory neuropathy, tinnitus, hearing loss, and vertigo. OBJECTIVE: We aimed to evaluate, for the first time, how genetic ancestry impacts cisplatin-induced neurotoxicities and if disparities are related to population differences in allele frequency. METHODS: In a cohort of cisplatin-treated testicular cancer survivors, relationships between genetic ancestry and neurotoxicities, medications, and lifestyle factors were assessed using logistic regression and Kruskal-Wallis tests and multiple pairwise comparisons using the Wilcoxon rank-sum test (Benjamini-Hochberg adjustment). Associations between single nucleotide polymorphism (SNP) genotypes and neurotoxicities with significant inter-population disparities were calculated to identify independent, functional variants with population allele frequency differentiation associated with toxicities. RESULTS: Following four cycles of cisplatin-based chemotherapy, African ancestry survivors were significantly more likely to have neuropathy and vertigo versus European and Asian-axis ancestry survivors, although Asian axis survivors were significantly younger at evaluation than other ancestries. Following filtering for population allele frequency differentiation, functional relevance, and independence, 19,992 SNPs were tested for association with toxicities. Although none passed the Bonferroni threshold, two and four SNPs were associated with neuropathy and vertigo, respectively, at suggestively significant p < 1.0 × 10-4. For neuropathy, rs34904346 (p = 2.0 × 10-5) was an expression quantitative trait locus (eQTL) for RNF24 in nerve tissue, with three other RNF24 eQTLs associated with neuropathy (p < 0.01). For vertigo, rs3777909 (p = 3.1 × 10-5) was an eQTL for MFSD4B in nerve and REV3L in brain tissue, along with three other eQTLs for MFSD4B and four for REV3L associated with vertigo (p < 0.05). In silico, higher MFSD4B and REV3L expression in cancer cell lines were associated with significantly greater cisplatin sensitivity. CONCLUSION: African ancestry was associated with increased cisplatin-induced peripheral sensory neuropathy and vertigo versus European ancestry. Population allele frequency differences and expression levels of RNF24, MFSD4B, and REV3L were potentially implicated
Novel Therapeutic Strategies for Metastatic Prostate Cancer Care.
No full textBACKGROUND AND OBJECTIVE: The elucidation of prostate cancer biology and genomics has led to new therapies improving disease outcomes with novel androgen receptor (AR) pathway inhibitors (ARPIs), taxanes, and targeted therapeutics that require disease molecular stratification. METHODS: We are presenting a narrative and qualitative synthesis based on a systematic search. Medline (PubMed) and Embase (OvidSP) were searched (October 1, 2024, covering 2019-2024) using keywords and Medical Subject Headings terms; ClinicalTrials.gov and ASCO/ESMO abstracts were also reviewed. The inclusion criteria were phase 1-3 studies on molecular targets or therapies for metastatic prostate cancer with posted results. The exclusion criteria included non-English articles, reviews, meta-analyses, commentaries, case reports, duplicates, nonhuman/preclinical studies, protocols, and studies lacking molecular targets. KEY FINDINGS AND LIMITATIONS: Targeted therapies have emerged for specific molecular subtypes of advanced prostate cancer. For instance, poly(ADP)-ribose polymerase inhibitors target DNA repair defective prostate cancer (especially BRCA2 and PALB2 biallelic loss). Immune checkpoint inhibitors against PD-1/PD-L1 are effective in hypermutated prostate cancer cases, especially those with mismatch repair defective (MMRd) disease. Additionally, 177Lu-PSMA-617 impacts prostate-specific membrane antigen (folate hydrolase) expressing disease. Several other major therapeutic advances are envisioned in the near future, including targeting novel cell surface proteins with T-cell engager antibody constructs, immunoconjugates, and radiopharmaceuticals. Other rational therapeutic strategies are being pursued, targeting continued AR signalling; AR cofactors, for example, P300; PI3K/AKT signalling; the PRC2 complex protein including EZH2; as well as novel synthetic lethal strategies. CONCLUSIONS AND CLINICAL IMPLICATIONS: A rapidly evolving standard of care is anticipated for metastatic prostate cancer, making it imperative that rational registration trial designs incorporating multipurpose biomarkers to accelerate anticancer drug development are pursued
