Diversity of US participants in AstraZeneca-sponsored clinical trials.

BACKGROUND: To develop medicines that are safe and efficacious to all patients, clinical trials must enroll appropriate target populations, but imbalances related to race, ethnicity and sex have been reported. A comprehensive analysis and improvement in understanding representativeness of patient enrollment in industry-sponsored trials are key public health needs. METHODS: We assessed race/ethnicity and sex representation in AstraZeneca (AZ)-sponsored clinical trials in the United States (US) from 2010 to 2022, compared with the 2019 US Census. RESULTS: In total, 246 trials representing 95,372 patients with complete race/ethnicity and sex records were analyzed. The proportions of different race/ethnicity subgroups in AZ-sponsored clinical trials and the US Census were similar (White: 69.5% vs 60.1%, Black or African American: 13.3% vs 12.5%, Asian: 1.8% vs 5.8%, Hispanic: 14.4% vs 18.5%). We also observed parity in the proportions of males and females between AZ clinical trials and US Census (males: 52.4% vs 49.2%, females: 47.6% vs 50.8%). Comparisons of four distinct therapy areas within AZ (Respiratory and Immunology [R&I]; Cardiovascular, Renal, and Metabolism [CVRM]; Solid Tumors; and Hematological Malignancies), including by trial phases, revealed greater variability, with proportions observed above and below US Census levels. CONCLUSION: This analysis provides the first detailed insights into the representativeness of AZ trials. Overall, the proportions of different race/ethnicity and sex subgroups in AZ-sponsored clinical trials were broadly aligned with the US Census. We outline some of AZ's planned health equity initiatives that are intended to continue to improve equitable patient enrollment.

Differential Response of Lung Cancer Cells, with Various Driver Mutations, to Plant Polyphenol Resveratrol and Vitamin D Active Metabolite PRI-2191.

Plant polyphenols and vitamins D exhibit chemopreventive and therapeutic anticancer effects. We first evaluated the biological effects of the plant polyphenol resveratrol (RESV) and vitamin D active metabolite PRI-2191 on lung cancer cells having different genetic backgrounds. RESV and PRI-2191 showed divergent responses depending on the genetic profile of cells. Antiproliferative activity of PRI-2191 was noticeable in EGFRmut cells, while RESV showed the highest antiproliferative and caspase-3-inducing activity in KRASmut cells. RESV upregulated p53 expression in wtp53 cells, while downregulated it in mutp53 cells with simultaneous upregulation of p21 expression in both cases. The effect of PRI-2191 on the induction of CYP24A1 expression was enhanced by RESV in two KRASmut cell lines. The effect of RESV combined with PRI-2191 on cytokine production was pronounced and modulated. RESV cooperated with PRI-2191 in regulating the expression of IL-8 in EGFRmut cells, while OPN in KRASmut cells and PD-L1 in both cell subtypes. We hypothesize that the differences in response to RESV and PRI-2191 between EGFRmut and KRASmut cell lines result from the differences in epigenetic modifications since both cell subtypes are associated with the divergent smoking history that can induce epigenetic alterations.

Differential response of lung cancer cell lines to vitamin D derivatives depending on EGFR, KRAS, p53 mutation status and VDR polymorphism.

Vitamin D reveals antiproliferative activity against many types of cancer cells. Calcitriol (1,25D3), the most active form of vitamin D3, acts mainly through the vitamin D receptor, regulating the expression of target genes. Cells with reasonable expression of VDR are considered to be sensitive to antiproliferative activity of 1,25D3. However, a few alleles of the VDR gene are correlated with higher or lower response to 1,25D3 treatment. The goal of our study was to establish if cells differing in EGFR, KRAS, p53 mutation status and VDR polymorphism were sensitive to antiproliferative activity of selected vitamin D derivatives (VDDs). In our search for the lead VDD against human lung cancer cells, we selected, for this study, low calcemic analogs of active forms of vitamin D2 and D3 that had previously shown anticancer potential. The selected cell lines revealed differential response to VDDs. The highest proliferation inhibition was observed for EGFR mutant cells while a weaker response was observed for KRAS and/or p53 mutant cells. 24,24-Dihomo-1,25D3 (PRI-1890) showed the highest activity on the VDD-sensitive cell lines (A549, HCC827, NCI-H1299, and NCI-H1703). Therefore, PRI-1890 was selected as the lead VDD for further structure optimization. None of the VDDs used in this study showed antiproliferative activity against A-427 and Calu-3. VDR polymorphisms correlated inversely with sensitivity to the antiproliferative activity of VDDs since we observed less transcriptionally active form of VDR in HCC827 cells sensitive to VDD, while more transcriptionally active form was observed in NCI-H358 cells that were stimulated by VDDs to proliferate. Lack of KRAS and p53 mutations in HCC827 cells may be, therefore, responsible for the higher antiproliferative activity of VDDs, while the presence of KRAS and/or p53 mutations in other cell lines might prevent antiproliferative activity even though the VDDs were transcriptionally active as assessed on increased CYP24A1 expression. VDR gene polymorphism is not directly responsible for the sensitivity of tested cells to VDDs.