Screening of GPCR drugs for repurposing in breast cancer

Drug repurposing can overcome both substantial costs and the lengthy process of new drug discovery and development in cancer treatment. Some Food and Drug Administration (FDA)-approved drugs have been found to have the potential to be repurposed as anti-cancer drugs. However, the progress is slow due to only a handful of strategies employed to identify drugs with repurposing potential. In this study, we evaluated GPCR-targeting drugs by high throughput screening (HTS) for their repurposing potential in triple-negative breast cancer (TNBC) and drug-resistant human epidermal growth factor receptor-2-positive (HER2+) breast cancer (BC), due to the dire need to discover novel targets and drugs in these subtypes. We assessed the efficacy and potency of drugs/compounds targeting different GPCRs for the growth rate inhibition in the following models: two TNBC cell lines (MDA-MB-231 and MDA-MB-468) and two HER2+ BC cell lines (BT474 and SKBR3), sensitive or resistant to lapatinib + trastuzumab, an effective combination of HER2-targeting therapies. We identified six drugs/compounds as potential hits, of which 4 were FDA-approved drugs. We focused on β-adrenergic receptor-targeting nebivolol as a candidate, primarily because of the potential role of these receptors in BC and its excellent long-term safety profile. The effects of nebivolol were validated in an independent assay in all the cell line models. The effects of nebivolol were independent of its activation of β3 receptors and nitric oxide production. Nebivolol reduced invasion and migration potentials which also suggests its inhibitory role in metastasis. Analysis of the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset found numerically but not statistically significant reduced risk of all-cause mortality in the nebivolol group. In-depth future analyses, including detailed in vivo studies and real-world data analysis with more patients, are needed to further investigate the potential of nebivolol as a repurposed therapy for BC

Comparative Effectiveness of Direct Oral Anticoagulants Versus Low Molecular Weight Heparins in Cancer Associated Thrombosis (CAT)

Introduction: Venous thromboembolism (VTE) is a fatal comorbidity found in cancer patients. Cancer patients are at an increased risk of developing VTE and bleeding. Low-molecular weight heparins (LMWHs) have been the therapy of choice for cancer associated thrombosis (CAT). Direct-oral anticoagulants (DOACs) are a relatively newer drug class used for the treatment of CAT and may be a reasonable choice of treatment due to their ease of administration and relatively lower cost. There is limited real-world data on the safety and effectiveness of DOACs in cancer patients. This study aimed to study the prevalence and predictors associated with the use of these drugs and also conducted a comparative safety and effectiveness assessment of DOACs versus LMWHs in cancer patients. Methods: This was a retrospective cohort study using SEER Medicare data from the years 2011-2019. Patients diagnosed with cancer (lung, pancreatic, breast, colorectal, prostate, or stomach) who were diagnosed with venous thromboembolism (VTE) and had a prescription of either a LMWH (dalteparin/enoxaparin) or a DOAC (rivaroxaban/edoxaban/ apixaban/dabigatran) were included in the cohort. Patients had to be age >=66 at the time of VTE diagnosis and continuously enrolled in Medicare parts A, B & D one year before the VTE diagnosis. An intention to treat approach was employed in which patients were categorized into either LMWH or the DOAC group depending on the first anticoagulant a patient was started on post CAT diagnosis. Multivariable logistic regression was employed to identify significant factors associated with the use of DOACs versus LMWHs. Patients were followed for 12 months and time to recurrent VTE and bleeding events between these two cohorts were compared using Cox Proportional Hazards Regression and Kaplan Meier Curves. Both the cohorts were balanced for their baseline differences using Inverse Probability of Treatment Weighting (IPTW) approach. Different sensitivity analyses were carried out to assess the robustness of the results. Results: The study cohort included 4892 LMWH and 5080 DOAC treated patients. Patients with more advanced (distant) cancer (OR=0.54, 95% CI=0.41-0.70) were significantly less likely to receive a DOAC as compared patients in the initial stages (In-Situ). Certain cancer types including breast (OR=1.93, 95% CI=1.65-2.25), colorectal (OR=1.50, 95% CI=1.18-1.90) and prostate (OR=2.12, 95% CI=1.77-2.52) were more likely than lung cancer patients to be prescribed DOACs. Patients were significantly more likely to be prescribed a DOAC in 2019 (OR=106.39, 95% CI= 42.19-268.28) and the more recent years as compared to 2011. Rate of recurrent VTE were found to be lower in DOAC patients in comparison to patients on LMWH (HR=0.66, 95% CI=0.54-0.81) in the intent to treat analysis as well as in the different sensitivity analyses. A significant reduction in the risk of major bleeding (HR=0.84, 95% CI=0.73-0.96) was found in the DOAC cohort in the intention to treat analysis, however when patients were censored at discontinuation/treatment switch and observation period was truncated to 12 months the two groups had similar bleeding rates. Conclusion: This study suggests that cancer patients on DOACs had significantly lower rates of recurrent VTE, however bleeding rates were found to be similar. Even in the absence of a consistent clinical guideline physicians have been prescribing DOACs to patients with CAT possibly due to the availability of safety data from clinical trials in the recent years. More research needs to be done on a larger population with more cancer types to assess its effectiveness in a larger cancer population

A naturalistic observation study of medication counseling practices at retail chain pharmacies

Objective: This study evaluated medication counseling procedures and trends at retail pharmacies in the Houston metropolitan area through a naturalistic observational study. Methods: A blinded cross-sectional observational study was conducted at retail pharmacies in the Houston metropolitan area. Data were collected by trained observers utilizing an observational log, to record various parameters that could have an impact on the duration of patient-pharmacist interaction in a naturalistic pharmacy practice setting. Additionally, indicators of counseling such as utilization of the counseling window and performance of show-and-tell were recorded. Statistical analyses included descriptive statistics, t-tests, Pearson correlations, ANOVAs, and multiple linear regressions. Results: One hundred and sixty-five interactions between patients and pharmacy staff were recorded at 45 retail pharmacies from 7 retail pharmacy chains. The counseling window was utilized in only 3 (1.81%) out of 165 observations and the show-and-tell process was observed in just 1(0.61%) interaction during this study. Mean (SD) interaction time between patient and pharmacists [159.50 (84.50)] was not statistically different (p>0.05) from the mean interaction time between patients and pharmacy technicians [139.30 (74.19)], irrespective of type of the retail chain observed. However, it was influenced by the number of patients waiting in queue. Patient wait time significantly differed by the time of the day the interaction was observed, weekends and weekdays had significantly different wait times and patient interaction times Multiple linear regression analyses indicated that, patient interaction time, pharmacy chain type, initial contact (pharmacist/technician), and time of the day, were significantly associated with patient wait time whereas patient wait time, pharmacy chain type, number of patients in queue, and number of pharmacy technician were significantly associated with interaction time. Conclusions: Our study found that the key indicators of counseling including the use of the counseling window and the show-and-tell process were absent, suggesting lack of adequate pharmacists counseling. Further studies are needed to evaluate the validity of this conclusion and the role of pharmacy services and its value towards medication use and safety

Table3_Screening of GPCR drugs for repurposing in breast cancer.XLSX

Drug repurposing can overcome both substantial costs and the lengthy process of new drug discovery and development in cancer treatment. Some Food and Drug Administration (FDA)-approved drugs have been found to have the potential to be repurposed as anti-cancer drugs. However, the progress is slow due to only a handful of strategies employed to identify drugs with repurposing potential. In this study, we evaluated GPCR-targeting drugs by high throughput screening (HTS) for their repurposing potential in triple-negative breast cancer (TNBC) and drug-resistant human epidermal growth factor receptor-2-positive (HER2+) breast cancer (BC), due to the dire need to discover novel targets and drugs in these subtypes. We assessed the efficacy and potency of drugs/compounds targeting different GPCRs for the growth rate inhibition in the following models: two TNBC cell lines (MDA-MB-231 and MDA-MB-468) and two HER2+ BC cell lines (BT474 and SKBR3), sensitive or resistant to lapatinib + trastuzumab, an effective combination of HER2-targeting therapies. We identified six drugs/compounds as potential hits, of which 4 were FDA-approved drugs. We focused on β-adrenergic receptor-targeting nebivolol as a candidate, primarily because of the potential role of these receptors in BC and its excellent long-term safety profile. The effects of nebivolol were validated in an independent assay in all the cell line models. The effects of nebivolol were independent of its activation of β3 receptors and nitric oxide production. Nebivolol reduced invasion and migration potentials which also suggests its inhibitory role in metastasis. Analysis of the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset found numerically but not statistically significant reduced risk of all-cause mortality in the nebivolol group. In-depth future analyses, including detailed in vivo studies and real-world data analysis with more patients, are needed to further investigate the potential of nebivolol as a repurposed therapy for BC.</p

DataSheet2_Screening of GPCR drugs for repurposing in breast cancer.PDF

Drug repurposing can overcome both substantial costs and the lengthy process of new drug discovery and development in cancer treatment. Some Food and Drug Administration (FDA)-approved drugs have been found to have the potential to be repurposed as anti-cancer drugs. However, the progress is slow due to only a handful of strategies employed to identify drugs with repurposing potential. In this study, we evaluated GPCR-targeting drugs by high throughput screening (HTS) for their repurposing potential in triple-negative breast cancer (TNBC) and drug-resistant human epidermal growth factor receptor-2-positive (HER2+) breast cancer (BC), due to the dire need to discover novel targets and drugs in these subtypes. We assessed the efficacy and potency of drugs/compounds targeting different GPCRs for the growth rate inhibition in the following models: two TNBC cell lines (MDA-MB-231 and MDA-MB-468) and two HER2+ BC cell lines (BT474 and SKBR3), sensitive or resistant to lapatinib + trastuzumab, an effective combination of HER2-targeting therapies. We identified six drugs/compounds as potential hits, of which 4 were FDA-approved drugs. We focused on β-adrenergic receptor-targeting nebivolol as a candidate, primarily because of the potential role of these receptors in BC and its excellent long-term safety profile. The effects of nebivolol were validated in an independent assay in all the cell line models. The effects of nebivolol were independent of its activation of β3 receptors and nitric oxide production. Nebivolol reduced invasion and migration potentials which also suggests its inhibitory role in metastasis. Analysis of the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset found numerically but not statistically significant reduced risk of all-cause mortality in the nebivolol group. In-depth future analyses, including detailed in vivo studies and real-world data analysis with more patients, are needed to further investigate the potential of nebivolol as a repurposed therapy for BC.</p

Table1_Screening of GPCR drugs for repurposing in breast cancer.XLSX

Drug repurposing can overcome both substantial costs and the lengthy process of new drug discovery and development in cancer treatment. Some Food and Drug Administration (FDA)-approved drugs have been found to have the potential to be repurposed as anti-cancer drugs. However, the progress is slow due to only a handful of strategies employed to identify drugs with repurposing potential. In this study, we evaluated GPCR-targeting drugs by high throughput screening (HTS) for their repurposing potential in triple-negative breast cancer (TNBC) and drug-resistant human epidermal growth factor receptor-2-positive (HER2+) breast cancer (BC), due to the dire need to discover novel targets and drugs in these subtypes. We assessed the efficacy and potency of drugs/compounds targeting different GPCRs for the growth rate inhibition in the following models: two TNBC cell lines (MDA-MB-231 and MDA-MB-468) and two HER2+ BC cell lines (BT474 and SKBR3), sensitive or resistant to lapatinib + trastuzumab, an effective combination of HER2-targeting therapies. We identified six drugs/compounds as potential hits, of which 4 were FDA-approved drugs. We focused on β-adrenergic receptor-targeting nebivolol as a candidate, primarily because of the potential role of these receptors in BC and its excellent long-term safety profile. The effects of nebivolol were validated in an independent assay in all the cell line models. The effects of nebivolol were independent of its activation of β3 receptors and nitric oxide production. Nebivolol reduced invasion and migration potentials which also suggests its inhibitory role in metastasis. Analysis of the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset found numerically but not statistically significant reduced risk of all-cause mortality in the nebivolol group. In-depth future analyses, including detailed in vivo studies and real-world data analysis with more patients, are needed to further investigate the potential of nebivolol as a repurposed therapy for BC.</p

DataSheet3_Screening of GPCR drugs for repurposing in breast cancer.PDF

Drug repurposing can overcome both substantial costs and the lengthy process of new drug discovery and development in cancer treatment. Some Food and Drug Administration (FDA)-approved drugs have been found to have the potential to be repurposed as anti-cancer drugs. However, the progress is slow due to only a handful of strategies employed to identify drugs with repurposing potential. In this study, we evaluated GPCR-targeting drugs by high throughput screening (HTS) for their repurposing potential in triple-negative breast cancer (TNBC) and drug-resistant human epidermal growth factor receptor-2-positive (HER2+) breast cancer (BC), due to the dire need to discover novel targets and drugs in these subtypes. We assessed the efficacy and potency of drugs/compounds targeting different GPCRs for the growth rate inhibition in the following models: two TNBC cell lines (MDA-MB-231 and MDA-MB-468) and two HER2+ BC cell lines (BT474 and SKBR3), sensitive or resistant to lapatinib + trastuzumab, an effective combination of HER2-targeting therapies. We identified six drugs/compounds as potential hits, of which 4 were FDA-approved drugs. We focused on β-adrenergic receptor-targeting nebivolol as a candidate, primarily because of the potential role of these receptors in BC and its excellent long-term safety profile. The effects of nebivolol were validated in an independent assay in all the cell line models. The effects of nebivolol were independent of its activation of β3 receptors and nitric oxide production. Nebivolol reduced invasion and migration potentials which also suggests its inhibitory role in metastasis. Analysis of the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset found numerically but not statistically significant reduced risk of all-cause mortality in the nebivolol group. In-depth future analyses, including detailed in vivo studies and real-world data analysis with more patients, are needed to further investigate the potential of nebivolol as a repurposed therapy for BC.</p

DataSheet1_Screening of GPCR drugs for repurposing in breast cancer.PDF

Drug repurposing can overcome both substantial costs and the lengthy process of new drug discovery and development in cancer treatment. Some Food and Drug Administration (FDA)-approved drugs have been found to have the potential to be repurposed as anti-cancer drugs. However, the progress is slow due to only a handful of strategies employed to identify drugs with repurposing potential. In this study, we evaluated GPCR-targeting drugs by high throughput screening (HTS) for their repurposing potential in triple-negative breast cancer (TNBC) and drug-resistant human epidermal growth factor receptor-2-positive (HER2+) breast cancer (BC), due to the dire need to discover novel targets and drugs in these subtypes. We assessed the efficacy and potency of drugs/compounds targeting different GPCRs for the growth rate inhibition in the following models: two TNBC cell lines (MDA-MB-231 and MDA-MB-468) and two HER2+ BC cell lines (BT474 and SKBR3), sensitive or resistant to lapatinib + trastuzumab, an effective combination of HER2-targeting therapies. We identified six drugs/compounds as potential hits, of which 4 were FDA-approved drugs. We focused on β-adrenergic receptor-targeting nebivolol as a candidate, primarily because of the potential role of these receptors in BC and its excellent long-term safety profile. The effects of nebivolol were validated in an independent assay in all the cell line models. The effects of nebivolol were independent of its activation of β3 receptors and nitric oxide production. Nebivolol reduced invasion and migration potentials which also suggests its inhibitory role in metastasis. Analysis of the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset found numerically but not statistically significant reduced risk of all-cause mortality in the nebivolol group. In-depth future analyses, including detailed in vivo studies and real-world data analysis with more patients, are needed to further investigate the potential of nebivolol as a repurposed therapy for BC.</p

Table2_Screening of GPCR drugs for repurposing in breast cancer.XLSX

Drug repurposing can overcome both substantial costs and the lengthy process of new drug discovery and development in cancer treatment. Some Food and Drug Administration (FDA)-approved drugs have been found to have the potential to be repurposed as anti-cancer drugs. However, the progress is slow due to only a handful of strategies employed to identify drugs with repurposing potential. In this study, we evaluated GPCR-targeting drugs by high throughput screening (HTS) for their repurposing potential in triple-negative breast cancer (TNBC) and drug-resistant human epidermal growth factor receptor-2-positive (HER2+) breast cancer (BC), due to the dire need to discover novel targets and drugs in these subtypes. We assessed the efficacy and potency of drugs/compounds targeting different GPCRs for the growth rate inhibition in the following models: two TNBC cell lines (MDA-MB-231 and MDA-MB-468) and two HER2+ BC cell lines (BT474 and SKBR3), sensitive or resistant to lapatinib + trastuzumab, an effective combination of HER2-targeting therapies. We identified six drugs/compounds as potential hits, of which 4 were FDA-approved drugs. We focused on β-adrenergic receptor-targeting nebivolol as a candidate, primarily because of the potential role of these receptors in BC and its excellent long-term safety profile. The effects of nebivolol were validated in an independent assay in all the cell line models. The effects of nebivolol were independent of its activation of β3 receptors and nitric oxide production. Nebivolol reduced invasion and migration potentials which also suggests its inhibitory role in metastasis. Analysis of the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset found numerically but not statistically significant reduced risk of all-cause mortality in the nebivolol group. In-depth future analyses, including detailed in vivo studies and real-world data analysis with more patients, are needed to further investigate the potential of nebivolol as a repurposed therapy for BC.</p

Table4_Screening of GPCR drugs for repurposing in breast cancer.XLSX

Drug repurposing can overcome both substantial costs and the lengthy process of new drug discovery and development in cancer treatment. Some Food and Drug Administration (FDA)-approved drugs have been found to have the potential to be repurposed as anti-cancer drugs. However, the progress is slow due to only a handful of strategies employed to identify drugs with repurposing potential. In this study, we evaluated GPCR-targeting drugs by high throughput screening (HTS) for their repurposing potential in triple-negative breast cancer (TNBC) and drug-resistant human epidermal growth factor receptor-2-positive (HER2+) breast cancer (BC), due to the dire need to discover novel targets and drugs in these subtypes. We assessed the efficacy and potency of drugs/compounds targeting different GPCRs for the growth rate inhibition in the following models: two TNBC cell lines (MDA-MB-231 and MDA-MB-468) and two HER2+ BC cell lines (BT474 and SKBR3), sensitive or resistant to lapatinib + trastuzumab, an effective combination of HER2-targeting therapies. We identified six drugs/compounds as potential hits, of which 4 were FDA-approved drugs. We focused on β-adrenergic receptor-targeting nebivolol as a candidate, primarily because of the potential role of these receptors in BC and its excellent long-term safety profile. The effects of nebivolol were validated in an independent assay in all the cell line models. The effects of nebivolol were independent of its activation of β3 receptors and nitric oxide production. Nebivolol reduced invasion and migration potentials which also suggests its inhibitory role in metastasis. Analysis of the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset found numerically but not statistically significant reduced risk of all-cause mortality in the nebivolol group. In-depth future analyses, including detailed in vivo studies and real-world data analysis with more patients, are needed to further investigate the potential of nebivolol as a repurposed therapy for BC.</p