BACKGROUND: Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors exhibit promising activity against ovarian cancers, but their efficacy can be limited by acquired drug resistance. This study explores the role of autophagy in regulating the sensitivity of ovarian cancer cells to PARP inhibitors. METHODS: Induction of autophagy was detected by punctate LC3 fluorescence staining, LC3I to LC3II conversion on Western blot analysis, and electron microscopy. Enhanced growth inhibition and apoptosis were observed when PARP inhibitors were used with hydroxychloroquine, chloroquine (CQ), or LYS05 to block the hydrolysis of proteins and lipids in autophagosomes or with small interfering RNA against ATG5 or ATG7 to prevent the formation of autophagosomes. The preclinical efficacy of the combination of CQ and olaparib was evaluated with a patient-derived xenograft (PDX) and the OVCAR8 human ovarian cancer cell line. RESULTS: Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) induced autophagy in a panel of ovarian cancer cells. Inhibition of autophagy with CQ enhanced the sensitivity of ovarian cancer cells to PARP inhibitors. In vivo, olaparib and CQ produced additive growth inhibition in OVCAR8 xenografts and a PDX. Olaparib inhibited PARP activity, and this led to increased reactive oxygen species (ROS) and an accumulation of γ-H2AX. Inhibition of autophagy also increased ROS and γ-H2AX and enhanced the effect of olaparib on both entities. Treatment with olaparib increased phosphorylation of ATM and PTEN while decreasing the phosphorylation of AKT and mTOR and inducing autophagy. CONCLUSIONS: PARP inhibitor-induced autophagy provides an adaptive mechanism of resistance to PARP inhibitors in cancer cells with wild-type BRCA, and a combination of PARP inhibitors with CQ or other autophagy inhibitors could improve outcomes for patients with ovarian cancer. Cancer 2020;126:894-907.
#2048 Background: The presence of disseminated tumor cells (DTC) in the bone marrow is associated with an increased risk for subsequent bone metastases. Bisphosphonates reduce the occurence of bone metastases in patients (pts) with primary breast cancer (BC) with DTC. The aim of this trial was to evaluate the effect of adjuvant zoledronic acid (ZOL) on DTC in the bone marrow and the Patients and methods: Eligibilty criteria for this prospective, randomized multicenter trial were primary BC pts (pT1-4, N1-2, M0) with positive bone marrow status as determined by a standardized immunocytochemistry staining procedure. Ninety-eight pts were enrolled between April 2002 and January 2006. Randomization and medication had to be started within 28 days of primary surgery. Consenting pts were randomized to the treatment arm (ZOL 4mg i.v. q 4 weekly) or control arm. During the study, all pts received adjuvant treatment in the form of chemotherapy ± hormonal therapy or hormonal therapy alone. Bone marrow aspirations were performed to analyze the presence of DTC at surgery (baseline) and 12 months later. Efficacy and tolerability of intravenous ZOL in pts with primary Result: Bone marrow status was available for 76 patients both at baseline and 12 months after surgery. At baseline a median of 2.0 / range 1-6 (mean 2.1±1.1) DTC were detected in the ZOL group and a median of 2.0 / range 1-35 (mean 2.9±5.5) DTC in the control group. In both groups the number of detected tumor cells decreased during the 12 months follow-up with 0.5±0.8 (median 0.0; 0-2) DTC in the ZOL group and 0.9±0.8 (median 1.0; 0-2) DTC in the control group. By ANCOVA analysis a trend was seen towards a reduction of the number of DTC in the ZOL group compared with the control group (p=0.066). In addition, bone marrow-positive pts treated with ZOL were more likely to become bone marrow negative after 12 months (66.7% versus 35.1%, (p=0.009) compared to the control group. Most frequently reported AEs were musculoskeletal,arthralgia and myalgia in Conclusions: In this first prospective, randomized, multicenter trial we were able to show, that both treatment groups have a reduction in the number of DTC after 12 months as compared to baseline. There is a tendency to more reduction of DTC in the ZOL group. More pts under ZOL achieved a change from positive to negative bone marrow status than controls (p=0.009). Treatment with ZOL was safe and well tolerated. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2048.
Background: School-supervised asthma therapy improves asthma medication adherence and morbidity, particularly among low-income and underrepresented minority (URM) children. However, COVID-19-related school closures abruptly suspended this therapy. In response, we developed a school-linked text message intervention.Objective: The purpose of the study is to investigate the feasibility and acceptability of a school-linked text message intervention.Methods: In December 2020, children previously enrolled in school-supervised asthma therapy in Central Massachusetts were recruited into this school-linked text message intervention. We sent two-way, automated, daily text reminders in English or Spanish to caregivers of these children, asking if they had given their child their daily preventive asthma medicine. Our study team notified the school nurse if the caregiver did not consistently respond to text messages. School nurses performed weekly remote check-ins with all families. The primary outcome of the study was feasibility: recruitment, retention, and intervention fidelity. Secondarily we examined intervention acceptability and asthma health outcomes.Results: Twenty-six children (54% male, 69% Hispanic, 8% Black, 23% White, 93% Medicaid insured) and their caregivers were enrolled in the intervention with 96% participant retention at 6 months. Caregiver response rate to daily text messages was 81% over the study period. Children experienced significant improvements in asthma health outcomes. The intervention was well accepted by nurses and caregivers. Conclusion:A school-linked text messaging intervention for pediatric asthma is feasible and acceptable. This simple, accessible intervention may improve health outcomes for low-income and URM children with asthma. It merits further study as a potential strategy to advance health equity.
Purpose: Anaplastic Lymphoma Kinase (ALK) aberrations have been identified in pediatric type infant gliomas, but their occurrence across age groups, functional effects, and treatment response have not been broadly established. Experimental Design: We performed a comprehensive analysis of ALK expression and genomic aberrations in both newly generated and retrospective data from 371 glioblastomas (156 adult, 205 infant/pediatric and 10 congenital) with in vitro and in vivo validation of aberrations. Results: ALK aberrations at the protein or genomic level were detected in 12% of gliomas (45/371) in a wide age range (0-80 years). Recurrent as well as novel ALK fusions (LRRFIP1-ALK, DCTN1-ALK, PRKD3-ALK) were present in 50% (5/10) of congenital/infant, 1.4% (3/205) of pediatric, and 1.9% (3/156) of adult GBMs. ALK fusions were present as the only candidate driver in congenital/infant GBMs and were sometimes focally amplified. In contrast, adult ALK fusions co-occurred with other oncogenic drivers. No activating ALK mutations were identified in any age group. Novel and recurrent ALK rearrangements promoted STAT3 and ERK1/2 pathways and transformation in vitro and in vivo.ALK-fused GBM cellular and mouse models were responsive to ALK inhibitors, including in patient cells derived from a congenital GBM. Relevant to treatment of infant gliomas, we showed that ALK protein appears minimally expressed in the forebrain at perinatal stages and no gross effects on perinatal brain development was seen in pregnant mice treated with the ALK inhibitor ceritinib. Conclusions:These findings support use of brain-penetrant ALK inhibitors in clinical trials across infant, pediatric, and adult GBMs.
Background The majority of breast cancer patients suffer from persistent impairments after completion of their primary oncological therapy. Cancer-related fatigue (CRF) in particular is a multidimensional syndrome having a profound negative impact on the quality of life. To counter CRF symptoms, physical activities are suggested as first-line interventions, mind-body therapies have been shown to be effective, and music therapy can also reduce anxiety and stress in breast cancer patients. Tango therapy that combines various elements can have an impact on physical, psychological, and cognitive abilities and could therefore have a beneficial effect on breast cancer patients. The purpose of this study is to investigate whether a 6-week tango module is suited as a therapeutic approach for people after primary breast cancer therapy to favorably influence their quality of life, especially CRF levels. Methods Sixty patients with a diagnosis for stage I–III breast cancer 12–48 months before enrollment and with CRF (age > 18) will be recruited and randomized 1:1 to a tango or a waiting-list group. Movement concepts using elements of Argentine tango (self-awareness, musical and spatial perception, self-perception, playfulness, shared experience) will be examined with the participants during six consecutive weekly 1-h tango sessions. The primary outcome will be the improvement of CRF (German version of the Cancer Fatigue Scale), and the secondary outcomes will be the improvement in sleep quality (Pittsburgh Sleep Quality Index) and quality of life (EORTC-QLQ-C30). Patient-reported outcomes will be measured at baseline and 6 weeks later; follow-up will be performed 6, 12, and 24 months after baseline. An evaluation will be performed by means of descriptive data analyses. Discussion Argentine tango, as a music-based movement therapy, can influence different skills and may improve several outcomes. The therapeutic use of Argentine tango in the care of breast cancer patients has not yet been reported. It is anticipated that participants receiving the tango module will have improved CRF, sleep, and quality of life scores compared to a waitlist control. Trial registration German Clinical Trials Registry (DRKS) DRKS00021601. Retrospectively registered on 21 August 2020
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.