RESUMEN
ARID1A, an epigenetic tumor suppressor, is the most common gene mutation in clear-cell ovarian cancers (CCOCs). CCOCs are often resistant to standard chemotherapy and lack effective therapies. We hypothesized that ARID1A loss would increase CCOC cell dependency on chromatin remodeling and DNA repair pathways for survival. We demonstrate that combining BRD4 inhibitor (BRD4i) with DNA damage response inhibitors (ATR or WEE1 inhibitors; e.g. BRD4i-ATRi) was synergistic at low doses leading to decreased survival, and colony formation in CCOC in an ARID1A dependent manner. BRD4i-ATRi caused significant tumor regression and increased overall survival in ARID1AMUT but not ARID1AWT patient-derived xenografts. Combination BRD4i-ATRi significantly increased γH2AX, and decreased RAD51 foci and BRCA1 expression, suggesting decreased ability to repair DNA double-strand-breaks (DSBs) by homologous-recombination in ARID1AMUT cells, and these effects were greater than monotherapies. These studies demonstrate BRD4i-ATRi is an effective treatment strategy that capitalizes on synthetic lethality with ARID1A loss in CCOC.
RESUMEN
Purpose: PARP inhibition (PARPi) has modest clinical activity in recurrent BRCA-mutant (BRCAMUT) high-grade serous ovarian cancers (HGSOC). We hypothesized that PARPi increases dependence on ATR/CHK1 such that combination PARPi with ATR/CHK1 blockade results in increased cell death and tumor regression.Experimental Design: Effects of PARPi (olaparib), CHK1 inhibition (CHK1i;MK8776), or ATR inhibition (ATRi;AZD6738) alone or in combination on survival, colony formation, cell cycle, genome instability, and apoptosis were evaluated in BRCA1/2MUT HGSOC cells. Tumor growth in vivo was evaluated using a BRCA2MUT patient-derived xenograft (PDX) model.Results: PARPi monotherapy resulted in a decrease in BRCAMUT cell survival, colony formation and suppressed but did not eliminate tumor growth at the maximum tolerated dose (MTD) in a BRCA2MUT PDX. PARPi treatment increased pATR and pCHK1, indicating activation of the ATR-CHK1 fork protection pathway is relied upon for genome stability under PARPi. Indeed, combination of ATRi or CHK1i with PARPi synergistically decreased survival and colony formation compared with single-agent treatments in BRCAMUT cells. Notably, PARPi led to G2 phase accumulation, and the addition of ATRi or CHK1i released cells from G2 causing premature mitotic entry with increased chromosomal aberrations and apoptosis. Moreover, the combinations of PARPi with ATRi or CHK1i were synergistic in causing tumor suppression in a BRCA2MUT PDX with the PARPi-ATRi combination inducing tumor regression and in most cases, complete remission.Conclusions: PARPi causes increased reliance on ATR/CHK1 for genome stability, and combination PARPi with ATR/CHK1i is more effective than PARPi alone in reducing tumor burden in BRCAMUT models. Clin Cancer Res; 23(12); 3097-108. ©2016 AACR.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Neoplasias Ováricas/tratamiento farmacológico , Animales , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Proteína BRCA1/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Inestabilidad Genómica/efectos de los fármacos , Humanos , Indoles , Ratones , Terapia Molecular Dirigida , Morfolinas , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Sulfonamidas , Sulfóxidos/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The vulnerability of children in Haiti has increased dramatically since the earthquake in January 2010. Prior to the earthquake, the prevalence of orphans and at-risk children was high but since the earthquake, more than 1 million people-with more than 380,000 children remaining displaced and living in over 1200 displacement sites. These existing conditions leave orphans and at-risk children vulnerable to exploitation, abuse, and increased risk of HIV/AIDS. This article will focus on the complex issues affecting orphans and at-risk children and the intersection with HIV/AIDS and human rights. Specific recommendations by United Nations Children's Fund are discussed. Nursing in Haiti must address the policy-related and population-specific approaches for the care of children living with or affected by HIV/AIDS.