Enhanced Antitumoral Activity of Encapsulated BET Inhibitors When Combined with PARP Inhibitors for the Treatment of Triple-Negative Breast and Ovarian Cancers

Abstract

Simple Summary Poly (adenosine diphosphate ribose) polymerase inhibitors (PARPis) have demonstrated antitumoral activity in several cancers harbouring germline and somatic BRCA1/2 mutations. The widespread use of these agents in clinical practice is restricted by the development of acquired resistance due to the presence of compensatory pathways. A strategy to deal with this is the use of combination therapies with drugs that act synergistically against the tumour. BETis can completely disrupt the HR pathway by repressing the expression of BRCA1 and could be aimed at generation combination regimes to overcome PARPi resistance and enhance PARPi efficacy. However, this strategy is hampered by the poor pharmacokinetic profile and short half-life of BETis. In this work and as a proof of concept, we discuss the potential preclinical benefit provided by the combination of the PARPi olaparib and the BET inhibitor JQ1 encapsulated into nanoparticles for the treatment of BRCAness tumours. Abstract BRCA1/2 protein-deficient or mutated cancers comprise a group of aggressive malignancies. Although PARPis have shown considerably efficacy in their treatment, the widespread use of these agents in clinical practice is restricted by various factors, including the development of acquired resistance due to the presence of compensatory pathways. BETis can completely disrupt the HR pathway by repressing the expression of BRCA1 and could be aimed at generation combination regimes to overcome PARPi resistance and enhance PARPi efficacy. Due to the poor pharmacokinetic profile and short half-life, the first-in-class BETi JQ1 was loaded into newly developed nanocarrier formulations to improve the effectivity of olaparib for the treatment of BRCAness cancers. First, polylactide polymeric nanoparticles were generated by double emulsion. Moreover, liposomes were prepared by ethanol injection and evaporation solvent method. JQ1-loaded drug delivery systems display optimal hydrodynamic radii between 60 and 120 nm, with a very low polydispersity index (PdI), and encapsulation efficiencies of 92 and 16% for lipid- and polymeric-based formulations, respectively. Formulations show high stability and sustained release. We confirmed that all assayed JQ1 formulations improved antiproliferative activity compared to the free JQ1 in models of ovarian and breast cancers. In addition, synergistic interaction between JQ1 and JQ1-loaded nanocarriers and olaparib evidenced the ability of encapsulated JQ1 to enhance antitumoral activity of PARPis.

Chemical inhibition of bromodomain proteins in insect stage African trypanosomes perturbs silencing of the Variant Surface Glycoprotein repertoire and results in widespread changes in the transcriptome

“…Bromodomain inhibitors have garnered quite a bit of attention in recent years because of their potential as anti-cancer therapeutics. BET inhibitors have been shown to inhibit tumor growth in a number of models, including Acute Myeloid Leukemia (AML) [33][34][35][36][37] , prostate cancer 38 , neuroblastoma 39 , and breast cancer 40 . In parasites, bromodomain inhibitors have been shown to bind to bromodomain proteins in T. brucei, T. cruzi, P. falciparum, and L. dovani 23,27,[41][42][43][44] .…”

Chemical Inhibition of Bromodomain Proteins in Insect-Stage African Trypanosomes Perturbs Silencing of the Variant Surface Glycoprotein Repertoire and Results in Widespread Changes in the Transcriptome

“…Bromodomain inhibitors have garnered quite a bit of attention in recent years because of their potential as anticancer therapeutics. BET (bromodomain and extraterminal) inhibitors have been shown to inhibit tumor growth in a number of models, including acute myeloid leukemia (AML) ( 33 – 37 ), prostate cancer ( 38 ), neuroblastoma ( 39 ), and breast cancer ( 40 ). In parasites, bromodomain inhibitors have been shown to bind to bromodomain proteins in T. brucei , Trypanosoma cruzi , Plasmodium falciparum , and Leishmania donovani ( 23 , 27 , 41 – 44 ).…”

Anti-EGFR conjugated nanoparticles to deliver Alpelisib as targeted therapy for head and neck cancer

“…Loading efficiency (LE) and encapsulation efficiency (EE) of nanoparticles were determined using the nanoparticle destruction method (Cimas et al 2020;Juan et al 2022) and calculated by means of the following equations: LE % = (weight of encapsulated Alpelisib or DiR (mg))/(weight of total (Alpelisib or DiR encapsulated + scaffold weight) (mg)) × 100% EE % = (weight of encapsulated Alpelisib or DiR (mg))/(weight of Alpelisib or DiR feeding (mg)) × 100% Independent experiments were carried out 3 times and standard deviation calculated.…”