Identification of a Molecularly-Defined Subset of Breast and Ovarian Cancer Models that Respond to WEE1 or ATR Inhibition, Overcoming PARP Inhibitor Resistance

Cáncer de mama y de ovario; Inhibición WEE1Càncer de mama i d'ovari; Inhibició WEE1Breast and ovarian cancer; WEE1 inhibitionPurpose: PARP inhibitors (PARPi) induce synthetic lethality in homologous recombination repair (HRR)-deficient tumors and are used to treat breast, ovarian, pancreatic, and prostate cancers. Multiple PARPi resistance mechanisms exist, most resulting in restoration of HRR and protection of stalled replication forks. ATR inhibition was highlighted as a unique approach to reverse both aspects of resistance. Recently, however, a PARPi/WEE1 inhibitor (WEE1i) combination demonstrated enhanced antitumor activity associated with the induction of replication stress, suggesting another approach to tackling PARPi resistance. Experimental Design: We analyzed breast and ovarian patient-derived xenoimplant models resistant to PARPi to quantify WEE1i and ATR inhibitor (ATRi) responses as single agents and in combination with PARPi. Biomarker analysis was conducted at the genetic and protein level. Metabolite analysis by mass spectrometry and nucleoside rescue experiments ex vivo were also conducted in patient-derived models. Results: Although WEE1i response was linked to markers of replication stress, including STK11/RB1 and phospho-RPA, ATRi response associated with ATM mutation. When combined with olaparib, WEE1i could be differentiated from the ATRi/olaparib combination, providing distinct therapeutic strategies to overcome PARPi resistance by targeting the replication stress response. Mechanistically, WEE1i sensitivity was associated with shortage of the dNTP pool and a concomitant increase in replication stress. Conclusions: Targeting the replication stress response is a valid therapeutic option to overcome PARPi resistance including tumors without an underlying HRR deficiency. These preclinical insights are now being tested in several clinical trials where the PARPi is administered with either the WEE1i or the ATRi.This work was supported by the Spanish Instituto de Salud Carlos III (ISCIII), an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds (FIS PI17/01080 to V. Serra, PI12/02606 to J. Balmaña); European Research Area-NET, Transcan-2 (AC15/00063), Asociación Española contra el Cáncer (AECC; LABAE16020PORTT), the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR; 2017 SGR 540), La Marató TV3 (654/C/2019), and ERAPERMED2019–215 to V. Serra. We also acknowledge the GHD-Pink program, the FERO Foundation, and the Orozco Family for supporting this study (to V. Serra). V. Serra was supported by the Miguel Servet Program (ISCIII; CPII19/00033); M. Castroviejo-Bermejo and C. Cruz (AIOC15152806CRUZ) by AECC; A. Herencia-Ropero by Generalitat de Catalunya-PERIS (SLT017/20/000081); M. Palafox by Juan de la Cierva (FJCI-2015–25412); A. Lau by AECC and Generalitat de Catalunya-PERIS (INVES20095LLOP, SLT002/16/00477); A. Gris-Oliver by FI-AGAUR (2015 FI_B 01075). This work was supported by Breast Cancer Research Foundation (BCRF-19–08), Instituto de Salud Carlos III Project Reference number AC15/00062, and the EC under the framework of the ERA-NET TRANSCAN-2 initiative co-financed by FEDER, Instituto de Salud Carlos III (CB16/12/00449 and PI19/01181), and Asociación Española Contra el Cáncer (to J. Arribas). The xenograft program in the Caldas laboratory was supported by Cancer Research UK and also received funding from an EU H2020 Network of Excellence (EuroCAN). The RPPA facility is funded by NCI #CA16672

High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer

Breast cancer; Cancer models; Predictive markersCáncer de mama; Modelos de cáncer; Marcadores predictivosCàncer de pulmó; Models de càncer; Marcadors predictiusCDK4/6 inhibitors combined with endocrine therapy have demonstrated higher antitumor activity than endocrine therapy alone for the treatment of advanced estrogen receptor-positive breast cancer. Some of these tumors are de novo resistant to CDK4/6 inhibitors and others develop acquired resistance. Here, we show that p16 overexpression is associated with reduced antitumor activity of CDK4/6 inhibitors in patient-derived xenografts (n = 37) and estrogen receptor-positive breast cancer cell lines, as well as reduced response of early and advanced breast cancer patients to CDK4/6 inhibitors (n = 89). We also identified heterozygous RB1 loss as biomarker of acquired resistance and poor clinical outcome. Combination of the CDK4/6 inhibitor ribociclib with the PI3K inhibitor alpelisib showed antitumor activity in estrogen receptor-positive non-basal-like breast cancer patient-derived xenografts, independently of PIK3CA, ESR1 or RB1 mutation, also in drug de-escalation experiments or omitting endocrine therapy. Our results offer insights into predicting primary/acquired resistance to CDK4/6 inhibitors and post-progression therapeutic strategies

Precariedad, exclusión social y diversidad funcional (discapacidad): lógicas y efectos subjetivos del sufrimiento social contemporáneo (III). Innovación docente en Filosofía

El PIMCD Precariedad, exclusión social y diversidad funcional (discapacidad): lógicas y efectos subjetivos del sufrimiento social contemporáneo (III). Innovación docente en Filosofía se ocupa de conceptos que generalmente han tendido a ser eludidos en la enseñanza académica de filosofía. Se trata de la tercera edición de un PIMCD que ha venido recibiendo financiación en las últimas convocatorias PIMCD UCM, de los que se han derivado publicaciones colectivas publicadas por Ediciones Complutense y Siglo XXI

Preparation of coated nanoparticles for a new mucosal vaccine delivery system

It has been found that the adsorption of antigens onto chitosan particles is an easy and unique mild loading process suitable to be used with vaccines. In order to increase the stability of this particles and to prevent an immediate desorption in gastrointestinal fluids, a coating process with sodium alginate was developed. One of the challenges of this developing process was to keep the particles in the nanosized range in order to be taken up by M-cells of the Peyer's patches. The observed inversion of the particles' zeta potential values after coating suggested the presence of an alginate coating layer. These results were confirmed by FTIR and DSC techniques. Additionally, in vitro release studies showed that the presence of the alginate layer around the particles was able to prevent a burst release of loaded ovalbumin and to improve the stability of the nanoparticles in simulated intestinal fluid at 37 °C. The optimisation of the coating process resulted in 35% (w/w) for the loading capacity of the coated particles. SEM investigations confirmed a suitable size of the coated nanoparticles for the uptake by M-cells.http://www.sciencedirect.com/science/article/B6T7W-4GJKTSJ-1/1/555d86da8f88d8d33ad90f6e41f68e2

Where Brain, Body and World Collide

The production cross section of electrons from semileptonic decays of beauty hadrons was measured at mid-rapidity (|y| < 0.8) in the transverse momentum range 1 < pt < 8 Gev/c with the ALICE experiment at the CERN LHC in pp collisions at a center of mass energy sqrt{s} = 7 TeV using an integrated luminosity of 2.2 nb^{-1}. Electrons from beauty hadron decays were selected based on the displacement of the decay vertex from the collision vertex. A perturbative QCD calculation agrees with the measurement within uncertainties. The data were extrapolated to the full phase space to determine the total cross section for the production of beauty quark-antiquark pairs