A5047370165- CRISPR and Genetic Engineering
- PI3K/AKT/mTOR signaling in cancer
- PARP inhibition in cancer therapy
- Advanced Breast Cancer Therapies
- DNA Repair Mechanisms
- Cancer-related Molecular Pathways
- BRCA gene mutations in cancer
- HER2/EGFR in Cancer Research
- Melanoma and MAPK Pathways
- Lung Cancer Treatments and Mutations
- Colorectal Cancer Treatments and Studies
- Monoclonal and Polyclonal Antibodies Research
- Microtubule and mitosis dynamics
- Cancer, Hypoxia, and Metabolism
- Prostate Cancer Treatment and Research
- Protein Kinase Regulation and GTPase Signaling
- Cancer Treatment and Pharmacology
- Chronic Lymphocytic Leukemia Research
- Head and Neck Cancer Studies
- Biotin and Related Studies
- Protein Degradation and Inhibitors
- Medical Imaging and Pathology Studies
- Breast Lesions and Carcinomas
- Multiple and Secondary Primary Cancers
- Fibroblast Growth Factor Research
Vall d'Hebron Institute of Oncology
2015-2025
Vall d'Hebron Institut de Recerca
2013-2024
Mexican Social Security Institute
2024
Vall d'Hebron Hospital Universitari
2010-2023
CIBBIM-Nanomedicine
2015-2022
Hebron University
2021
Georgetown University Medical Center
2020
Georgetown University
2020
Georgetown Lombardi Comprehensive Cancer Center
2017
Hospital de Cruces
2014
Small-molecule inhibitors of the CDK4/6 cell-cycle kinases have shown clinical efficacy in estrogen receptor (ER)-positive metastatic breast cancer, although their cytostatic effects are limited by primary and acquired resistance. Here we report that ER-positive cancer cells can adapt quickly to inhibition evade cytostasis, part, via noncanonical cyclin D1-CDK2-mediated S-phase entry. This adaptation was prevented cotreatment with hormone therapies or PI3K inhibitors, which reduced levels D1...
PARP inhibitors are active in tumors with defects DNA homologous recombination (HR) due to BRCA1/2 mutations. The phosphoinositide 3-kinase (PI3K) signaling pathway preserves HR steady state. We hypothesized that BRCA-proficient triple-negative breast cancer (TNBC), PI3K inhibition would result impairment and subsequent sensitization inhibitors. show TNBC cells leads damage, downregulation of BRCA1/2, gain poly-ADP-ribosylation, inhibition. In patient-derived primary tumor xenografts, dual...
There is a strong rationale to therapeutically target the phosphatidylinositol 3-kinase/protein kinase B/mammalian of rapamycin (PI3K/AKT/mTOR) pathway in breast cancer since it highly deregulated this disease and also mediates resistance anti-HER2 therapies. However, initial studies with rapalogs, allosteric inhibitors mTORC1, have resulted limited clinical efficacy probably due release negative regulatory feedback loop that triggers AKT ERK signaling. Since activation occurs via PI3K, we...
BackgroundBRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) enhanced sensitivity to DNA damaging agents or poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed clinical trials. Numerous mechanisms of PARPi resistance have described, whose relevance gBRCA-mutated cancer is unknown. This highlights the need identify functional biomarkers...
Clinical benefits from trastuzumab and other anti-HER2 therapies in patients with HER2 amplified breast cancer remain limited by primary or acquired resistance. To identify potential mechanisms of resistance, we established trastuzumab-resistant cells chronic exposure to treatment. Genomewide copy-number variation analyses the resistant compared parental revealed a focal amplification genomic DNA containing cyclin E gene. In cohort 34 + treated trastuzumab-based therapy, found that...
Research Article30 October 2018Open Access Source DataTransparent process A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation Marta Castroviejo-Bermejo Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain Search for more papers by this author Cristina Cruz High Risk and Familial Cancer Department Medical Hospital d'Hebron, Universitat Autònoma de Alba Llop-Guevara Sara Gutiérrez-Enríquez Oncogenetics Mandy Ducy...
The PI3K signaling pathway regulates diverse cellular processes, including proliferation, survival, and metabolism, is aberrantly activated in human cancer. As such, numerous compounds targeting the are currently being clinically evaluated for treatment of cancer, several have shown some early indications efficacy breast However, resistance against these agents, both de novo acquired, may ultimately limit compounds. Here, we taken a systematic functional approach to uncovering potential...
Abstract PARP inhibitors (PARPi) are approved drugs for platinum-sensitive, high-grade serous ovarian cancer (HGSOC) and breast, prostate, pancreatic cancers (PaC) harboring genetic alterations impairing homologous recombination repair (HRR). Detection of nuclear RAD51 foci in tumor cells is a marker HRR functionality, we previously established test to detect foci. Here, aimed validate the score cut off compare performance this other deficiency (HRD) detection methods. Laboratory models from...
Abstract CDK4/6 inhibitors combined with endocrine therapy have demonstrated higher antitumor activity than alone for the treatment of advanced estrogen receptor-positive breast cancer. Some these tumors are de novo resistant to and others develop acquired resistance. Here, we show that p16 overexpression is associated reduced in patient-derived xenografts ( n = 37) cancer cell lines, as well response early patients 89). We also identified heterozygous RB1 loss biomarker resistance poor...
Poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors (PARPi) are targeted therapies approved for homologous recombination repair (HRR)-deficient breast, ovarian, pancreatic, prostate cancers. Since inhibition of PARP1 is sufficient to cause synthetic lethality in tumors with deficiency (HRD), selective such as saruparib (AZD5305) being developed. It expected that leads a safer profile facilitates its combination other DNA damage inhibitors. Here, we aimed characterize the antitumor...
The oncogenic PI3K/Akt/mTOR pathway is an attractive therapeutic target in cancer. However, it unknown whether the blockade required for tumor growth inhibition clinically achievable. Therefore, we conducted pharmacodynamic studies with GDC-0068, ATP competitive, selective Akt1/2/3 inhibitor, preclinical models and patients treated this compound.We used a reverse phase protein array (RPPA) platform to identify biomarker set indicative of Akt cell lines human-tumor xenografts, correlated...
PARP inhibitors (PARPi) induce synthetic lethality in homologous recombination repair (HRR)-deficient tumors and are used to treat breast, ovarian, pancreatic, prostate cancers. Multiple PARPi resistance mechanisms exist, most resulting restoration of HRR protection stalled replication forks. ATR inhibition was highlighted as a unique approach reverse both aspects resistance. Recently, however, PARPi/WEE1 inhibitor (WEE1i) combination demonstrated enhanced antitumor activity associated with...
Abstract Homologous recombination deficiency (HRD) contributes to genomic instability and leads sensitivity poly ADP-ribose polymerase inhibitors (PARPi). HRD also activates the cyclic GMP–AMP synthase (cGAS)-STimulator of INterferon Genes (STING)-Interferon (IFN) pathway, highlighting need understand impact cGAS-STING-IFN signaling on PARPi efficacy. In this study, we analyzed a cohort thirty-five breast cancer (BC) patient-derived xenografts (PDX) mouse-derived allografts (MDA). correlated...
Hsp90 facilitates the maturation and stability of numerous oncoproteins, including HER2. The aim this study was to assess antitumor activity inhibitor IPI-504 in trastuzumab-resistant, HER2-overexpressing breast cancer cells. Therapy with trastuzumab, IPI-504, combination trastuzumab evaluated trastuzumab-sensitive trastuzumab-resistant Inhibition protein targets, cell proliferation, tumor growth assessed vitro xenograft models. inhibited proliferation both Administration markedly reduced...
Abstract Purpose: AZD5363/capivasertib is a pan-AKT catalytic inhibitor with promising activity in combination paclitaxel triple-negative metastatic breast cancer harboring PI3K/AKT-pathway alterations and estrogen receptor–positive fulvestrant. Here, we aimed to identify response biomarkers uncover mechanisms of resistance AZD5363 its paclitaxel. Experimental Design: Genetic proteomic markers were analyzed 28 HER2-negative patient-derived xenografts (PDXs) patient samples, correlated...
FGFR1 amplification (FGFR1amp) is recurrent in metastatic breast cancer (MBC) and associated with resistance to endocrine therapy CDK4/6 inhibitors (CDK4/6is). Multi-tyrosine kinase (MTKIs) selective pan-FGFR (FGFRis) are being developed for FGFR1amp cancer. High-level FGFR protein expression by IHC have identified responders FGFRis or MTKIs, respectively.Here, we used preclinical models patient samples identify predictive biomarkers these drugs. We evaluated the antitumor activity of an...
PI3K pathway activation occurs in concomitance with RAS/BRAF mutations colorectal cancer, limiting the sensitivity to targeted therapies. Several clinical studies are being conducted test tolerability and activity of dual MEK blockade solid tumors.In present study, we explored efficacy cancer preclinical models harboring concomitant ERK pathways. Moreover, investigated if TP53 mutation affects response this therapy.Dual mTORC1/2 resulted synergistic antiproliferative effects cell lines...
Abstract Triple‐negative breast cancer (TNBC) often develops resistance to single‐agent treatment, which can be circumvented using targeted combinatorial approaches. Here, we demonstrate that the simultaneous inhibition of LOXL2 and BRD4 synergistically limits TNBC proliferation in vitro vivo . Mechanistically, interacts nucleus with short isoform (BRD4S), MED1, cell cycle transcriptional regulator B‐MyB. These interactions sustain formation MED1 nuclear foci control progression at gene...
Aims & Objectives: Infections in the pediatric intensive care unit contribute significantly to morbidity and mortality infants. Our cardiovascular therapy unit, a regional referral center, faces delays transfers, exacerbating comorbidities, particularly post-cardiovascular surgery. Therefore, our aim is ensuring an antimicrobial regimen tailored most frequently reported pathogens paramount for patient improvement clinical discharge. Methods: A retrospective study spanning from 2021 2023...
Aims & Objectives: Background: The management of the systemic-to-pulmonary shunt (mBTS) continues to be a challenge in pediatric cardiovascular intensive care unit (PCICU). Mortality described worldwide varies between 2.3-16%. Pulmonary overcirculation is one main complications after mBTS procedure, associated with longer hospital stay, days on mechanical ventilation, acute kidney injury and sudden cardiac arrest. Therefore, early identification during PCICU stay essential for establishment...
Abstract Background: Although platinum salts (Pt) or Poly (ADP-Ribose) Polymerase inhibitors (PARPi) are effective in treating homologous recombination defective (HRD) breast cancer, resistance often emerges, especially advanced disease. Predicting response and relapse is complex, even patients with germline BRCA1/2 mutations (gBRCA1/2m). Clinically approved HRD detection methods limited to identification of pathogenic HR genes mutational signatures the genome tumors caused by HRD. In PDX...
Supplementary Data from Identification of a Molecularly-Defined Subset Breast and Ovarian Cancer Models that Respond to WEE1 or ATR Inhibition, Overcoming PARP Inhibitor Resistance
Abstract Ewing's Sarcoma Family of Tumors (ESFT) is an undifferentiated neoplasm the bone and soft tissue. ESFT characterized by a specific chromosomal translocation occurring between chromosome 22 (in most cases) 11, which generates aberrant transcription factor, EWS-FLI1. We have previously shown that GLI1 direct transcriptional target EWS-FLI1, important for tumorigenicity. Thus, potential therapeutic in ESFT. Arsenic Trioxide (ATO) FDA approved drug used treatment Acute Promyelocytic...