Biology subjects

Villanueva, A.

Publications and source records attributed to Villanueva, A..

23 records · Page 2Linked to original sources

bioRxiv2020

Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood and adolescence. Refractory/relapsed RMS patients present a bad prognosis that combined with the lack of specific biomarkers difficult the development of new therapies. We here utilize dynamic BH3 Profiling (DBP), a functional predictive biomarker that measures net changes in mitochondrial apoptotic signaling, to identify anti-apoptotic adaptations upon treatment. We use this information to guide the use of BH3 mimetics to specifically inhibit BCL-2 pro-survival proteins, defeat resistance and avoid relapse to therapy. Indeed, we found that BH3 mimetics that selectively target BCL-xL and MCL-1 synergistically enhance the effect of the clinically used chemotherapeutic agents vincristine and doxorubicin in RMS cells. We validated this strategy in vivo using a RMS patient-derived xenograft (PDX) model and observed a reduction on tumor growth with a tendency to its stabilization with the sequential combination of vincristine and the MCL-1 inhibitor S63845. Finally, we identified the molecular mechanism by which RMS cells acquire resistance to vincristine: through the anti-apoptotic protein MCL-1 for which we observed an enhanced binding between MCL-1 and BID after drug exposure, which is suppressed by the sequential addition of S63845. In conclusion, our findings validate the use of DBP as a functional assay to predict treatment effectiveness in RMS and provide a rationale for BH3 mimetic combination with chemotherapeutic agents to avoid tumor resistance, improve treatment efficiency and decrease undesired secondary effects.

cancer biology↗

bioRxiv2019

Multiple Low Dose therapy: an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours

Targeted cancer drugs often elicit powerful initial responses, but generally fail to deliver long-term benefit due to the emergence of resistant cells1,2. This is thought to be the consequence of strong selective pressure exerted on the cancer drug target by a Maximum Tolerated Dose (MTD) of a drug3-5. We hypothesized that partial inhibition of multiple components in the same oncogenic signalling pathway might add up to complete pathway inhibition, while at the same time decreasing the selective pressure on each individual component to acquire a resistance mutation. We report here testing of this Multiple Low Dose (MLD) model of drug administration in Epidermal Growth Factor Receptor (EGFR) mutant non-small cell lung cancer (NSCLC). We show that as little as 20% of the individual drug doses required for full inhibition of cell viability is sufficient to completely block MAPK signalling and proliferation when used in 3D (RAF+MEK+ERK inhibitors) or 4D (EGFR+RAF+MEK+ERK inhibitors) combinations. Importantly, EGFR mutant NSCLC cells treated with EGFR inhibitors at a high dose rapidly developed resistance in vitro, but the cells treated with 3D or 4D MLD therapy did not. Moreover, NSCLC cells that had gained resistance to high dose anti-EGFR therapies were still sensitive to MLD therapy. Using several animal models, including patient derived xenografts of NSCLC tumours that are resistant to EGFR inhibitors erlotinib and osimertinib6,7, we found durable responses to MLD therapy without associated toxicity. These data support the notion that partial inhibition of multiple components of cancer-activated signalling pathways is difficult to circumvent and suggest that MLD therapy could deliver clinical benefit. We propose that MLD strategy could be an effective treatment option for EGFR mutant NSCLC patients, especially those having acquired resistance to even third generation EGFR inhibitor therapy.

cancer biology↗

bioRxiv2019

Tumor fitness, immune exhaustion and clinical outcomes: impact of immune checkpoint inhibitors

Recently proposed tumor fitness measures, based on profiling neoepitopes for reactive viral epitope similarity, have been proposed to predict response to immune checkpoint inhibitors in melanoma and small-cell lung cancer. Here we apply these checkpoint based fitness measures measures to the matched checkpoint treatment naive TCGA samples where cytolytic activity imparts a known survival benefit. We observed no significant survival predictive power beyond that of overall patient tumor mutation burden, and furthermore, found no association between checkpoint based fitness and tumor T-cell infiltration, cytolytic activity (CYT), and abundance (TIL burden). In addition, we investigated the key assumption of viral epitope similarity driving immune response in the hepatitis B virally infected liver cancer TCGA cohort, and uncover suggestive evidence that tumor neoepitopes actually dominate viral epitopes in putative immunogenicity and plausibly drive immune response and recruitment.

cancer biology↗

bioRxiv2019

MS.liverK: an R package for transcriptome-based computation of molecular subtypes and functional signatures in liver cancer

SummaryLiver cancer is a highly heterogeneous disease in terms of etiology, tissue and cellular morphology, tumor molecular characteristics, microenvironment composition and prognosis. Several studies, based on tumor gene-expression profiling (GEP) data, have dissected the molecular heterogeneity of liver cancer. They resulted in various tools, either delineating homogeneous tumor subtypes or calculating molecular scores of prognostic or biological functions. Here, we present MS.liverK, an easy-to-use R package providing a comprehensive implementation of these tools, for research use. Availability and implementationThe MS.liverK R package is available from GitHub (https://github.com/cit-bioinfo/MS.liverK).

bioinformatics↗

bioRxiv2017

Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatin

Cisplatin and derivatives are commonly used as chemotherapeutic agents. Although the cytotoxic action of cisplatin on cancer cells is very efficient, clinical oncologists need to deal with two major difficulties: (i) the onset of resistance to the drug, and (ii) the cytotoxic effect in patients. Here we use Caenorhabditis elegans to investigate factors influencing the response to cisplatin in multicellular organisms. In this hermaphroditic model organism, we observed that sperm failure is a major cause in cisplatin-induced infertility. RNA-seq data indicate that cisplatin triggers a systemic stress response in which DAF-16/FOXO and SKN-1/Nrf2, two conserved transcription factors, are key regulators. We determined that inhibition of the DNA-damage induced apoptotic pathway does not confer cisplatin protection to the animal. However, mutants for the pro-apoptotic BH3-only gene ced-13 are sensitive to cisplatin, suggesting a protective role of the intrinsic apoptotic pathway. Finally, we demonstrate that our system can also be used to identify mutations providing resistance to cisplatin and therefore potential biomarkers of innate cisplatin-refractory patients. We show that mutants for the redox regulator trxr-1, ortholog of the mammalian Thioredoxin-Reductase-1 TrxR1, display cisplatin resistance and that such resistance relies on a single selenocysteine residue.

cancer biology↗