Biology subjects

Pecoraro, C.

Publications and source records attributed to Pecoraro, C..

3 recordsLinked to original sources

bioRxiv2024

Exploring the therapeutic potential of a novel series of imidazothiadiazoles targeting focal adhesion kinase (FAK) for pancreatic cancer treatment: Synthesis, mechanistic Insights and promising antitumor and safety profile

Focal Adhesion Kinase (FAK) is a non-receptor protein tyrosine kinase that plays a crucial role in various oncogenic processes related to cell adhesion, migration, proliferation, and survival. The strategic targeting of FAK represents a burgeoning approach to address resistant tumors, such as pancreatic ductal adenocarcinoma (PDAC). Herein, we report a new series of twenty imidazo[2,1-b][1,3,4]thiadiazole derivatives assayed for their antiproliferative activity against the National Cancer Institute (NCI-60) panel and a wide panel of PDAC models. Lead compound 10l exhibited effective antiproliferative activity against immortalized (SUIT-2, CAPAN-1, PANC-1, PATU-T, BxPC-3), primary (PDAC-3) and gemcitabine-resistant clone (PANC-1-GR) PDAC cells, eliciting IC50 values in the low micromolar range (1.04-3.44 {micro}M), associated with a significant reduction in cell-migration and spheroid shrinkage in vitro. High-throughput kinase arrays revealed a significant inhibition of the FAK signalling network, associated to induction of cell cycle arrest in G2/M phase, suppression of tumor cell invasion and apoptosis induction. The low selectivity index/toxicity prompted studies using PDAC mouse xenografts, demonstrating significant inhibition of tumor growth and safety. In conclusion, compound 10l displayed antitumor activity and safety in both in vitro and in vivo models, emerging as a highly promising lead for the development of FAK inhibitors in PDAC.

cancer biology↗

bioRxiv2024

The Cyclin-Like Protein Spy1 Mediates Tumourigenic Potential of Triple Negative Breast Cancer

Triple negative breast cancer is an aggressive subtype of breast cancer that relies on systemic chemotherapy as its primary means of treatment. Cell cycle regulators are enriched in drug resistant forms of the disease supporting the potential of targeting cell cycle checkpoints as a therapeutic direction to re-sensitize patients to treatment. Spy1 is an atypical cyclin-like protein that can override cell cycle checkpoints and is elevated in triple negative breast cancer. We report for the first time the effects of CRISPR-Cas9 mediated knockout of Spy1 on functional characteristics of triple negative breast cancer cells and perform unbiased analysis of protein expression to assess global changes in expression which correlate with functional changes in cell properties. Loss of Spy1 reduced rates of proliferation, decreased metastatic potential, and led to a reduction in stemness properties of triple negative breast cancer cells. Importantly, knockout of Spy1 delayed tumour onset in an in vivo model and significantly increased response to chemotherapy, pushing cells towards a senescent state. This data reveals that changes in expression of proteins that are not essential for proliferation and only transiently expressed can have significant impacts on cell dynamics and provides support for targeting the Spy1-CDK2 complex as a new therapeutic avenue in triple negative breast cancer. Statement of SignificanceTargeting the atypical cell cycle regulator Spy1 induces senescence and increases responsiveness of triple negative breast cancer to standard of care chemotherapy.

cancer biology↗

bioRxiv2023

Teaching transposon classification as a means to crowd source the curation of repeat annotation - a tardigrade perspective

The advancement of sequencing technologies results in the rapid release of hundreds of new genome assemblies a year providing unprecedented resources for the study of genome evolution. Within this context, the significance of in-depth analyses of repetitive elements, transposable elements (TEs) in particular, is increasingly recognized in understanding genome evolution. Despite the plethora of available bioinformatic tools for identifying and annotating TEs, the phylogenetic distance of the target species from a curated and classified database of repetitive element sequences constrains any automated annotation effort. Manual curation of raw repeat libraries is deemed essential due to the frequent incompleteness of automatically generated consensus sequences. However, manual curation and classification are time-consuming processes that offer limited short-term academic rewards and are typically confined to a few research groups where methods are taught through hands-on experience. Crowd sourcing efforts could offer a significant opportunity to bridge the gap between learning the methods of curation effectively and empowering the scientific community with high-quality, reusable repeat libraries. Here, we present an example of such crowd sourcing effort developed through both in-person and online courses built around a collaborative peer-reviewed teaching process that can be used as teaching reference guide for similar projects. The collaborative manual curation of TEs from two tardigrade species, for which there were no TE libraries available, resulted in the successful characterization of hundreds of new and diverse TEs: A hidden treasure awaits discovery within non-model organisms.

evolutionary biology↗