Publications by authors named "Gabriele De Rubis"

5 Publications

  • Page 1 of 1

Extracellular Vesicles in Chemoresistance.

Subcell Biochem 2021 ;97:211-245

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, Australia.

Chemotherapy represents the current mainstay therapeutic approach for most types of cancer. Despite the development of targeted chemotherapeutic strategies, the efficacy of anti-cancer drugs is severely limited by the development of drug resistance. Multidrug resistance (MDR) consists of the simultaneous resistance to various unrelated cytotoxic drugs and is one of the main causes of anticancer treatment failure. One of the principal mechanisms by which cancer cells become MDR involves the overexpression of ATP Binding Cassette (ABC) transporters, such as P-glycoprotein (P-gp), mediating the active efflux of cytotoxic molecules from the cytoplasm. Extracellular vesicles (EVs) are submicron lipid-enclosed vesicles that are released by all cells and which play a fundamental role in intercellular communication in physiological and pathological contexts. EVs have fundamental function at each step of cancer development and progression. They mediate the transmission of MDR through the transfer of vesicle cargo including functional ABC transporters as well as nucleic acids, proteins and lipids. Furthermore, EVs mediate MDR by sequestering anticancer drugs and stimulate cancer cell migration and invasion. EVs also mediate the communication with the tumour microenvironment and the immune system, resulting in increased angiogenesis, metastasis and immune evasion. All these actions contribute directly and indirectly to the development of chemoresistance and treatment failure. In this chapter, we describe the many roles EVs play in the acquisition and spread of chemoresistance in cancer. We also discuss possible uses of EVs as pharmacological targets to overcome EV-mediated drug resistance and the potential that the analysis of tumour-derived EVs offers as chemoresistance biomarkers.
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http://dx.doi.org/10.1007/978-3-030-67171-6_9DOI Listing
January 2021

A liquid biopsy to detect multidrug resistance and disease burden in multiple myeloma.

Blood Cancer J 2020 03 13;10(3):37. Epub 2020 Mar 13.

Graduate School of Health, Discipline of Pharmacy, University of Technology Sydney, Ultimo, NSW, 2007, Australia.

Multiple myeloma is an incurable cancer of bone marrow plasma cells, with a 5-year survival rate of 43%. Its incidence has increased by 126% since 1990. Treatment typically involves high-dose combination chemotherapy, but therapeutic response and patient survival are unpredictable and highly variable-attributed largely to the development of multidrug resistance (MDR). MDR is the simultaneous cross-resistance to a range of unrelated chemotherapeutic agents and is associated with poor prognosis and survival. Currently, no clinical procedures allow for a direct, continuous monitoring of MDR. We identified circulating large extracellular vesicles (specifically microparticles (MPs)) that can be used to monitor disease burden, disease progression and development of MDR in myeloma. These MPs differ phenotypically in the expression of four protein biomarkers: a plasma-cell marker (CD138), the MDR protein, P-glycoprotein (P-gp), the stem-cell marker (CD34); and phosphatidylserine (PS), an MP marker and mediator of cancer spread. Elevated levels of P-gp and PS MPs correlate with disease progression and treatment unresponsiveness. Furthermore, P-gp, PS and CD34 are predominantly expressed in CD138 MPs in advanced disease. In particular, a dual-positive (CD138P-gpCD34) population is elevated in aggressive/unresponsive disease. Our test provides a personalised liquid biopsy with potential to address the unmet clinical need of monitoring MDR and treatment failure in myeloma.
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http://dx.doi.org/10.1038/s41408-020-0304-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070076PMC
March 2020

Liquid Biopsies in Cancer Diagnosis, Monitoring, and Prognosis.

Trends Pharmacol Sci 2019 03 5;40(3):172-186. Epub 2019 Feb 5.

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney Australia, PO Box 123, Broadway, NSW 2007, Australia. Electronic address:

Liquid biopsies, comprising the noninvasive analysis of circulating tumor-derived material (the 'tumor circulome'), represent an innovative tool in precision oncology to overcome current limitations associated with tissue biopsies. Within the tumor circulome, circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) are the only components the clinical application of which is approved by the US Food and Drug Administration (FDA). Extracellular vesicles (EVs), circulating tumor RNA (ctRNA), and tumor-educated platelets (TEPs) are relatively new tumor circulome constituents with promising potential at each stage of cancer management. Here, we discuss the clinical applications of each element of the tumor circulome and the prevailing factors that currently limit their implementation in clinical practice. We also detail the most recent technological developments in the field, which demonstrate potential in improving the clinical value of liquid biopsies.
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http://dx.doi.org/10.1016/j.tips.2019.01.006DOI Listing
March 2019

Circulating tumor DNA - Current state of play and future perspectives.

Pharmacol Res 2018 10 22;136:35-44. Epub 2018 Aug 22.

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney Australia, PO Box 123, Broadway, NSW, 2007, Australia. Electronic address:

Cancer management paradigms are shifting towards a personalized approach thanks to the advent of the -omics technologies. Liquid biopsies, consisting in the sampling of blood and other bodily fluids, are emerging as a valid alternative to circulating tumor biomarkers and tumor tissue biopsies for cancer diagnosis, routine monitoring and prognostication. The content of a liquid biopsy is referred to as the "tumor circulome". Among its components, circulating tumor DNA (ctDNA), including both cell-free and exosome-associated DNA, is the most widely characterized element. ctDNA analysis has a tremendous capability in the diagnostic arena. Its potential has been demonstrated at each level of disease staging and management and supported by a recent FDA approval for companion diagnostic, and the investments being made by pharmaceutical companies in this sector are numerous. The approaches available for ctDNA analysis allow both quantitative and qualitative studies and range from PCR and dPCR-mediated single/multiple gene mutational assessment to whole genome next generation sequencing and methylation mapping. Although the principal object of a liquid biopsy is blood, other body fluids such as urine and saliva show potential as complementary DNA sources for tumor analysis. In this review we provide a synopsis on the state of play of current ctDNA application. We discuss the clinical significance of ctDNA analysis and review the state of the art of technologies being currently developed to this aim. We also discuss the current issues limiting ctDNA application and highlight the promising approaches being developed to overcome these.
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http://dx.doi.org/10.1016/j.phrs.2018.08.017DOI Listing
October 2018

CARMA2sh and ULK2 control pathogen-associated molecular patterns recognition in human keratinocytes: psoriasis-linked CARMA2sh mutants escape ULK2 censorship.

Cell Death Dis 2017 02 23;8(2):e2627. Epub 2017 Feb 23.

Biogem, Via Camporeale, Ariano Irpino, Italy.

The molecular complexes formed by specific members of the family of CARMA proteins, the CARD domain-containing adapter molecule BCL10 and MALT1 (CBM complex) represent a central hub in regulating activation of the pleiotropic transcription factor NF-κB. Recently, missense mutations in CARMA2sh have been shown to cause psoriasis in a dominant manner and with high penetrancy. Here, we demonstrate that in human keratinocytes CARMA2sh plays an essential role in the signal transduction pathway that connects pathogen-associated molecular patterns recognition to NF-κB activation. We also find that the serine/threonine kinase ULK2 binds to and phosphorylates CARMA2sh, thereby inhibiting its capacity to activate NF-κB by promoting lysosomal degradation of BCL10, which is essential for CARMA2sh-mediated NF-κB signaling. Remarkably, CARMA2sh mutants associated with psoriasis escape ULK2 inhibition. Finally, we show that a peptide blocking CARD-mediated BCL10 interactions reduces the capacity of psoriasis-linked CARMA2sh mutants to activate NF-κB. Our work elucidates a fundamental signaling mechanism operating in human keratinocytes and opens to novel potential tools for the therapeutical treatment of human skin disorders.
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http://dx.doi.org/10.1038/cddis.2017.51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386493PMC
February 2017