Publications by authors named "Sabna Rajeev Krishnan"

5 Publications

  • Page 1 of 1

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

Multiple myeloma and persistence of drug resistance in the age of novel drugs (Review).

Int J Oncol 2016 Jul 11;49(1):33-50. Epub 2016 May 11.

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

Multiple myeloma (MM) is a mature B cell neoplasm that results in multi-organ failure. The median age of onset, diverse clinical manifestations, heterogeneous survival rate, clonal evolution, intrinsic and acquired drug resistance have impact on the therapeutic management of the disease. Specifically, the emergence of multidrug resistance (MDR) during the course of treatment contributes significantly to treatment failure. The introduction of the immunomodulatory agents and proteasome inhibitors has seen an increase in overall patient survival, however, for the majority of patients, relapse remains inevitable with evidence that these agents, like the conventional chemotherapeutics are also subject to the development of MDR. Clinical management of patients with MM is currently compromised by lack of a suitable procedure to monitor the development of clinical drug resistance in individual patients. The current MM prognostic measures fail to pick the clonotypic tumor cells overexpressing drug efflux pumps, and invasive biopsy is insufficient in detecting sporadic tumors in the skeletal system. This review summarizes the challenges associated with treating the complex disease spectrum of myeloma, with an emphasis on the role of deleterious multidrug resistant clones orchestrating relapse.
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http://dx.doi.org/10.3892/ijo.2016.3516DOI Listing
July 2016

Isolation of Human CD138(+) Microparticles from the Plasma of Patients with Multiple Myeloma.

Neoplasia 2016 Jan;18(1):25-32

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

The confinement of multiple myeloma (MM) to the bone marrow microenvironment requires an invasive bone marrow biopsy to monitor the malignant compartment. The existing clinical tools used to determine treatment response and tumor relapse are limited in sensitivity mainly because they indirectly measure tumor burden inside the bone marrow and fail to capture the patchy, multisite tumor infiltrates associated with MM. Microparticles (MPs) are 0.1- to 1.0-μm membrane vesicles, which contain the cellular content of their originating cell. MPs are functional mediators and convey prothrombotic, promalignant, proresistance, and proinflammatory messages, establishing intercellular cross talk and bypassing the need for direct cell-cell contact in many pathologies. In this study, we analyzed plasma cell-derived MPs (CD138(+)) from deidentified MM patients (n = 64) and normal subjects (n = 18) using flow cytometry. The morphology and size of the MPs were further analyzed using scanning electron microscopy. Our study shows the proof of a systemic signature of MPs in MM patients. We observed that the levels of MPs were significantly elevated in MM corresponding to the tumor burden. We provide the first evidence for the presence of MPs in the peripheral blood of MM patients with potential applications in personalized MM clinical monitoring.
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http://dx.doi.org/10.1016/j.neo.2015.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735625PMC
January 2016