Publications
44 results found
Al-Akkad W, Acedo P, Vilia M-G, et al., 2022, Tissue-specific human extracellular matrix scaffolds promote pancreatic tumour progression and chemotherapy resistance, Cells, Vol: 11, Pages: 1-23, ISSN: 2073-4409
Over 80% of patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed at a late stage and are locally advanced or with concurrent metastases. The aggressive phenotype and relative chemo- and radiotherapeutic resistance of PDAC is thought to be mediated largely by its prominent stroma, which is supported by an extracellular matrix (ECM). Therefore, we investigated the impact of tissue-matched human ECM in driving PDAC and the role of the ECM in promoting chemotherapy resistance. Decellularized human pancreata and livers were recellularized with PANC-1 and MIA PaCa-2 (PDAC cell lines), as well as PK-1 cells (liver-derived metastatic PDAC cell line). PANC-1 cells migrated into the pancreatic scaffolds, MIA PaCa-2 cells were able to migrate into both scaffolds, whereas PK-1 cells were able to migrate into the liver scaffolds only. These differences were supported by significant deregulations in gene and protein expression between the pancreas scaffolds, liver scaffolds, and 2D culture. Moreover, these cell lines were significantly more resistant to gemcitabine and doxorubicin chemotherapy treatments in the 3D models compared to 2D cultures, even after confirmed uptake by confocal microscopy. These results suggest that tissue-specific ECM provides the preserved native cues for primary and metastatic PDAC cells necessary for a more reliable in vitro cell culture.
Vassileva V, Braga M, Barnes C, et al., 2021, Effective detection and monitoring of glioma using [18F]FPIA PET imaging, Biomedicines, Vol: 9, Pages: 1-14, ISSN: 2227-9059
Background: Reprogrammed cellular metabolism is a cancer hallmark. In addition to increased glycolysis, the oxidation of acetate in the citric acid cycle is another common metabolic phenotype. We have recently developed a novel fluorine-18-labelled trimethylacetate-based radiotracer, [18F]fluoro-pivalic acid ([18F]FPIA), for imaging the transcellular flux of short-chain fatty acids, and investigated whether this radiotracer can be used for the detection of glioma growth. Methods: We evaluated the potential of [18F]FPIA PET to monitor tumor growth in orthotopic patient-derived (HSJD-GBM-001) and cell line-derived (U87, LN229) glioma xenografts, and also included [18F]FDG PET for comparison. We assessed proliferation (Ki-67) and the expression of lipid metabolism and transport proteins (CPT1, SLC22A2, SLC22A5, SLC25A20) by immunohistochemistry, along with etomoxir treatment to provide insights into [18F]FPIA uptake. Results: Longitudinal PET imaging showed gradual increase in [18F]FPIA uptake in orthotopic glioma models with disease progression (p < 0.0001), and high tumor-to-brain contrast compared to [18F]FDG (p < 0.0001). [18F]FPIA uptake correlated positively with Ki-67 (p < 0.01), SLC22A5 (p < 0.001) and SLC25A20 (p = 0.001), and negatively with CPT1 (p < 0.01) and SLC22A2 (p < 0.01). Etomoxir reduced [18F]FPIA uptake, which correlated with decreased Ki-67 (p < 0.05). Conclusions: Our findings support the use of [18F]FPIA PET for the detection and longitudinal monitoring of glioma, showing a positive correlation with tumor proliferation, and suggest transcellular flux-mediated radiotracer uptake.
Vassileva V, McColl ER, Piquette-Miller M, 2021, Drug Transporters: Efflux, Publisher: Elsevier
Efflux transporters are membrane-bound proteins that pump their substrates out of cells or cellular compartments. Most efflux transporters belong to the ABC superfamily which uses active transport (hydrolysis of ATP) to drive the movement of their substrates across biological membranes. The exceptions to this are MATEs, a subfamily of SLC transporters that use proton gradients to efflux their substrates instead of active transport. While efflux transporters have endogenous substrates, many of them also transport clinically relevant drugs and their metabolites. These transporters are located in multiple organs and tissues including the intestine, liver, kidneys, and blood-tissue barriers. Depending on their localization to either the apical or basolateral membrane of epithelial cells, efflux transporters regulate the movement of drugs into or out of these organs and tissues. Due to their ability to either restrict or facilitate the movement of drugs between systemic circulation and tissues, efflux transporters play important roles in determining drug pharmacokinetics. This article will review the major efflux transporters and their involvement in drug absorption, distribution, and hepatic and renal clearance.
Mohammad GH, Vassileva V, Acedo P, et al., 2019, Targeting pyruvate kinase M2 and lactate dehydrogenase a is an effective combination strategy for the treatment of pancreatic cancer, Cancers, Vol: 11, ISSN: 2072-6694
Reprogrammed glucose metabolism is one of the hallmarks of cancer, and increased expression of key glycolytic enzymes, such as pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA), has been associated with poor prognosis in various malignancies. Targeting these enzymes could attenuate aerobic glycolysis and inhibit tumor proliferation. We investigated whether the PKM2 activator, TEPP-46, and the LDHA inhibitor, FX-11, can be combined to inhibit in vitro and in vivo tumor growth in preclinical models of pancreatic cancer. We assessed PKM2 and LDHA expression, enzyme activity, and cell proliferation rate after treatment with TEPP-46, FX-11, or a combination of both. Efficacy was validated in vivo by evaluating tumor growth, PK and LDHA activity in plasma and tumors, and PKM2, LDHA, and Ki-67 expression in tumor tissues following treatment. Dual therapy synergistically inhibited pancreatic cancer cell proliferation and significantly delayed tumor growth in vivo without apparent toxicity. Treatment with TEPP-46 and FX-11 resulted in increased PK and reduced LDHA enzyme activity in plasma and tumor tissues and decreased PKM2 and LDHA expression in tumors, which was reflected by a decrease in tumor volume and proliferation. The targeting of glycolytic enzymes such as PKM2 and LDHA represents a promising therapeutic approach for the treatment of pancreatic cancer.
Vassileva V, Stribbling S, Barnes C, et al., 2019, Evaluation of apoptosis imaging biomarkers in a genetic model of cell death, EJNMMI Research, Vol: 9, ISSN: 2191-219X
PurposeWe have previously developed the caspase-based radiotracer, 18F-ICMT-11, for PET imaging to monitor treatment response. We further validated 18F-ICMT-11 specificity in a murine melanoma death-switch tumour model with conditional activation of caspase-3 induced by doxycycline.MethodsCaspase-3/7 activity and cellular uptake of 18F-ICMT-11, 18F-ML-10 and 18F-FDG were assessed in B16ova and B16ovaRevC3 cells after death-switch induction.Death-switch induction was confirmed in vivo in xenograft tumours, and 18F-ICMT-11 and 18F-ML-10 biodistribution was assessed by ex vivo gamma counting of select tissues. PET imaging was performed with 18F-ICMT-11, 18F-ML-10 and 18F-FDG. Caspase-3 activation was confirmed by immunohistochemistry.ResultsSignificantly increased caspase-3/7 activity was observed only in B16ovaRevC3 cells after death-switch induction, accompanied by significantly increased 18F-ICMT-11 (p < 0.001) and 18F-ML-10 (p < 0.05) and decreased 18F-FDG (p < 0.001) uptake compared with controls.B16ova and B16ovaRevC3 tumours had similar growth in vivo; however, B16ovaRevC3 growth was significantly reduced with death-switch induction (p < 0.01). Biodistribution studies showed significantly increased 18F-ICMT-11 tumour uptake following death-switch induction (p < 0.01), but not for 18F-ML-10. Tumour uptake of 18F-ICMT-11 was higher than that of 18F-ML-10 after death-switch induction. PET imaging studies showed that 18F-ICMT-11 can be used to detect apoptosis after death-switch induction, which was accompanied by significantly increased expression of cleaved caspase-3. 18F-FDG signal decreased in tumours after death-switch induction.ConclusionsWe demonstrate that 18F-ICMT-11 can be used to detect caspase-3 activation in a death-switch tumour model, independent of the confounding effects of cancer therapeutics, thus confirming its specificity and supporting the development of this r
Stahl T, Bofinger R, Lam I, et al., 2017, Tunable semiconducting polymer nanoparticles with INDT-based conjugated polymers for photoacoustic molecular imaging, Bioconjugate Chemistry, Vol: 28, Pages: 1734-1740, ISSN: 1043-1802
Photoacoustic imaging combines both excellent spatial resolution with high contrast and specificity, without the need for patients to be exposed to ionizing radiation. This makes it ideal for the study of physiological changes occurring during tumorigenesis and cardiovascular disease. In order to fully exploit the potential of this technique, new exogenous contrast agents with strong absorbance in the near-infrared range, good stability and biocompatibility, are required. In this paper, we report the formulation and characterization of a novel series of endogenous contrast agents for photoacoustic imaging in vivo. These contrast agents are based on a recently reported series of indigoid π-conjugated organic semiconductors, coformulated with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, to give semiconducting polymer nanoparticles of about 150 nm diameter. These nanoparticles exhibited excellent absorption in the near-infrared region, with good photoacoustic signal generation efficiencies, high photostability, and extinction coefficients of up to three times higher than those previously reported. The absorption maximum is conveniently located in the spectral region of low absorption of chromophores within human tissue. Using the most promising semiconducting polymer nanoparticle, we have demonstrated wavelength-dependent differential contrast between vasculature and the nanoparticles, which can be used to unambiguously discriminate the presence of the contrast agent in vivo.
Reardon PJT, Parhizkar M, Harker AH, et al., 2017, Electrohydrodynamic fabrication of core-shell PLGA nanoparticles with controlled release of cisplatin for enhanced cancer treatment, International Journal of Nanomedicine, Vol: 12, Pages: 3913-3926, ISSN: 1176-9114
Increasing the clinical efficacy of toxic chemotherapy drugs such as cisplatin (CDDP), via targeted drug delivery, is a key area of research in cancer treatment. In this study, CDDP-loaded poly(lactic-co-glycolic acid) (PLGA) polymeric nanoparticles (NPs) were successfully prepared using electrohydrodynamic atomization (EHDA). The configuration was varied to control the distribution of CDDP within the particles, and high encapsulation efficiency (>70%) of the drug was achieved. NPs were produced with either a core–shell (CS) or a matrix (uniform) structure. It was shown that CS NPs had the most sustained release of the 2 formulations, demonstrating a slower linear release post initial “burst” and longer duration. The role of particle architecture on the rate of drug release in vitro was confirmed by fitting the experimental data with various kinetic models. This indicated that the release process was a simple diffusion mechanism. The CS NPs were effectively internalized into the endolysosomal compartments of cancer cells and demonstrated an increased cytotoxic efficacy (concentration of a drug that gives half maximal response [EC50] reaching 6.2 µM) compared to free drug (EC50 =9 µM) and uniform CDDP-distributed NPs (EC50 =7.6 µM) in vitro. Thus, these experiments indicate that engineering the structure of PLGA NPs can be exploited to control both the dosage and the release characteristics for improved clinical chemotherapy treatment.
Nunes JPM, Vassileva V, Robinson E, et al., 2017, Use of a next generation maleimide in combination with THIOMAB (TM) antibody technology delivers a highly stable, potent and near homogeneous THIOMAB (TM) antibody-drug conjugate (TDC), RSC Advances, Vol: 7, Pages: 24828-24832, ISSN: 2046-2069
Herein we demonstrate that conjugation of a next generation maleimide (NGM) to engineered cysteines in a THIOMAB™ antibody delivers a THIOMAB™ antibody-drug conjugate (TDC) with a drug loading of ca. 2. This TDC is highly stable in blood serum conditions, selective and potent towards HER2 expressing cell lines and meets the current criteria for optimised antibody-drug conjugates (ADCs).
Robinson E, Nunes JPM, Vassileva V, et al., 2017, Pyridazinediones deliver potent, stable, targeted and efficacious antibody-drug conjugates (ADCs) with a controlled loading of 4 drugs per antibody, RSC Advances, Vol: 7, Pages: 9073-9077, ISSN: 2046-2069
Herein we report the use of pyridazinediones to functionalise the native solvent accessible interstrand disulfide bonds in trastuzumab with monomethyl auristatin E (MMAE). This method of conjugation delivers serum stable antibody–drug conjugates (ADCs) with a controlled drug loading of 4. Moreover, we demonstrate that the MMAE-bearing ADCs are potent, selective and efficacious against cancer cell lines in both in vitro and in vivo models.
Vassileva V, Rajkumar V, Mazzantini M, et al., 2015, Significant Therapeutic Efficacy with Combined Radioimmunotherapy and Cetuximab in Preclinical Models of Colorectal Cancer, JOURNAL OF NUCLEAR MEDICINE, Vol: 56, Pages: 1239-1245, ISSN: 0161-5505
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- Citations: 13
Nunes JPM, Morais M, Vassileva V, et al., 2015, Functional native disulfide bridging enables delivery of a potent, stable and targeted antibody-drug conjugate (ADC), Chemical Communications, Vol: 51, Pages: 10624-10627, ISSN: 1359-7345
Herein we report the use of next generation maleimides (NGMs) for the construction of a potent antibody–drug conjugate (ADC) via functional disulfide bridging. The linker has excellent stability in blood serum and the ADC, armed with monomethyl auristatin E (MMAE), shows excellent potency and cancer cell selectivity in vitro.
Vassileva V, Piquette-Miller M, 2014, Inflammation: The Dynamic Force of Health and Disease, CLINICAL PHARMACOLOGY & THERAPEUTICS, Vol: 96, Pages: 401-405, ISSN: 0009-9236
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- Citations: 5
Coward J, Kulbe H, Chakravarty P, et al., 2011, Interleukin-6 as a Therapeutic Target in Human Ovarian Cancer, CLINICAL CANCER RESEARCH, Vol: 17, Pages: 6083-6096, ISSN: 1078-0432
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- Citations: 296
Vassileva V, Piquette-Miller M, 2010, Inflammation: Extinguishing the Fires Within, CLINICAL PHARMACOLOGY & THERAPEUTICS, Vol: 87, Pages: 375-379, ISSN: 0009-9236
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- Citations: 5
Vassileva V, 2010, SRAP-new prognostic marker, Nature Reviews Clinical Oncology, Vol: 7, ISSN: 1759-4774
Vassileva V, 2010, Targeted therapies: Farletuzumab-promising new agent in ovarian cancer, Nature Reviews Clinical Oncology, Vol: 7, ISSN: 1759-4774
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Vassileva V, 2010, Screening: IL-12 polymorphism linked to cervical cancer risk, Nature Reviews Clinical Oncology, Vol: 7, ISSN: 1759-4774
Vassileva V, 2009, Aberrant methylation - Early biomarker for CRC, Nature Reviews Clinical Oncology, Vol: 6, ISSN: 1759-4774
Vassileva V, 2009, Diagnostic markers for ovarian cancer, Nature Reviews Clinical Oncology, Vol: 6, ISSN: 1759-4774
Vassileva V, 2009, MRI and molecular profiles: Improving prediction, Nature Reviews Clinical Oncology, Vol: 6, ISSN: 1759-4774
Vassileva V, 2009, Survivin: Surviving gastric cancer, Nature Reviews Clinical Oncology, Vol: 6, ISSN: 1759-4774
Vassileva V, 2009, Surgical oncology: Markers of long-term survival in pancreatic cancer, Nature Reviews Clinical Oncology, Vol: 6, ISSN: 1759-4774
Vassileva V, 2009, Pathology: Protein kinase a predicts response to radiation and androgen deprivation therapy, Nature Reviews Clinical Oncology, Vol: 6, ISSN: 1759-4774
Vassileva V, 2009, Pediatric oncology: Aggressive treatment of osteosarcoma improves health-related quality of life, Nature Reviews Clinical Oncology, Vol: 6, ISSN: 1759-4774
Vassileva V, 2009, Prostate cancer: Check it out, Nature Reviews Clinical Oncology, Vol: 6, ISSN: 1759-4774
Vassileva V, 2009, Surgery: Rectal cancer—treatment on the less invasive side, Nature Reviews Clinical Oncology, Vol: 6, ISSN: 1759-4774
Vassileva V, 2009, Chemotherapy: Metastatic breast cancer—optimal front-line therapy, Nature Reviews Clinical Oncology, Vol: 6, ISSN: 1759-4774
Vassileva V, 2009, Screening: Ovarian cancer: Feasibility of early detection, Nature Reviews Clinical Oncology, Vol: 6, ISSN: 1759-4774
Vassileva V, 2009, Targeted therapies: Bevacizumab and chemotherapy in NSCLC, Nature Reviews Clinical Oncology, Vol: 6, ISSN: 1759-4774
Vassileva V, 2009, Chemotherapy: Predictors of chemotherapy response in advanced CRC, Nature Reviews Clinical Oncology, Vol: 6, ISSN: 1759-4774
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