Person: Wang, Xiaoen
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Wang
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Xiaoen
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Wang, Xiaoen
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Publication Cox-2 Inhibition Enhances the Activity of Sunitinib in Human Renal Cell Carcinoma Xenografts(Nature Publishing Group, 2013) Wang, Xiaoen; Zhang, L; O'Neill, A; Bahamon, B; Alsop, David; Mier, James; Goldberg, S.; Signoretti, Sabina; Atkins, M B; Wood, C G; Bhatt, RupalBackground: Sunitinib (Su), a tyrosine kinase inhibitor of VEGFR, is effective at producing tumour response in clear cell renal cell carcinoma (cRCC), but resistance to therapy is inevitable. As COX-2 is a known mediator of tumour growth, we explored the potential benefit of COX-2 inhibition in combination with VEGFR inhibition in attempts at delaying tumour progression on Su. Methods: COX-2 expression was compared with areas of hypoxia in tumours that progressed on Su vs untreated tumours. Mice bearing human cRCC xenografts were treated with Su and the COX-2 inhibitor, celecoxib, and the effects on tumour growth were assessed. Sequential vs concurrent regimens were compared. Results: COX-2 expression was increased in cRCC xenografts in areas of tumour hypoxia. The combination of Su and celecoxib achieved longer times to tumour progression compared to treatment with either agent alone or to untreated control animals in four models. This effect was seen with concurrent but not with sequential therapy. Conclusion: COX-2 inhibition can extend the effectiveness of VEGFR inhibition. This effect is dependent on the timing of therapy. Clinical trials combining Su and COX-2 inhibitors should be considered as a means delaying time to progression on sunitinib in patients with metastatic cRCC.Publication High Dose Intermittent Sorafenib Shows Improved Efficacy Over Conventional Continuous Dose in Renal Cell Carcinoma(BioMed Central, 2011) Wang, Xiaoen; Zhang, Liang; Goldberg, S.; Bhasin, Manoj; Brown, Victoria; Alsop, David; Signoretti, Sabina; Mier, James; Atkins, Michael B.; Bhatt, RupalBackground: Renal cell carcinoma (RCC) responds to agents that inhibit vascular endothelial growth factor (VEGF) pathway. Sorafenib, a multikinase inhibitor of VEGF receptor, is effective at producing tumor responses and delaying median progression free survival in patients with cytokine refractory RCC. However, resistance to therapy develops at a median of 5 months. In an effort to increase efficacy, we studied the effects of increased sorafenib dose and intermittent scheduling in a murine RCC xenograft model. Methods: Mice bearing xenografts derived from the 786-O RCC cell line were treated with sorafenib according to multiple doses and schedules: 1) Conventional dose (CD) continuous therapy; 2) high dose (HD) intermittent therapy, 3) CD intermittent therapy and 4) HD continuous therapy. Tumor diameter was measured daily. Microvessel density was assessed after 3 days to determine the early effects of therapy, and tumor perfusion was assessed serially by arterial spin labeled (ASL) MRI at day 0, 3, 7 and 10. Results: Tumors that were treated with HD sorafenib exhibited slowed tumor growth as compared to CD using either schedule. HD intermittent therapy was superior to CD continous therapy, even though the total dose of sorafenib was essentially equivalent, and not significantly different than HD continuous therapy. The tumors exposed to HD sorafenib had lower microvessel density than the untreated or the CD groups. ASL MRI showed that tumor perfusion was reduced to a greater extent with the HD sorafenib at day 3 and at all time points thereafter relative to CD therapy. Further the intermittent schedule appeared to maintain RCC sensitivity to sorafenib as determined by changes in tumor perfusion. Conclusions: A modification of the sorafenib dosing schedule involving higher dose intermittent treatment appeared to improve its efficacy in this xenograft model relative to conventional dosing. MRI perfusion imaging and histologic analysis suggest that this benefit is related to enhanced and protracted antiangiogenic activity. Thus, better understanding of dosing and schedule issues may lead to improved therapeutic effectiveness of VEGF directed therapy in RCC and possibly other tumors.Publication Resistance of Renal Cell Carcinoma to Sorafenib Is Mediated by Potentially Reversible Gene Expression(Public Library of Science, 2011) Bhasin, Manoj; Schor-Bardach, Rachel; Collins, Michael P.; Zhang, Liang; Wang, Xiaoen; Panka, David; Putheti, P; Signoretti, Sabina; Alsop, David; Libermann, Towia; Atkins, Michael B.; Mier, James; Goldberg, S.; Bhatt, RupalPurpose: Resistance to antiangiogenic therapy is an important clinical problem. We examined whether resistance occurs at least in part via reversible, physiologic changes in the tumor, or results solely from stable genetic changes in resistant tumor cells. Experimental Design: Mice bearing two human RCC xenografts were treated with sorafenib until they acquired resistance. Resistant 786-O cells were harvested and reimplanted into naïve mice. Mice bearing resistant A498 cells were subjected to a 1 week treatment break. Sorafenib was then again administered to both sets of mice. Tumor growth patterns, gene expression, viability, blood vessel density, and perfusion were serially assessed in treated vs control mice. Results: Despite prior resistance, reimplanted 786-O tumors maintained their ability to stabilize on sorafenib in sequential reimplantation steps. A transcriptome profile of the tumors revealed that the gene expression profile of tumors upon reimplantation reapproximated that of the untreated tumors and was distinct from tumors exhibiting resistance to sorafenib. In A498 tumors, revascularization was noted with resistance and cessation of sorafenib therapy and tumor perfusion was reduced and tumor cell necrosis enhanced with re-exposure to sorafenib. Conclusions: In two RCC cell lines, resistance to sorafenib appears to be reversible. These results support the hypothesis that resistance to VEGF pathway therapy is not solely the result of a permanent genetic change in the tumor or selection of resistant clones, but rather is due to a great extent to reversible changes that likely occur in the tumor and/or its microenvironment.Publication Foot Muscle Energy Reserves in Diabetic Patients Without and With Clinical Peripheral Neuropathy(American Diabetes Association, 2009) Doupis, John; Kuchibhotla, Sarada; Julliard, Walker; Gnardellis, Charalambos; Dinh, Thanh; Lyons, Thomas Edward; Rosenblum, Barry; Wang, Xiaoen; Giurini, John; Greenman, Robert L.; Veves, AristidisObjective: To investigate changes in the foot muscle energy reserves in diabetic non-neuropathic and neuropathic patients. Research Design and Methods: We measured the phosphocreatinine (PCr)/inorganic phosphate (Pi) ratio, total \(^{31}\)P concentration, and the lipid/water ratio in the muscles in the metatarsal head region using MRI spectroscopy in healthy control subjects and non-neuropathic and neuropathic diabetic patients. Results: The PCr/Pi ratio was higher in the control subjects (3.23 \(\pm\) 0.43) followed by the non-neuropathic group (2.61 \(\pm\) 0.36), whereas it was lowest in the neuropathic group (0.60 \(\pm\) 1.02) (P < 0.0001). There were no differences in total \(^{31}\)P concentration and lipid/water ratio between the control and non-neuropathic groups, but both measurements were different in the neuropathic group (P < 0.0001). Conclusions: Resting foot muscle energy reserves are affected before the development of peripheral diabetic neuropathy and are associated with the endothelial dysfunction and inflammation.Publication Selective spectroscopic imaging of hyperpolarized pyruvate and its metabolites using a single-echo variable phase advance method in balanced SSFP(Wiley, 2015-10-28) Varma, Gopal; Wang, Xiaoen; Vinogradov, Elena; Bhatt, Rupal S.; Sukhatme, Vikas P.; Seth, Pankaj; Lenkinski, Robert E.; Alsop, David; Grant, Aaron K.Purpose—In balanced steady state free precession (bSSFP), the signal intensity has a wellknown dependence on the off-resonance frequency, or, equivalently, the phase advance between successive radiofrequency (RF) pulses. The signal profile can be used to resolve the contributions from the spectrally separated metabolites. This work describes a method based on use of a variable RF phase advance to acquire spatial and spectral data in a time-efficient manner for hyperpolarized 13C MRI. Theory and Methods—The technique relies on the frequency response from a bSSFP acquisition to acquire relatively rapid, high-resolution images that may be reconstructed to separate contributions from different metabolites. The ability to produce images from spectrally separated metabolites was demonstrated in-vitro, as well as in-vivo following administration of hyperpolarized 1-13C pyruvate in mice with xenograft tumors. Results—In-vivo images of pyruvate, alanine, pyruvate hydrate and lactate were reconstructed from 4 images acquired in 2 seconds with an in-plane resolution of 1.25 × 1.25mm2 and 5mm slice thickness. Conclusions—The phase advance method allowed acquisition of spectroscopically selective images with high spatial and temporal resolution. This method provides an alternative approach to hyperpolarized 13C spectroscopic MRI that can be combined with other techniques such as multiecho or fluctuating equilibrium bSSFP.