Wilson Xuan Mai

All Publications

• Integrated molecular and functional characterization of the intrinsic apoptotic machinery identifies therapeutic vulnerabilities in glioma. Nature communications Fernandez, E. G., Mai, W. X., Song, K., Bayley, N. A., Kim, J., Zhu, H., Pioso, M., Young, P., Andrasz, C. L., Cadet, D., Liau, L. M., Li, G., Yong, W. H., Rodriguez, F. J., Dixon, S. J., Souers, A. J., Li, J. J., Graeber, T. G., Cloughesy, T. F., Nathanson, D. A. 2024; 15 (1): 10089

  Abstract

  Genomic profiling often fails to predict therapeutic outcomes in cancer. This failure is, in part, due to a myriad of genetic alterations and the plasticity of cancer signaling networks. Functional profiling, which ascertains signaling dynamics, is an alternative method to anticipate drug responses. It is unclear whether integrating genomic and functional features of solid tumours can provide unique insight into therapeutic vulnerabilities. We perform combined molecular and functional characterization, via BH3 profiling of the intrinsic apoptotic machinery, in glioma patient samples and derivative models. We identify that standard-of-care therapy rapidly rewires apoptotic signaling in a genotype-specific manner, revealing targetable apoptotic vulnerabilities in gliomas containing specific molecular features (e.g., TP53 WT). However, integration of BH3 profiling reveals high mitochondrial priming is also required to induce glioma apoptosis. Accordingly, a machine-learning approach identifies a composite molecular and functional signature that best predicts responses of diverse intracranial glioma models to standard-of-care therapies combined with ABBV-155, a clinical drug targeting intrinsic apoptosis. This work demonstrates how complementary functional and molecular data can robustly predict therapy-induced cell death.

  View details for DOI 10.1038/s41467-024-54138-9

  View details for PubMedID 39572533

  View details for PubMedCentralID 2263014

• A Pilot Study to Evaluate Percussive Ventilation Breathhold to Improve Lung Stereotactic Ablative Radiotherapy (PVB-SABR) Mai, W., Swamy, A., Flores, K., Langer, J., Free, D., Gebeyehu, P., Skinner, L., Wong, S., Huang, K., Pranoto, A., Lao, O., Loo, B., Blomain, E. LIPPINCOTT WILLIAMS & WILKINS. 2024: S3-S4

  View details for Web of Science ID 001365165700004

• Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma NATURE MEDICINE Mai, W. X., Gosa, L., Daniels, V. W., Ta, L., Tsang, J. E., Higgins, B., Gilmore, W., Bayley, N. A., Harati, M., Lee, J. T., Yong, W. H., Kornblum, H. I., Bensinger, S. J., Mischel, P. S., Rao, P., Clark, P. M., Cloughesy, T. F., Letai, A., Nathanson, D. A. 2017; 23 (11): 1342-+

  Abstract

  Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies.

  View details for DOI 10.1038/nm.4418

  View details for Web of Science ID 000414548300016

  View details for PubMedID 29035366

  View details for PubMedCentralID PMC5683421

• Emerging Approaches for Targeting Metabolic Vulnerabilities in Malignant Glioma. Current neurology and neuroscience reports Clark, P. M., Mai, W. X., Cloughesy, T. F., Nathanson, D. A. 2016; 16 (2): 17

  Abstract

  Malignant gliomas are intractable and among the most lethal human malignancies. Like other cancers, metabolic reprogramming is a key feature of glioma and is thought to accommodate the heightened nutrient requirements for tumor cell proliferation, growth, and survival. This metabolic rewiring, driven by oncogenic signaling and molded by the unique environment of the brain, may impose vulnerabilities that could be exploited therapeutically for increased tumor control. In this review, we discuss the prominent metabolic features of malignant glioma, the key pathways regulating glioma metabolism, and the potential therapeutic opportunities for targeting metabolic processes.

  View details for DOI 10.1007/s11910-015-0613-6

  View details for PubMedID 26759318

• Quantitative assessments of glycolysis from single cells. Technology Shin, Y. S., Kim, J., Johnson, D., Dooraghi, A. A., Mai, W. X., Ta, L., Chatziioannou, A. F., Phelps, M. E., Nathanson, D. A., Heath, J. R. 2015; 3 (4): 172-178

  Abstract

  The most common positron emission tomography (PET) radio-labeled probe for molecular diagnostics in patient care and research is the glucose analog, 2-deoxy-2-[F-18]fluoro-D-glucose (18F-FDG). We report on an integrated microfluidics-chip/beta particle imaging system for in vitro18F-FDG radioassays of glycolysis with single cell resolution. We investigated the kinetic responses of single glioblastoma cancer cells to targeted inhibitors of receptor tyrosine kinase signaling. Further, we find a weak positive correlation between cell size and rate of glycolysis.

  View details for DOI 10.1142/S2339547815200058

  View details for PubMedID 26835505

  View details for PubMedCentralID PMC4728151

• Chemical methods for the simultaneous quantitation of metabolites and proteins from single cells. Journal of the American Chemical Society Xue, M., Wei, W., Su, Y., Kim, J., Shin, Y. S., Mai, W. X., Nathanson, D. A., Heath, J. R. 2015; 137 (12): 4066-9

  Abstract

  We describe chemical approaches for integrated metabolic and proteomic assays from single cells. Quantitative assays for intracellular metabolites, including glucose uptake and three other species, are designed as surface-competitive binding assays with fluorescence readouts. This enables integration into a microarray format with functional protein immunoassays, all of which are incorporated into the microchambers of a single-cell barcode chip (SCBC). By using the SCBC, we interrogate the response of human-derived glioblastoma cancer cells to epidermal growth factor receptor inhibition. We report, for the first time, on both the intercellular metabolic heterogeneity as well as the baseline and drug-induced changes in the metabolite-phosphoprotein correlation network.

  View details for DOI 10.1021/jacs.5b00944

  View details for PubMedID 25789560

  View details for PubMedCentralID PMC4883658

• Two-wave nanotherapy to target the stroma and optimize gemcitabine delivery to a human pancreatic cancer model in mice. ACS nano Meng, H., Zhao, Y., Dong, J., Xue, M., Lin, Y. S., Ji, Z., Mai, W. X., Zhang, H., Chang, C. H., Brinker, C. J., Zink, J. I., Nel, A. E. 2013; 7 (11): 10048-65

  Abstract

  Pancreatic ductal adenocarcinoma (PDAC) elicits a dense stromal response that blocks vascular access because of pericyte coverage of vascular fenestrations. In this way, the PDAC stroma contributes to chemotherapy resistance in addition to causing other problems. In order to improve the delivery of gemcitabine, a first-line chemotherapeutic agent, a PEGylated drug-carrying liposome was developed, using a transmembrane ammonium sulfate gradient to encapsulate the protonated drug up to 20% w/w. However, because the liposome was precluded from entering the xenograft site due to the stromal interference, we developed a first-wave nanocarrier that decreases pericyte coverage of the vasculature through interference in the pericyte recruiting TGF-β signaling pathway. This was accomplished using a polyethyleneimine (PEI)/polyethylene glycol (PEG)-coated mesoporous silica nanoparticle (MSNP) for molecular complexation to a small molecule TGF-β inhibitor, LY364947. LY364947 contains a nitrogen atom that attaches, through H-bonding, to PEI amines with a high rate of efficiency. The copolymer coating also facilitates systemic biodistribution and retention at the tumor site. Because of the high loading capacity and pH-dependent LY364947 release from the MSNPs, we achieved rapid entry of IV-injected liposomes and MSNPs at the PDAC tumor site. This two-wave approach provided effective shrinkage of the tumor xenografts beyond 25 days, compared to the treatment with free drug or gemcitabine-loaded liposomes only. Not only does this approach overcome stromal resistance to drug delivery in PDAC, but it also introduces the concept of using a stepwise engineered approach to address a range of biological impediments that interfere in nanocancer therapy in a spectrum of cancers.

  View details for DOI 10.1021/nn404083m

  View details for PubMedID 24143858

  View details for PubMedCentralID PMC3878438

• Codelivery of an optimal drug/siRNA combination using mesoporous silica nanoparticles to overcome drug resistance in breast cancer in vitro and in vivo. ACS nano Meng, H., Mai, W. X., Zhang, H., Xue, M., Xia, T., Lin, S., Wang, X., Zhao, Y., Ji, Z., Zink, J. I., Nel, A. E. 2013; 7 (2): 994-1005

  Abstract

  We used a multifunctional mesoporous silica nanoparticle (MSNP) carrier to overcome doxorubicin (Dox) resistance in a multidrug resistant (MDR) human breast cancer xenograft by codelivering Dox and siRNA that targets the P-glycoprotein (Pgp) drug exporter. The Pgp siRNA selection from among a series of drug resistance targets was achieved by performing high throughput screening in a MDR breast cancer cell line, MCF-7/MDR. Following the establishment of a MCF-7/MDR xenograft model in nude mice, we demonstrated that a 50 nm MSNP, functionalized by a polyethyleneimine-polyethylene glycol (PEI-PEG) copolymer, provides protected delivery of stably bound Dox and Pgp siRNA to the tumor site. The effective biodistribution and reduced reticuloendothelial uptake, as a result of our nanocarrier design, allowed us to achieve an 8% enhanced permeability and retention effect at the tumor site. Compared to free Dox or the carrier loaded with either drug or siRNA alone, the dual delivery system resulted in synergistic inhibition of tumor growth in vivo. Analysis of multiple xenograft biopsies demonstrated significant Pgp knockdown at heterogeneous tumor sites that correspond to the regions where Dox was released intracellularly and induced apoptosis. We emphasize that the heterogeneity originates in the tumor microenvironment, which influences the vascular access, rather than heterogeneous Pgp expression in the MDR cells. Taken together, these data provide proof-of-principle testing of the use of a dual drug/siRNA nanocarrier to overcome Dox resistance in a xenograft. The study also provides the first detailed analysis of the impact of heterogeneity in the tumor microenvironment on the efficacy of siRNA delivery in vivo.

  View details for DOI 10.1021/nn3044066

  View details for PubMedID 23289892

  View details for PubMedCentralID PMC3620006

• Mesoporous silica nanoparticles: A multifunctional nano therapeutic system. Integrative biology : quantitative biosciences from nano to macro Mai, W. X., Meng, H. 2013; 5 (1): 19-28

  Abstract

  Efficient and safe drug delivery has always been a challenge in medicine. The use of nanotechnology, such as the development of nano drug delivery systems (DDS), has received great attention with high enthusiasm owing to the potential that nanocarriers can theoretically act as "magic bullets" and selectively target affected organs and cells while sparing normal tissues. The family of nano DDS includes conventional nano drug delivery materials such as lipids and polymers that have been scaled to the nanometer size range. With the rapid development of synthesis and characterization techniques for engineered nanomaterials, new DDS platforms have emerged, including inorganic based nanocarriers, such as mesoporous silica nanoparticles (MSNP). MSNP are able to act as a multifunctional delivery platform that is capable of delivering therapeutic elements to a variety of disease models (especially cancer) at cellular and in vivo levels. Furthermore, MSNP have shown to be exceptional delivery platforms capable of protectively packaging hydrophobic and hydrophilic drug molecules as well as other therapeutic elements for controlled on-demand delivery. In addition, MSNP have demonstrated the capability to image the delivery site for theranostic purposes. These functionalities have led to the development of MSNP as novel multifunctional nanocarriers, and therefore provide them with unique advantages compared to other nanocarriers.

  View details for DOI 10.1039/c2ib20137b

  View details for PubMedID 23042147