Xu, Lei, MD, PhD

Xu
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My areas of expertise are 1) the biology of tumor-host interaction, and 2) the development of novel therapeutic targets for cancer. I aim to translate this knowledge into improved therapies by conducting preclinical and clinical studies in collaboration with MGH clinicians. I’m currently leading the following projects:


Overcoming chemoresistance in human ovarian cancer


One aspect of my research interest is in the role and the molecular mechanism of miRNA in cancer metastasis and chemoresistance. Chemoresistance remains a major obstacle to successful cancer treatment. Chemoresistance may be due to increased drug efflux, dysregulated DNA repair and decreased tumor cell apoptosis. Our exciting preliminary findings show that microRNA-155 (miR-155) directly targets X-linked Inhibitor of Apoptosis Protein (XIAP) and mdr1/P-glycoprogein (P-gp). XIAP inhibits the apoptotic pathway and P-gp exports drugs and decreases their cellular accumulation, both are important mediators contributing to chemoresistance. We propose to investigate if miR-155 increases chemosensitivity via negative regulation of XIAP and P-gp, which increase chemo-induced apoptosis and decreases drug efflux.


Development of new adjunct therapies in NF2 vestibular schwannoma


Over the past few decades, radiation therapy has become a standard treatment for vestibular schwannoma. For patients with sporadic vestibular schwannomas, radiation therapy is associated with long-term tumor control rates exceeding 95%. However, hearing preservation rates after radiation therapy range from 50% to 80%. Thus, hearing loss is the main limitation of radiation therapy for vestibular schwannoma and identifying options that minimize hearing loss are urgently needed. Clinical trial of Anti-VEGF treatment in patients with NF2 vestibular schwannoma patients showed that it inhibited tumor progression and improved hearing. However, not all NF2 patients with hearing loss respond to bevacizumab monotherapy, and for the patients whose hearing improved, the response is transient. Furthermore, some patients are unable to tolerate long-term bevacizumab treatment. Based on these, we proposed to develop new adjunct therapies to radiation and bevacizumab treatment. First, we study the effect of combining radiation with VEGF inhibition for treatment of NF2-related schwannoma. The results of this study will determine the rationale for combining anti-VEGF treatment and radiation therapy in humans and for the timing of radiation therapy relative to bevacizumab treatment. In addition, the study will provide critical information on biomarkers for the normalization window that may be used in human studies to guide dosing and assess efficacy and toxicity. In parallel, we are studying the effect of targeting the TGF-beta and HGF/cMet pathway in combination with anti-VEGF or radiation therapy in vestibular schwannoma.


Improve the tuberculosis treatment efficacy by modulating the granuloma microenvironment


Anti-VEGF treatment are widely studied and tested in the oncology field, however, whether it can be applied to infectious disease is not known. We studied granulomas lesions from human tuberculosis patients and rabbit models, we found that blood vessels in TB granulomas are very similar to tumor blood vessels in that they are collapsed and structurally abnormal, lacking pericyte coverage of the endothelial layer. This functional abnormality lead to increased hypoxia and may hinder drug delivery. Further more, we applied anti-VEGF treatment to rabbit TB model and are examine its effect on drug delivery and efficacy.


Mechanism of evasion from anti-angiogenic treatment


At the same time, I also study the host contribution to tumor progression. In particular, I studied NK cell, an important component of the innate immune system, recruitment and function affected by anti-angiogenic therapy. We found that anti-angiogenic therapy increased NK cell recruitment and enhanced its cytotoxic activity.


Dr. Lei Xu CV

Selected Publications (from total of 47)

Zhang N, Gao X, Zhao Y, Datta M, Liu P, Xu L
Rationally combining anti-VEGF therapy with radiation in NF2 schwannoma.
J Rare Dis Res Treat. 2017;1(2):51-55 - PMID: 28191549 - PMCID: PMC5300073
Kloepper J, Riedemann L, Amoozgar Z, Seano G, Susek K, Yu V, Dalvie N, Amelung RL, Datta M, Song JW, Askoxylakis V, Taylor JW, Lu-Emerson C, Batista A, Kirkpatrick ND, Jung K, Snuderl M, Muzikansky A, Stubenrauch KG, Krieter O, Wakimoto H, Xu L, Munn LL, Duda DG, Fukumura D, Batchelor TT, Jain RK
Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival.
Proc Natl Acad Sci U S A. 2016;113(16):4476-81 - PMID: 27044098 - PMCID: PMC4843473
Peterson TE, Kirkpatrick ND, Huang Y, Farrar CT, Marijt KA, Kloepper J, Datta M, Amoozgar Z, Seano G, Jung K, Kamoun WS, Vardam T, Snuderl M, Goveia J, Chatterjee S, Batista A, Muzikansky A, Leow CC, Xu L, Batchelor TT, Duda DG, Fukumura D, Jain RK
Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages.
Proc Natl Acad Sci U S A. 2016;113(16):4470-5 - PMID: 27044097 - PMCID: PMC4843449
Gao X, Zhao Y, Stemmer-Rachamimov AO, Liu H, Huang P, Chin S, Selig MK, Plotkin SR, Jain RK, Xu L
Anti-VEGF treatment improves neurological function and augments radiation response in NF2 schwannoma model.
Proc Natl Acad Sci U S A. 2015;112(47):14676-81 - PMID: 26554010 - PMCID: PMC4664377
Datta M, Via LE, Chen W, Baish JW, Xu L, Barry CE, Jain RK
Mathematical Model of Oxygen Transport in Tuberculosis Granulomas.
Ann Biomed Eng. 2015;44(4):863-872 - PMID: 26253038 - PMCID: PMC4795989
Datta M, Via LE, Kamoun WS, Liu C, Chen W, Seano G, Weiner DM, Schimel D, England K, Martin JD, Gao X, Xu L, Barry CE, Jain RK
Anti-vascular endothelial growth factor treatment normalizes tuberculosis granuloma vasculature and improves small molecule delivery.
Proc Natl Acad Sci U S A. 2015;112(6):1827-32 - PMID: 25624495 - PMCID: PMC4330784
Snuderl M, Batista A, Kirkpatrick ND, Ruiz de Almodovar C, Riedemann L, Walsh EC, Anolik R, Huang Y, Martin JD, Kamoun W, Knevels E, Schmidt T, Farrar CT, Vakoc BJ, Mohan N, Chung E, Roberge S, Peterson T, Bais C, Zhelyazkova BH, Yip S, Hasselblatt M, Rossig C, Niemeyer E, Ferrara N, Klagsbrun M, Duda DG, Fukumura D, Xu L, Carmeliet P, Jain RK
Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma.
Cell. 2013;152(5):1065-76 - PMID: 23452854 - PMCID: PMC3587980
Liu J, Liao S, Diop-Frimpong B, Chen W, Goel S, Naxerova K, Ancukiewicz M, Boucher Y, Jain RK, Xu L
TGF-? blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma.
Proc Natl Acad Sci U S A. 2012;109(41):16618-23 - PMID: 22996328 - PMCID: PMC3478596
Goel S, Duda DG, Xu L, Munn LL, Boucher Y, Fukumura D, Jain RK
Normalization of the vasculature for treatment of cancer and other diseases.
Physiol Rev. 2011;91(3):1071-121 - PMID: 21742796 - PMCID: PMC3258432
Liu J, Liao S, Huang Y, Samuel R, Shi T, Naxerova K, Huang P, Kamoun W, Jain RK, Fukumura D, Xu L
PDGF-D improves drug delivery and efficacy via vascular normalization, but promotes lymphatic metastasis by activating CXCR4 in breast cancer.
Clin Cancer Res. 2011;17(11):3638-48 - PMID: 21459800 - PMCID: PMC3107920
Duda DG, Kozin SV, Kirkpatrick ND, Xu L, Fukumura D, Jain RK
CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies?
Clin Cancer Res. 2011;17(8):2074-80 - PMID: 21349998 - PMCID: PMC3079023
Liao S, Liu J, Lin P, Shi T, Jain RK, Xu L
TGF-beta blockade controls ascites by preventing abnormalization of lymphatic vessels in orthotopic human ovarian carcinoma models.
Clin Cancer Res. 2011;17(6):1415-24 - PMID: 21278244 - PMCID: PMC3060297
Gerstner ER, Eichler AF, Plotkin SR, Drappatz J, Doyle CL, Xu L, Duda DG, Wen PY, Jain RK, Batchelor TT
Phase I trial with biomarker studies of vatalanib (PTK787) in patients with newly diagnosed glioblastoma treated with enzyme inducing anti-epileptic drugs and standard radiation and temozolomide.
J Neurooncol. 2011;103(2):325-32 - PMID: 20821342 - PMCID: PMC4090923
Xu L, Czito BG, Willett CG
Epigenetic markers in rectal cancer.
Clin Cancer Res. 2010;16(10):2699-701 - PMID: 20460492
Xu L, Duda DG, di Tomaso E, Ancukiewicz M, Chung DC, Lauwers GY, Samuel R, Shellito P, Czito BG, Lin PC, Poleski M, Bentley R, Clark JW, Willett CG, Jain RK
Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1alpha, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer.
Cancer Res. 2009;69(20):7905-10 - PMID: 19826039 - PMCID: PMC2859041
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