Lei Xu
Xu Lab Research
The goals of my research team are to dissect mechanisms of disease progression and treatment resistance and to develop innovative strategies to enhance treatment efficacy and improve patient quality of life. My current research is focused on 3 diseases:
Neurofibromatosis type 2:
Neurofibromatosis type 2 (NF2) is a genetic disorder characterized by non-malignant tumors grown on the hearing nerve, disrupting hearing and causing social impairment and clinical depression. The major unmet medical needs for NF2 are i) no drug is FDA-approved to treat the tumor or the associated hearing loss, and ii) the current standard treatment (surgery and radiation therapy) can further damage the nerve and aggravate hearing loss. Thus novel therapies with enhanced efficacy and reduced toxicity-related hearing loss are urgently needed.
The NF2 research is limited by i) the lack of orthotopic mouse models that reproduce tumor-induced hearing loss, ii) the lack of patient-derived cell lines, and iii) the lack of a targeted therapy that can simultaneously prevent hearing loss and control tumor growth.
I have made several contributions to advance NF research and management. First, my group established novel mouse models that faithfully reproduce schwannoma-induced hearing loss and neurologic deficit (PNAS 2015; Nature Protocol 2019, Experimental Neurology 2018, NeuroMethods 2021). In mice, the short length and small caliber of the vestibular nerves, and their encasement in the bony internal auditory canal pose significant technical challenges for orthotopic tumor implantation. My group developed a novel cerebellopontine angle (CPA) model that allows the measurement of hearing function in tumor-bearing mice. This model addresses a major bottleneck in the NF field and provides the NF research and clinical community with a robust and biologically relevant tool to explore new therapeutic targets to tackle this devastating disease. Then, using this new model, I discovered that cMET and angiotensin signaling are potential targets for NF2. Blockade of cMET signaling enhanced radiation efficacy and reduced the radiation dose required for tumor control and thus limited radiation toxicity (PNAS 2018). Blockade of angiotensin signaling prevented tumor-induced hearing loss (Science Translational Medicine 2021). Based on our compelling data, the Department of Radiation Oncology at MGH has amended the current ongoing clinical trial (NCT01199978), to include 10 patients to be treated with losartan concurrently with fractionated proton therapy, with follow-up evaluations for hearing function.
Ovarian cancer:
Ovarian cancer (OvCa) is the most lethal gynecologic malignancy. My ovarian cancer research is focused on: i) deciphering mechanisms of treatment-resistance, ii) identifying novel strategies to enhance treatment efficacy, and iii) reducing malignant ascites, which contribute to poor quality of life in patients with OvCa.
I discovered that normalizing the ovarian cancer tumor microenvironment by targeting TGF-b (Clinical Cancer Research 2011; PNAS 2012) and angiotensin signaling (PNAS 2019) not only enhances the delivery and efficacy of chemotherapy but also improves the diaphragm lymphatic vessel drainage function, leading to reduced ascites. These findings suggest a potential treatment to improve patients’ quality of life. In collaboration with MGH Gynecological Oncologists, I further demonstrated that in ~300 ovarian cancer patients treated at two Harvard Medical School-affiliated teaching hospitals (MGH and Brigham and Women’s Hospital) who received losartan survived 30 months longer than those taking other anti-hypertension drugs (PNAS 2019).
Schwannomatosis:
Schwannomatosis (SWN), a type of neurofibromatosis, is a rare genetic disordered characterized by multiple non-malignant schwannomas growing on the spine and peripheral nerves. Patients with SWN overwhelmingly present with intractable, debilitating chronic pain, severe enough to cause permanent disability.
Recognizing that one of the biggest challenges in finding a cure for SWN is the lack of clinically-relevant models, I collected patient samples and successfully established a biobank of patient-derived SWN cells. I also developed the first orthotopic patient-derived xenograft (PDX) SWN spine model in mice. Currently, using my novel PDX models, I’m investigating the etiology of tumor-induced pain response and testing the treatment efficacy of potential targets.
Lab News
Cerebellopontine Angle (CPA) Model: A Novel Tool for Investigating Immunotherapy in Neurofibromatosis Type 2 Vestibular Schwannomas
Cancer drug targets molecular pathway contributing to tumor progression, radiation-induced hearing loss