Research News

 

July 14 , 2021

Antihypertension drug may help patients with noncancerous brain tumors affecting hearing

Losartan prevented tumor-induced hearing loss and augmented radiation efficacy in mice.

BOSTON – New research led by investigators at Massachusetts General Hospital (MGH) and Massachusetts Eye and Ear indicates that the blood pressure drug losartan may benefit patients with neurofibromatosis type 2 (NF2), a hereditary condition associated with vestibular schwannomas, or noncancerous tumors along the nerves in the brain that are involved with hearing and balance. The findings, which are published in Science Translational Medicine, are especially important because vestibular schwannomas are currently treated with surgery and radiation therapy (which carry risks of nerve damage), and no drug is approved by the U.S. Food and Drug Administration to treat these tumors or their associated hearing loss.

“Developing effective therapeutics to preserve hearing function in patients with NF2 is an urgent unmet medical need. The greatest barrier to managing NF2-related auditory impairment is our incomplete understanding of how schwannomas cause hearing loss,” says co–senior author Lei Xu, MD, PhD, an investigator in the Steele Laboratories for Tumor Biology within the MGH Department of Radiation Oncology. A previous report showing that scarring, or fibrosis, exists in schwannomas and correlates with hearing loss prompted the team to test whether a drug that blocks fibrosis might be effective.

Losartan blocks a component of the renin-angiotensin system, which is involved not only in regulating blood pressure but also in stimulating fibrosis and inflammation. The entire class of angiotensin-targeting drugs, which includes losartan, has been shown to reduce collagen accumulation in cardiac and kidney fibrotic disease. Using a mouse model of NF2, Xu  and her colleagues found that losartan treatment had several effects on vestibular schwannomas and the brain: It reduced inflammatory signaling and swelling and thus prevented hearing loss, and it increased oxygen delivery to enhance the effectiveness of radiation therapy (which may help lower the radiation dose needed to control tumor growth and limit radiation-associated toxicities). 

In preparation to translate these findings into the clinic, co–senior author Konstantina Stankovic, MD, PhD, former chief of the Division of Otology and Neurotology at Massachusetts Eye and Ear, now Bertarelli Professor and Chair of the Department of Otolaryngology – Head and Neck Surgery at Stanford University School of Medicine, examined patient samples and data. Her team found that vestibular schwannomas associated with poor hearing had more pronounced inflammatory signaling than tumors associated with good hearing. This inflammatory signaling in tumors was capable of directly damaging cochlear cells that are essential for hearing. Also, patients with vestibular schwannoma who took losartan or other drugs in its class experienced no progression in hearing loss, unlike patients on other or no antihypertensive drugs. This study illustrates the advantages offered by an integrated approach and teamwork that spans basic research, translational investigation and clinical care.

The findings support the need for a prospective clinical trial of losartan in patients with NF2 and vestibular schwannomas. “As one of the most commonly prescribed drugs for hypertension, the safety and low cost of losartan warrants rapid translation of our research to patients with vestibular schwannomas to try to prevent tumor-induced sensorineural hearing loss,” Stankovic says.

Xu is an assistant professor at Harvard Medical School. Co-authors included Limeng Wu, Sasa Vasilijic, Yao Sun, Jie Chen, Lukas D. Landegger, Yanling Zhang, Wenjianlong Zhou, Jun Ren, Samuel Early, Zhenzhen Yin, William W. Ho, Na Zhang, Xing Gao, Grace Y. Lee, Meenal Datta, Jessica E. Sagers, Alyssa Brown,Alona Muzikansky, Anat Stemmer-Rachamimov, Luo Zhang, Scott R. Plotkin and Rakesh K. Jain.

This study was supported by the Department of Defense, the Children’s Tumor Foundation Drug
Discovery Initiative, the National Cancer Institute, the Advanced Medical Research Foundation, Jane’s Trust Foundation, the Lustgarten Foundation, the Ludwig Center at Harvard, the National Foundation for Cancer
Research, the Gates Foundation, the Cancer Research Institute, the American Association of Cancer Research, the National Institute on Deafness and Other Communication Disorders, Nancy Sayles Day Foundation, Lauer Tinnitus Research Center, the Barnes Foundation, the Zwanziger Foundation, and Sheldon and Dorothea Buckler.

April , 2021

Dr. Rosenthal and his team receives a new grant from the America Cancer Society!

Project Title: "Minimally Invasive Nodal Staging in Head and Neck Cancer".

Dr. Rosenthal and his team receives a new grant from the America Cancer Society! Project Title: Minimally Invasive Nodal Staging in Head and Neck Cancer!

His team is funded to conduct an innovative intraoperative molecular imaging approach to identify tumor positive lymph nodes in patients with head and neck cancer. They will assess whether their imaging agent can specifically identify metastatic LNs after intravenous administration. If successful, this proposal would be the first clinical study to show that systemic delivery of a targeted agent will be more accurate and provide significant advantages over the standard of care procedures. 


America Cancer Society

Grantee: Eben Rosenthal
Grant-maker: American Cancer Society
Program: Mission Boost Grant
Project Title: Minimally Invasive Nodal Staging in Head and Neck Cancer
Institution: Stanford University
Proposal Number: 595629
Award Number: MBG-21-024-01-MBG

April 14, 2021

Grillet lab’s new high impact paper makes the cover of Journal of Neuroscience!

Vol. 41, Issue 15, 14 Apr 2021

Trouillet, Alix, Katharine K. Miller, Shefin Sam George, Pei Wang, Noor-E.-Seher Ali, Anthony Ricci, and Nicolas Grillet. “Loxhd1 Mutations Cause Mechanotransduction Defects in Cochlear Hair Cells.” The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 41, no. 15 (April 14, 2021): 3331–43. https://doi.org/10.1523/JNEUROSCI.0975-20.2021.

Hearing loss occurs frequently due to the dysfunction of the auditory sensory cells in the inner ear, which transform mechanical stimulations into electric signals. Trouillet et al. demonstrate that the molecule LOXHD1 is required for this mechanotransduction process, but surprisingly, only in mature auditory cells. When LOXHD1 is mutated, some of the known molecules required for mechanotransduction are still correctly positioned in the sensory cells, suggesting that the mechanotransduction machinery is still present, but not activatable. Their research identified a new step in the auditory cell development. It will be critical to further understand them as they are responsible for congenital and age-related forms of hearing loss in humans.


About the Cover:

This scanning electron micrograph shows the hair bundle of a inner hair cell from a wild-type mouse cochlea. Sound-induced forces displace these mechanosensitive organelles, which comprise stereocilia organized into rows of increasing height. Hair bundle deflection tenses external filaments (called tip links) that connect stereocilia rows, and this gates mechanotransduction channels, initiating the auditory signal. A critical maturation step for hair bundle mechanotransduction that occurs between postnatal days 7 and 11 requires the integrity of the deafness gene LOXHD1. For more information, see the article by Trouillet et al. (pages 3331–3343). Cover image: Nicolas Grillet.

April 14, 2021

Dr. Santa Maria’s team publishes “Treatment with a Neutrophil Elastase Inhibitor and Ofloxacin Reduces P. Aeruginosa Burden in a Mouse Model of Chronic Suppurative Otitis Media,” in Open Access on April 6, 2021.

Dr. Santa Maria’s team publishes “Treatment with a Neutrophil Elastase Inhibitor and Ofloxacin Reduces P. Aeruginosa Burden in a Mouse Model of Chronic Suppurative Otitis Media,” in Open Access on April 6, 2021.

Abstract:
Chronic suppurative otitis media (CSOM) is a widespread, debilitating problem with poorly understood immunology. Here, we assess the host response to middle ear infection over the course of a month post-infection in a mouse model of CSOM and in human subjects with the disease. Using multiparameter flow cytometry and a binomial generalized linear machine learning model, we identified Ly6G, a surface marker of mature neutrophils, as the most informative factor of host response driving disease in the CSOM mouse model. Consistent with this, neutrophils were the most abundant cell type in infected mice and Ly6G expression tracked with the course of infection. Moreover, neutrophil-specific immunomodulatory treatment using the neutrophil elastase inhibitor GW 311616A significantly reduces bacterial burden relative to ofloxacin-only treated animals in this model. The levels of dsDNA in middle ear effusion samples are elevated in both humans and mice with CSOM and decreased during treatment, suggesting that dsDNA may serve as a molecular biomarker of treatment response. Together these data strongly implicate neutrophils in the ineffective immune response to P. aeruginosa infection in CSOM and suggest that immunomodulatory strategies may benefit drug-tolerant infections for chronic biofilm-mediated disease.

Khomtchouk, K. M., L. I. Joseph, B. B. Khomtchouk, A. Kouhi, S. Massa, A. Xia, I. Koliesnik, D. Pletzer, P. L. Bollyky, and P. L. Santa Maria. “Treatment with a Neutrophil Elastase Inhibitor and Ofloxacin Reduces P. Aeruginosa Burden in a Mouse Model of Chronic Suppurative Otitis Media.” Npj Biofilms and Microbiomes 7, no. 1 (December 2021): 31. https://bit.ly/3mKIaks

April 6, 2021

Dr. Eben Rosenthal and his team published an Open Access article that is currently in the top quarter of all research outputs scored by Altmetric.

An open access article published by Dr. Rosenthal’s team in Nov 2020 is currently In the top 25% of all research outputs scored by Altmetric.

"Co-administered antibody improves penetration of antibody–dye conjugate into human cancers with implications for antibody–drug conjugates”
Guolan Lu, Naoki Nishio, Nynke S. van den Berg, Brock A. Martin, Shayan Fakurnejad, Stan van Keulen, Alexander D. Colevas, Greg M. Thurber & Eben L. Rosenthal.

Abstract
Poor tissue penetration remains a major challenge for antibody-based therapeutics of solid tumors, but proper dosing can improve the tissue penetration and thus therapeutic efficacy of these biologics. Due to dose-limiting toxicity of the small molecule payload, antibody-drug conjugates (ADCs) are administered at a much lower dose than their parent antibodies, which further reduces tissue penetration. We conducted an early-phase clinical trial (NCT02415881) and previously reported the safety of an antibody-dye conjugate (panitumumab-IRDye800CW) as primary outcome. Here, we report a retrospective exploratory analysis of the trial to evaluate whether co-administration of an unconjugated antibody could improve the intratumoral distribution of the antibody-dye conjugate in patients. By measuring the multiscale distribution of the antibody-dye conjugate, this study demonstrates improved microscopic antibody distribution without increasing uptake (toxicity) in healthy tissue when co-administered with the parent antibody, supporting further clinical investigation of the co-administration dosing strategy to improve the tumor penetration of ADCs.

March 1, 2021

NIH awards $2.4M to Dr. Nayak's research, March 1, 2021

Dr. Nayak's R-01 independent investigator grant application to the NIH was funded this morning (3/1/2021) by the National Heart, Lung and Blood Institute (NHLBI). This is a 5-year award (3/1/2021 - 1/31/2026) totaling $2.4M, to support his laboratory group's pre-clinical in vitro and in vivo animal model work to optimize the transplantation of CRISPR gene-corrected human stem cells into the airway epithelium, as a candidate treatment for cystic fibrosis sinusitis. Co-Investigators on this award, all within Stanford University, include Drs. Matthew Porteus (Pediatrics and Biochemistry), Tushar Desai (Pulmonary Critical Care Medicine), Y. Peter Yang (Orthopedics), and Jeffrey Wine (Psychology, CF Biology).