Dr. Steinberg did her undergraduate work at the University of California, Riverside. She received her PhD in microbiology from the State University of New York, Stony Brook in 1976, working on bacterial viruses. She then did a postdoctoral fellowship at SUNY Stony Brook, studying tumor viruses.
After two years at Columbia University as a senior research associate, she joined the Department of Otolaryngology at Long Island Jewish Medical Center where she began her studies of human papillomaviruses and their role in diseases of the head and neck, including recurrent respiratory papillomatosis. Those studies have been supported by grants from the National Institutes of Health (NIH) since 1983. More recently, she has also been studying possible inhibitors of cancer metastasis.
She is the author or co-author of 114 peer-reviewed publications and 25 book chapters. Her research has been recognized by a number of awards, including the Elliot Osserman Award from the Israel Cancer Research Fund, the Karl Storz Award from the American Society of Pediatric Otolaryngology, the Israel Cancer Research Fund Award for Women of Excellence and the Lifetime Achievement Award from the International Papillomavirus Society.
Human papillomaviruses (HPVs) are a large family of viruses that cause a wide range of benign and malignant tumors ranging from common skin warts and genital warts to cervical cancer and some cancers in the oral cavity. Nearly everyone is infected by HPVs, but most infections are latent (silent), with no evidence of disease.
Dr. Steinberg’s research is primarily focused on diseases of the airway caused by HPVs. One of the diseases she studies is recurrent respiratory papillomatosis (RRP), a rare disease that affects both children and adults. The papillomas in RRP patients are benign, but the disease causes significant suffering and can even be fatal because the papillomas can block the airway. Surgical removal is the only approved treatment, but the papillomas often recur rapidly. In severe cases, surgery to clear the airway may be required as often as once a month. The papillomas are primarily located in the larynx, but approximately 17% of patients will have tracheal disease and 5% will have papillomas of the lung. There is no effective treatment for lung involvement, and the lung papillomas frequently convert to cancer. Improved treatments, based on better knowledge of the biology of the disease, are badly needed. HPVs also cause some head and neck cancers, especially tonsil cancers. Recent studies show that the cancers caused by HPVs are becoming much more common. Fortunately, those cancers usually respond well to treatment. Most of the research Dr. Steinberg has done on RRP is being directly applied to her studies of HPV-induced head and cancers as well, focusing on the interactions between the tumors and the immune system.
Promising avenues of research Dr. Steinberg and her team are following include the interactions between HPV and its target cells, the role of the immune system in controlling HPV-induced diseases, activation of latent HPV infection, studies on HPV-induced head and neck cancer, and studies of molecular mechanisms regulating metastasis of carcinomas and sarcomas.
Dr. Steinberg and her team have found that respiratory papilloma tissues and cultured papilloma cells express high levels of several membrane-associated proteins, including the EGF receptor (EGFR), and show constitutive activation of the EGFR. Papilloma cells also have alterations in several signaling pathways linked to the EGFR. These include activation of PI 3-kinase, increased expression and activation of the small GTPase Rac1, and subsequent activation of p50 NF-κB and p38 MAP kinase. They have recently discovered that Rac1 is overexpressed and constitutively active in clinically normal airway epithelium of RRP patients, and acts as a susceptibility factor for RRP. They are now asking whether that is also true of head and neck cancers. The Rac1 signal transduction cascade results in constitutive expression of the enzyme COX-2 and its product PGE2. Inhibition of COX-2 in papilloma cells slows proliferation, increases spontaneous apoptosis, and suppresses HPV transcription. PGE2 can also alter the immune response. We are currently asking how PGE2 contributes persistence of HPV and suppression of an effective immune response in patients with tonsil cancers.
Dr. Steinberg and her team are collaborating with Vincent Bonagura, MD, to solve this question, which has implications far beyond respiratory papillomatosis. Latent HPV infections are present in the airway, skin, and genital tract of many people and may be a source of subsequent skin warts, genital warts, and cervical and airway cancers. They have found that patients with RRP have a bias toward a TH2-like response to HPV proteins, have elevated levels of T-regulatory cells in the papillomas, and show altered expression of a number of innate and adaptive immune response genes. These altered responses may be genetic, at least in part. Patients have a skewed distribution of HLA Class II alleles, and may lack some activating Kir gene alleles. They also express higher levels of COX-2 in their airway tissues, which could bias the local immune response toward expression of TH2-like cytokines and chemokines, reduce clearance of active infection, and make the patients more likely to have disease. These studies are now being applied to head and neck cancer.
All cells release vesicles containing proteins and RNA that are used for communication. Dr. Steinberg group has found that respiratory papilloma cells contain high levels of the cytokine IL36γ, but it is absent in the vesicles they release, which may be one way they evade inducing an immune response. Moreover, they have found that different stimuli can induce normal epithelial cells to express IL-36γ, but only some stimuli induce its packaging in vesicles. Studies are now in progress to determine the mechanism for sorting this cytokine into vesicles for release.
Dr. Steinberg and her team are collaborating with Samuel Soffer, MD and Marc Symons, PhD, who are studying potential use of drugs to inhibit tumor invasion and metastasis by targeting macrophages of the immune system. These studies focus on osteosarcoma, a bone tumor primarily of children. They have found that macrophages promote lung metastasis in a mouse model of osteosarcoma, and that gefitinib, which “reprograms” macrophage function blocks this stimulation. They are now working on the mechanism of this effect.
Rana Ali Afzal, MD, PhD
Research: Studying the use of anti-viral botanicals to target HPV-infected cells.
Email: [email protected]
Michelle Kallis, MD
Research: Studies novel therapeutic drugs that could be used to block tumor invasion and metastasis.
Apurva Tandon, PhD
Research: Manages the laboratory, conducts experiments, and supervises volunteers.
Email: [email protected]
Christopher Papayannakos, MS
Graduate Student, Donald and Barbara Zucker School of Medicine
Research: Studies secretion of extracellular vesicles that cells use to communicate
University of California, Riverside, CA
Field of study: Biology
Adelphi University, Garden City, NY
Field of study: Biology
SUNY at Stony Brook, Stony Brook, NY
Field of study: Microbiology
Postdoctoral Fellow, SUNY at Stony Brook
Field of study: Virology