My research has focused on several basic and translational aspects of cancer biology. From a basic science perspective, my lab cloned NOL7, a novel gene that induces an anti-angiogenic phenotype and suppresses in vivo tumor growth. NOL7 acts as a master regulator of angiogenesis by modulating the expression of angiogenesis-associated mRNAs via both steady-state downregulation and posttranscriptional upregulation. NOL7 itself is positively regulated by the retinoblastoma (Rb) gene, supporting the paradigm shift that Rb can act as a positive regulator of gene transcription. Our long-term goal is to understand how transcriptional and posttranscriptional regulation of angiogenesis-related mRNAs contributes to the expression of the phenotype and to leverage this knowledge to develop novel therapeutic approaches. Our central hypothesis is that Rb positively regulates NOL7 expression and that loss of NOL7 protein expression results in decreased regulation of NOL7 target mRNA transcripts, the gain of expression of the pro-angiogenic phenotype and the loss of tumor growth inhibition. This research is innovative because it will define the mechanisms by which NOL7 acts as a master regulator of angiogenesis. Further, it provides fundamental insights into the poorly understood area of posttranscriptional regulation of angiogenesis. This research is expected to have a positive impact on human health because it may provide new therapeutic avenues for targeting angiogenesis in both physiologic and pathologic conditions. We have also been pursuing a number of translational research aspects of tumor angiogenesis using head and neck squamous cell carcinoma as a model. For example, we have been testing the hypothesis that inhibitors of angiogenesis are effective chemopreventive agents. The expression of the angiogenic phenotype is both an early and an essential step in the development of cancer, making it an attractive target for cancer prevention. The long-term goal of our work is to develop novel, nontoxic chemopreventive strategies for cancer that are based upon the inhibition of angiogenesis. These investigations have resulted in a number of clinical trials. Finally, we are currently using animal models and tissue derived from the clinical trials to investigate mechanisms of acquired resistance in response prolonged chemopreventive therapy. Such modeling will enable us to test the hypothesis that acquired resistance to inhibitors of angiogenesis can be reversed, thereby prolonging a drug’s chemopreventive activity.
From a patient care perspective, I have played a leading role in defining the clinical utility of oral cancer screening adjuncts/tests. I have served on the American Dental Association (ADA) Council of Scientific Affairs (CSA). In that capacity, I was a member and Chair of CSA Expert Panels that developed evidence-based guideline recommendations for the evaluation of potentially malignant disorders of the orders of the oral cavity. In addition, I was also a member of Cochrane Systematic Reviews Expert Panels that performed systematic reviews and made clinical guideline recommendations with respect to oral cancer screening. We have also sought ways to improve our ability to diagnose, prognosticate and monitor/predict response to therapy. As such, we have been involved in large scale genomic analyses to understand how treatment of head and neck tumors influences the transcriptome. In addition, we are seeking to establish a molecularly-based saliva screening test for the identification of high-risk patients that are likely to progress to cancer. We have performed targeted sequencing to determine the mutation rate of the most commonly altered genes in moderate dysplasia, severe dysplasia, and reactive hyperplasia (control group). These analyses identified dysplasia-specific molecular changes that underlie the pathogenesis of cancer development. Using the candidate mutations identified in dysplastic tissues, we are developing assays to determine their expression levels in saliva/tissue samples from a retrospective cohort of patients with oral dysplasia with known outcomes. Finally, in the future, the dysplasia-specific biomarkers will be tested using prospective samples derived from an ongoing oral dysplasia natural history study to validate the diagnostic accuracy of a salivary screening test. These studies are conceptually innovative because they are defining the mutational landscape oral premalignancy. In addition, they will determine if diagnostic efficacy of a non-invasive molecular salivary screening platform for oral dysplasia. The research will benefit human health by improving our ability to identify the subset of molecularly/biologically important premalignant oral lesions that are likely to progress to cancer, thereby allowing for more rapid and personalized intervention when the disease is at a more treatable stage.
PhD - Cellular & Molecular Pathology
Residency - Oral & Maxillofacial Pathology
DDS - Dentistry
BA - Zoology
Prospective study evaluating dynamic changes of cell-free HPV DNA in locoregional viral-associated oropharyngeal cancer treated with induction chemotherapy and response-adaptive treatment.
Rosenberg AJ, Izumchenko E, Pearson A, Gooi Z, Blair E, Karrison T, Juloori A, Ginat D, Cipriani N, Lingen M, Sloane H, Edelstein DL, Keyser K, Fredebohm J, Holtrup F, Jones FS, Haraf D, Agrawal N, Vokes EE. Prospective study evaluating dynamic changes of cell-free HPV DNA in locoregional viral-associated oropharyngeal cancer treated with induction chemotherapy and response-adaptive treatment. BMC Cancer. 2022 Jan 03; 22(1):17.
Clinical assessment for the detection of oral cavity cancer and potentially malignant disorders in apparently healthy adults.
Walsh T, Warnakulasuriya S, Lingen MW, Kerr AR, Ogden GR, Glenny AM, Macey R. Clinical assessment for the detection of oral cavity cancer and potentially malignant disorders in apparently healthy adults. Cochrane Database Syst Rev. 2021 12 10; 12:CD010173.
Application of liquid biopsy as multi-functional biomarkers in head and neck cancer.
Mishra V, Singh A, Chen X, Rosenberg AJ, Pearson AT, Zhavoronkov A, Savage PA, Lingen MW, Agrawal N, Izumchenko E. Application of liquid biopsy as multi-functional biomarkers in head and neck cancer. Br J Cancer. 2022 02; 126(3):361-370.
Why Doesn't Medicare Treat All Diagnostic Tests Equally?
Lingen MW, Kalmar JR. Why Doesn't Medicare Treat All Diagnostic Tests Equally? Oral Surg Oral Med Oral Pathol Oral Radiol. 2022 01; 133(1):1-2.
Risk and response adapted de-intensified treatment for HPV-associated oropharyngeal cancer: Optima paradigm expanded experience.
Rosenberg AJ, Agrawal N, Pearson A, Gooi Z, Blair E, Cursio J, Juloori A, Ginat D, Howard A, Chin J, Kochanny S, Foster C, Cipriani N, Lingen M, Izumchenko E, Seiwert TY, Haraf D, Vokes EE. Risk and response adapted de-intensified treatment for HPV-associated oropharyngeal cancer: Optima paradigm expanded experience. Oral Oncol. 2021 11; 122:105566.
Effector T cell responses unleashed by regulatory T cell ablation exacerbate oral squamous cell carcinoma.
Chao JL, Korzinkin M, Zhavoronkov A, Ozerov IV, Walker MT, Higgins K, Lingen MW, Izumchenko E, Savage PA. Effector T cell responses unleashed by regulatory T cell ablation exacerbate oral squamous cell carcinoma. Cell Rep Med. 2021 09 21; 2(9):100399.
Diagnostic tests for oral cancer and potentially malignant disorders in patients presenting with clinically evident lesions.
Walsh T, Macey R, Kerr AR, Lingen MW, Ogden GR, Warnakulasuriya S. Diagnostic tests for oral cancer and potentially malignant disorders in patients presenting with clinically evident lesions. Cochrane Database Syst Rev. 2021 07 20; 7:CD010276.
The journal welcomes new OMS section editor.
Lingen MW. The journal welcomes new OMS section editor. Oral Surg Oral Med Oral Pathol Oral Radiol. 2021 Jul; 132(1):1.
Proliferative Verrucous Leukoplakia: An Expert Consensus Guideline for Standardized Assessment and Reporting.
Thompson LDR, Fitzpatrick SG, Müller S, Eisenberg E, Upadhyaya JD, Lingen MW, Vigneswaran N, Woo SB, Bhattacharyya I, Bilodeau EA, Carlos R, Islam MN, Leon ME, Lewis JS, Magliocca KR, Mani H, Mehrad M, Purgina B, Richardson M, Wenig BM, Cohen DM. Proliferative Verrucous Leukoplakia: An Expert Consensus Guideline for Standardized Assessment and Reporting. Head Neck Pathol. 2021 Jun; 15(2):572-587.
Ultrasensitive detection of tumor-specific mutations in saliva of patients with oral cavity squamous cell carcinoma.
Shanmugam A, Hariharan AK, Hasina R, Nair JR, Katragadda S, Irusappan S, Ravichandran A, Veeramachaneni V, Bettadapura R, Bhati M, Ramaswamy V, Rao VUS, Bagadia RK, Manjunath A, Manjunath NML, Solomon MC, Maji S, Bahadur U, Bettegowda C, Papadopoulos N, Lingen MW, Hariharan R, Gupta V, Agrawal N, Izumchenko E. Ultrasensitive detection of tumor-specific mutations in saliva of patients with oral cavity squamous cell carcinoma. Cancer. 2021 05 15; 127(10):1576-1589.