Guojun Li, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] Squamous cell carcinoma of the oropharynx (SCCOP) is characterized by local tumor aggressiveness requiring morbid local-regional therapies with poor survival and high recurrence rates. Despite declining smoking prevalence, the incidence of SCCOP is stagnant and incidence is increasing in young adults. These trends may be due to the rising prevalence of oncogenic human papillomavirus (HPV) in the population. HPV+ SCCOP is a distinct epidemiologic, clinical, and molecular disease with potentially unique clinical behavior and treatment responses. Identification of those needing treatment intensification and those able to benefit from reduction of treatment intensity is critical to more effective and less morbid treatment. [unreadable] [unreadable] Oncogenic subtypes of HPV, principally type 16, are critical etiologic factors in a distinct subset of head and neck cancers, chiefly SCCOP. Inflammation/immune responses which control the HPV clearance and escape of immune surveillance may contribute to the risk and possibly the outcomes of HPV-associated SCCOP. In addition, the unique pattern of genetic profiles in HPV+ SCCOP might confound correlations with clinical outcome. Therefore, we speculate that genetic polymorphisms in the likely functional regions of these genes may pose individual difference in susceptibility to HPV infection and constitute the confounding effect on HPV-related clinical outcomes. [unreadable] [unreadable] In this case-case comparison study, the study subjects will be 300 patients with incident SCCOP retrospectively identified from an existing molecular epidemiologic study of squamous cell carcinoma of the head and neck. The specific aims for this R03 project are: 1) to establish a database with demographic, clinical and follow-up information, genotypes of the polymorphisms, and HPV16 DNA tumor status on 300 of these SCCOP patients, 2) to assess genotypes of Inflammation/immune response related genes involved in both pro- and anti-inflammation pathways as markers of susceptibility for HPV16 association among patients with SCCOP, and 3) To determine if variants of these genes in both pro- and anti-inflammation pathways modify HPV-related clinical outcomes (recurrence and survival) of SCCOP patients. The long-term goal of this project is to use these genetic polymorphisms as surrogate markers to help identify individuals at high risk of HPV16 infection and/or at risk for poor outcomes in order to better individualize SCCOP prevention and treatment as well as improve of both survival and quality of life. [unreadable] [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): My career goal is to develop active population-based cancer research programs on molecular and viral epidemiology of virus-associated cancers. This goal builds upon my previous training in several disciplines including biological sciences, but requires further training in epidemiologic methodology, virology, and immunology. At the end of this training period, I will be an established and independent researcher in cancer prevention. I have developed a comprehensive education and mentoring plan. My education plan will provide intensive instruction in the areas of epidemiology, virology, and immunology. I have chosen five mentors, two consultants and two collaborators who will supervise specific portions of my training. My research proposal will focus on identifying susceptibility markers for both HPV16 status and HPV16- associated outcome among squamous cell carcinoma of the oropharyx (SCCOP) patients. I propose a case-case comparison study capitalizing on two currently ongoing NIH-funded case-control study of head and neck cancer and HPV16 DNA in peripheral blood follow-up study of SCCOP. My research goal is to identify certain sexual behaviors and genetic polymorphisms in cell cycle control/apoptosis and inflammation/immune response pathways that could serve as predictors of risk of HPV16 status and modify HPV16-associated survival in SCCOP patients. The specific aims are: 1) To investigate if certain sexual behaviors are associated with an increased risk of HPV16* status among 300 incident SCCOP patients. The impact of a link between sexual behaviors and HPV16 status will help establish the environmental exposures associated with HPV16 in SCCOP, which has obvious public health implications especially in light of the recent approval of HPV vaccination to prevent cervical cancer; 2) To investigate if adverse genotypes in cell cycle control/apoptosis and inflammation/immune response pathways are associated with an increased risk of HPV16* status among SCCOP patients. Genetic polymorphisms involved in these pathways may play a significant role in person-to-person variability in susceptibility to HPV16 infection, having cancer prevention implications; and 3) To determine if selected common genetic variants of genes in cell cycle control/apoptosis and inflammation/immune response pathways modify clinical outcomes in patients with HPV16* SCCOP. While knowing the HPV16 status of SCCOP patients will likely become an important prognostic implication with potential influences on future treatment and prevention strategies for an improved survival and a better quality of life, understanding germline modifications of the outcomes associated with HPV16 positivity will be the next step toward the goal of more individualized, less morbid, and more successful cancer treatment. [unreadable] [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): Squamous cell carcinoma of the oropharynx (SCCOP) is characterized by local tumor aggressiveness requiring morbid local-regional therapies with poor survival and high recurrence rates. Despite declining smoking prevalence, the incidence of SCCOP is increasing, particularly in young adults. These trends may be due to the rising prevalence of oncogenic human papillomavirus (HPV) in the population. HPV-positive [(HPV+)] SCCOP is a distinct epidemiologic, clinical, and molecular disease with potentially unique clinical behavior and treatment responses. Identification of those needing treatment intensification and those able to benefit from reduction of treatment intensity is critical to more effective and less morbid treatment. Oncogenic subtypes of HPV are critical etiologic factors in a distinct subset of head and neck cancers, chiefly SCCOP. Inflammatory response miRNAs which control the HPV clearance and escape of immune surveillance may contribute to HPV(+) tumors and related outcomes of SCCOP. In addition, miRNAs in human serum hold a great potential for serum-based biomarker research. Thus, serum expression profiles of inflammatory response miRNAs before treatment may affect tumor HPV status and related outcomes of SCCOP patients; and exploitation of such associations may help develop clinically relevant non-tumor-based biomarkers for HPV- associated SCCOP patients. In this study, the study subjects will be 600 patients with incident SCCOP identified from an existing molecular epidemiologic study of squamous cell carcinoma of the head and neck. The specific aims for this R03 project are: Aim 1: To assess if serum expression profiles of selected inflammatory/immune response miRNAs before treatment are markers of tumor HPV status among the 600 SCCOP patients. We will determine serum expression of those selected miRNAs before treatment by using the miScript miRNA PCR arrays method and Aim 2: To determine if certain serum expression profiles of above miRNAs before treatment as blood-based and non-tumor predictors of clinical outcomes of HPV(+) SCCOP patients including disease-specific survival, disease-free survival, and overall survival among 600 SCCOP patients treated and followed at U.T. MDACC. By knowing the tumor HPV status and identifying novel prognostic biomarkers of HPV-associated SCCOP patients, physicians can effectively tailor treatment, screening, and follow-up strategies for an improved survival and a better quality of life as well as greatly enhanced secondary cancer prevention.

PROJECT SUMMARY Squamous cell carcinoma of the oropharynx (SCCOP) is a highly morbid, life-threatening disease. Despite declining smoking prevalence, the incidence of SCCOP is increasing, particularly among younger adults. This trend is the result of the rising prevalence of oncogenic human papillomavirus (HPV) infection in the population. The majority (approximately 70-80%) of SCCOP patients are HPV-positive [HPV(+)]. HPV(+) SCCOP is distinct from HPV-negative [HPV(-)] SCCOP in terms of epidemiologic, clinical, and molecular features, and especially in terms of clinical behavior, response to treatment and survival. Therefore, in patients with SCCOP, determination of HPV status is critical for defining prognosis and tailoring therapy. Unfortunately, there is currently no effective screening method to identify patients with tumor HPV(+) SCCOP. Further, among patients with HPV(+) SCCOP, there remains heterogeneity in clinical outcomes. Identification of patients with SCCOP needing treatment intensification and those able to benefit from reduction of treatment intensity is critical to more effective and less morbid treatment. Noncoding RNAs (ncRNAs) that affect the immuno-inflammatory response control HPV clearance and escape of immune surveillance, and may contribute to tumor HPV status and related clinical outcomes of SCCOP patients. NcRNAs exhibit stable expression in human serum. We hypothesize that pretreatment serum expression profiles of immuno-inflammatory response ncRNAs are associated with tumor HPV(+) SCCOP and related clinical outcomes. The specific aims for this project are as follows: Aim 1: To determine if pretreatment serum expression profiles of selected immuno-inflammatory response ncRNAs are markers of tumor HPV status in a cohort of 1500 patients with incident SCCOP recruited, treated, and followed at The University of Texas MD Anderson Cancer Center. Aim 2: To determine if pretreatment serum expression profiles of selected immuno-inflammatory response ncRNAs predict disease-specific survival, disease-free survival, and overall survival among HPV(+) SCCOP patients from the cohort described for Aim 1. Aim 3: To validate significant associations found in Aims 1 and 2. We will use an independent cohort of 625 SCCOP cases to control for potential false-positive or unbiased estimates of associations. Aim 4: To characterize functions of immuno-inflammatory response ncRNAs on tumor radiosensitivity in vitro. We will screen a panel of HPV(+) SCCOP cell lines for ncRNAs of interest in a clinical setting, in order to further validate these prognostic ncRNAs found in Aim 2. This functional study will validate 1 or more of these ncRNAs as biomarkers that can be incorporated into prognostic prediction models to permit more personalized treatment. Identifying novel biomarkers for tumor HPV status and prognosis of patients with HPV(+) SCCOP will allow physicians to more effectively tailor screening for patients at risk of HPV(+) SCCOP, as well as treatment, and surveillance strategies that optimize survival and quality of life for patients with HPV(+) SCCOP.