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CTRS Program Featured Investigators

Current Investigators

Abigail Gamble, PhD

Assistant Professor, Preventive Medicine
UMMC

Exploring exercise behavior in pregnant and postpartum adolescents in Mississippi

Pregnancy, infancy, and early childhood are critical developmental periods for intervention to prevent obesity and Type II Diabetes. The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) is a long-standing federal program that is ideally suited to stem the tide of early pediatric obesity among low-income populations through the provision of ancillary healthy foods, health care referrals, and nutritional education and counseling. Participation in WIC may offer a unique and timely opportunity to augment nutritional counseling with the promotion of exercise; a collective, energy-balanced approach that is likely to promote healthy gestational weight gain and postpartum weight loss, particularly for the 220,000 adolescent WIC mothers in the United States.

Formative research to support obesity prevention interventions delivered through existing public health service programs that low-income pregnant and postpartum adolescents, such as WIC, is paramount. Thus, the goal of this two-year exploratory study is to identify modifiable psychosocial, cultural, and environmental factors related to exercise behavior in pregnant and postpartum adolescent (≤19 years) WIC participants in Mississippi. We aim to: (1) utilize qualitative (parent/guardian focus groups; WIC staff interviews; adolescent small group interviews; adolescent photovoice projects) and quantitative (adolescent-parent/guardian dyad surveys) methods to explore multi-level predisposing, enabling, and reinforcing psychosocial, environmental, and cultural determinants of exercise behavior during pregnancy and postpartum periods, and in the transitional phase from pregnancy to postpartum; and (2) objectively assess rural environmental supports for exercise using the Rural Active Living Assessment (RALA) tools and the Physical Activity Resource Assessment (PARA) tool.

The outcomes of this investigation will bolster a K01 proposal (PAR-16-211) to develop and test the effectiveness, feasibility, and acceptability of a theory-based, multimodal digital exercise intervention rural, low-income pregnant and postpartum adolescents in Mississippi using an effectiveness-implementation research design. This is an important and understudied line of behavioral intervention research to prevent pediatric obesity during critical developmental periods from pregnancy through adolescence.

Honors and Awards

• Received Fed PHS – HRSA. PM-CALM: Preventive Medicine Curriculum for Access to Lifestyle Medicine. Total funds: $398,975.00.
• Received NIH/NHLBI – Jackson Heart Study. Telehealth Diabetes Prevention Intervention for the Next Generation of African American Youth (TELE-GEN). Total funds: $177,968
• Received the Excellence in Community-Engaged Research, University of Mississippi, April 2019
• Internal review panels: MCCTR Pilot Grants Program 
• External review panels: American Journal of Public Health; International Journal for Public Health

Presentations

• Gamble A. Qualitative interviews with WIC providers to probe recruitment, retention, and engagement strategies for exercise interventions. Oral presentation at the 14^th Annual UAB Health Disparities Research Symposium; March 2019; Birmingham, AL.
• Gamble A. Recruiting pregnant adolescents in an intervention study: perspectives of WIC providers using qualitative interviews; November 2019; Louisville, KY.
• Gamble A. Recruitment, retention and engagement strategies for exercise interventions with rural antenatal adolescents: qualitative interviews with WIC providers; February 2020; Orlando, FL.

Pubmed

Candace Howard, MD, PhD

Assistant Professor, Radiology
UMMC

Body Composition as a Biomarker of Obesity-Related Diseases in African-Americans

Dr. Howard-Claudio's proposal aims to characterize the body composition of a large cohort of African Americans to discern how anthropometric measures including SAD and waist circumference (WC) compare with VAT and/or fatty liver in their association with metabolic traits (fasting glucose, fasting insulin, HOMA-IR, lipid and cholesterol measures), and their ability to predict metabolic and CVD outcomes (e.g. incident type 2 diabetes, CVD events, and hepatic steatosis).

The overall intent is to identify reliable predictive measures of obesity-related diseases by assessing the correlation of SAD and CT imaging-derived measures of body composition and fat distribution to metabolic traits in African-Americans.

Honors and Awards

• Most Outstanding Poster, Research Day, University of Mississippi Medical Center, Department of Medicine, 2019
• Most Outstanding Oral Presentation in the Field of Medical Research, Mississippi Academy of Science, February 2019
• Travel Fellowship Award for Faculty, Southern Society of Clinical Investigation, February 2020
• Promoted to Associate Professor
•  Internal, MSRP Review Panel (September 2018, February 2019)
• Internal, MSRP Review Panel (October 2019, January 2020)

Presentations

• Howard CM. Analysis of abdominal body composition as a biomarker of cardiovascular and other obesity-related diseases in African Americans: The Jackson Heart Study. Oral presentation at the MCCTR-COBRE Joint Meeting; August 2017; Jackson, MS
• Howard C. Analysis of Abdominal Body Composition as a Biomarker of Cardiovascular and Other Obesity-Related Diseases in African Americans: The Jackson Heart Study. MCCTR-COBRE Joint Meeting, Jackson, MS. August 17, 2017.
• Howard C, Florez E, Varney E, Santos C. Body Composition Analysis and Metabolic Fat Deposition in African Americans. UMMC Clinical and Translational Science Health Disparities Conference, Jackson, MS. August 19, 2018.
• Howard C, Florez E, Varney E, Santos C. Sarcopenia and abdominal fat effects on liver surface nodularity in a high-risk population of African Americans. UMMC Clinical and Translational Science Health Disparities Conference, Jackson, MS. August 19, 2018.
• Edward Florez, Todd Nichols, Ellen E. Parker, Seth T. Lirette, Candace M. Howard, and Ali Fatemi. Multiparametric MR imaging in the assessment of primary brain tumors through radiomic features: a metric for guided radiation treatment planning. Cureus 2018, Oct Oct 8;10(10):e3426.
• De Carlo F., Thomas L., Brooke B., Varney E., Nande R., Boskovic O., Marshall G., Claudio P.P., Howard C.M. Evaluation of immune response after ultrasound targeted gene therapy in a mouse model of prostate cancer. J Transl Med. 2019 Jan 11;17(1):19.
• Howard C. Anthropometric measures of obesity as a predictor of liver surface nodularity in a diverse NAFLD population. UMMC Department of Medicine Research Day Poster Presentation, Jackson, MS. April 16, 2019. UMMC Department of Medicine Research Day, Jackson, MS. April 16, 2019.
• Reese J, Florez W, Flowers W, Dyess L, Miller S, Johnson CR, Rushing BJ, Khadivi AH, Howard C, Martin D, Robertson T, Varney E, Hamidi R, Lirette ST, Howard C. Association between abdominal fat density with simple anthropometric measures and its correlation with Cardiovascular Disease (CVD) risk factors in African-Americans. Poster presentation. UMMC Department of Medicine Research Day, Jackson, MS. April 16, 2019.
• Varney E, Howard C. Chemo-predictive assay to target cancer stem cells in glioblastoma patients. Oral Presentation. UMMC Department of Medicine Research Day, Jackson, MS. April 16, 2019.
• Adcock C, Florez H, Howard C, Khosravi H, Fatemi A. Consideration of tumor volume in the dosage calculation for Ytrium-90 Transarterial Radioembilization of Hepatocelluar Carcinoma. Poster Presentation. UMMC Department of Medicine Research Day, Jackson, MS. April 16, 2019.
• Howard C. A CT radiomic algorithm predicts metastatic Renal Cell Carcinoma (RCC) response to Anti-Angiogenic (AAG) therapy. Poster presentation. UMMC Department of Medicine Research Day, Jackson, MS. April 16, 2019.
• Miller S, Varney E, Florez E, Howard C, et al. Effect of liver surface nodularity, sarcopenia, and visceral obesity as risk factors in African American Adults. Poster presentation. UMMC Department of Medicine Research Day, Jackson, MS. April 16, 2019.
• Varney ET, Howard CM, Bou Zgheib N, Tang S, Claudio PP. Evaluation of cancer stem cell drug response assay in the treatment of recurrent ovarian cancer patients. Poster presentation. UMMC Department of Medicine Research Day, Jackson, MS. April 16, 2019.
• Varney ET, De Carlo F, Bell B, Marshal G, Claudio PP, Howard CM. Evaluation of immune response following ultrasound targeted gene therapy in a murine model of prostate cancer. Poster presentation. UMMC Department of Medicine Research Day, Jackson, MS. April 16, 2019. Abstract
• Johnson CR, Florez E, Flowers W, et al. Simple anthropometric measures on CT images as predictors of cardiovascular risk among African-Americans. Poster presentation. UMMC Department of Medicine Research Day, Jackson, MS. April 16, 2019.
• Varney E, Howard CM, Ranjan T, Tang S, Claudio PP. Use of cancer stem cell drug response assay to improve the outcome of glioblastoma patients. Poster presentation. UMMC Department of Medicine Research Day, Jackson, MS. April 16, 2019
• Rushing BJ, Florez E, Flowers W, Miller S, Varney E, Lirette ST, Howard CM. Anthropometric measures of obesity as a predictor of liver surface nodularity in a diverse NAFLD population. UMMC School of Health Related Professions (SHRP) Research Day Poster Presentation, Jackson, MS. April 26, 2019.
• Reese J, Florez E, Flowers W, Dyess L, Miller S, Johnson CR, Rushing BJ, Khadivi AH, Claudio C, Martin D, Robertson T, Varney E, Hamidi R, Lirette ST, Howard CM. Association between abdominal fat density with simple anthropometric measures and its correlation with Cardiovascular Disease (CVD) risk factors in African-Americans. UMMC School of Health Related Professions (SHRP) Research Day Poster Presentation, Jackson, MS. April 26, 2019.
• Miller S, Varney E, Florez E, Claudio C, Flowers W, Dyess L, Khadivi A, Johnson C, Martin D, Robertson T, Hamidi R, Gordy D, Rimes J, Lirette S, Fatemi A, Howard C. Effect of liver surface nodularity, sarcopenia and visceral obesity as risk factors in African Americans adults. Poster presentation. UMMC School of Health Related Professions (SHRP) Research Day, Jackson, MS. April 26, 2019.
• Johnson CR, Florez E, Flowers W, Dyess L, Miller S, Khadivi A, Reese J, Rushing B, Martin D, Robertson T, Varney E, Hamidi R, Lirette ST, Howard CM. Simple anthropometric measures on CT images as predictors of cardiovascular risk among African-Americans. Poster Presentation. UMMC School of Health Related Professions (SHRP) Research Day, Jackson, MS. April 26, 2019.
• E. Florez, C.M. Howard, S.T. Lirette, B.C. Allen, E.M. Remer, Z.J. Wang, J.E. Bieszczad, K.L. Cox, S.B. Nandwana, A.B. Shinagare, R. Sanyal, A.H. Goenka, H.C. Kang, A.D. Smith. CT Texture algorithm predicts metastatic RCC response to anti-angiogenic therapy. Oral presentation at 8th Annual Radiology / Radiation Oncology Research Scholars Day. May 4, 2018. UMMC School of Medicine, Jackson, Mississippi
• Flavia De Carlo, Litty Thomas, Rounak Nande, Olivia Boskovic, Gailen D. Marshall, Pier Paolo Claudio and Candace M. Howard.   Ultrasound Targeted Gene Therapy in a Mouse Model of Prostate Cancer: Evaluation of Immune Response. ASCO Genitourinary Cancers Symposium (Targeting Evidence to Multidisciplinary Care). San Francisco, CA, Feb 8-10, 2018.
• Howard C, Griswold M, Claudio PP. Prospective Analysis of Cancer Stem Cell Drug Response Assay for Glioblastoma Patients. University of Mississippi, Annual Pathology Research Day, Oxford, MS. May 10, 2018.
• Howard C. Body Composition Analysis in African Americans. NIH, NIGMS Seventh Biennial National IDeA Symposium of Biomedical Research Excellence, Washington, DC. June 24, 2018.
• Varney E., DeCarlo F., Claudio P., Howard C.M. ChemoID – Personalizing treatment in the management of newly diagnosed and recurrent glioblastoma. Big IDEAs for Improving the Lives of Mississippians, 2018 Mississippi IDeA Conference. July 27, 2018, Jackson, MS
• Howard C, Valluri J, Ranjan T, Yu A, Aziz K. Prospective Analysis of Cancer Stem Cell Drug Response Assay for Glioblastoma Patients. Cancer Stem Cells Conference 2018, Cleveland OH. August 6, 2018.
• Howard C, Florez E, Santos C, Varney E, Lirette, S. Body Composition Analysis and Metabolic Fat Deposition in African Americans. 2018 Mississippi IDeA Conference, Jackson, MS. August 27, 2018.
• Howard C, Florez E, Varney E, Santos C. The effects of abdominal fat and muscle mass on liver surface nodularity in a high-risk population using abdominal CT images. 2018 Mississippi IDeA Conference, Jackson, MS. August 27, 2018.
• Miller S, Howard CM. Can anthropometric measures of obesity predict liver surface nodularity in a diverse NAFLD population? Oral presentation. 84^th Annual Mississippi Academy of Sciences Meeting, Hattiesburg, MS. February 20-21, 2019.
• Miller S, Varney E, Claudio C, et al. Effect of liver surface nodularity, sarcopenia, and visceral obesity as risk factors in African American adults. Poster presentation. 84^th Annual Mississippi Academy of Sciences Meeting, Hattiesburg, MS. February 20-21, 2019.
• Varney E., Taylor C., Hooker J., Lirette S., Gordy D., Hamidi R., Joyner D., Nichols T., Parker E., Baird S., Rizvi T., Smith A.D., Howard C.M. Prospective validation of colored non- enhanced head CT images for detecting acute stroke in the setting of a Code Gray. Hattiesburg, MS 83rd Annual Mississippi Academy of Sciences Meeting. Feb 21-21, 2019.
• Howard C. Personalized medicine with chemo predictive assay to target cancer stem cells in glioblastoma. Oral presentation. 84^th Annual Mississippi Academy of Sciences Meeting, Hattiesburg, MS. February 20-21, 2019.
• Howard C. Personalized medicine with chemo predictive assay to target cancer stem cells in recurrent ovarian carcinoma. Oral presentation. 84^th Annual Mississippi Academy of Sciences Meeting, Hattiesburg, MS. February 20-21, 2019.
• Florez E, Howard C. The relationship of abdominal fat density with simple anthropometric measures and its correlation with cardiovascular disease (CVD) risk factors in African- Americans (AA). Oral presentation. 84^th Annual Mississippi Academy of Sciences Meeting, Hattiesburg, MS. February 20-21, 2019.
• Howard C, Florez E, Flowers W, Dyess L, Miller S. Simple anthropometric biomarkers of complex body composition as predictors of cardiovascular risk among African-Americans. 83^rd Annual Mississippi Academy of Sciences Meeting, Hattiesburg, MS. February 20-21, 2019.
• Howard C. Project update: Body composition as a biomarker of obesity related diseases in African Americans. Video-conference presentation. NIGMS progress update. April 9, 2019. 

Past investigators

Susan Mayfield-Johnson, PhD

Assistant Professor, Public Health
University of Southern Mississippi

Effectiveness of Community Health Workers in Reducing CVD in the Mississippi Delta

Dr. Mayfield-Johnson’s research focuses on understanding and improving population health and reducing health disparities.

The goal of the pilot project is to assess the effectiveness of a CHW model on the continued care and management of cardiovascular disease among patients at federally qualified health centers (FQHCs) and community health centers (CHCs) in the Mississippi Delta. The MCCTR Pilot Project aims to systematically assess Community Health Workers’ impact on improving clinical outcomes, patient satisfaction, and reducing costs among patients at FQHCs and CHCs in the Mississippi Delta. These efforts are the next step towards evaluating the effectiveness of CHWs as a best practice intervention model for CVD-risk factors including obesity.

Honors and Awards

• Received grant, Patient Chronic Disease Self-Management, MSDH. Total costs: $25,488
• Received NIH grant, Jackson Heart Study – Community Engagement Center. Project dates: 8/16/18-8/15/19. Total costs: $25,003
• Health Care Hero, Mississippi Business Journal 2016
• International Outbound Fellow, US State Department and Association of University Centers on Disabilities, ADA International Fellowship, Fellowship to Kenya, March 2018
• Tenure and promotion to Associate Professor, 2018
• Distinguished Researcher Award, College of Nursing and Health Professions, University of Southern Mississippi, May 2019
• Basic Research Award, Finalist, the University of Southern Mississippi, 2018
• Excellence in Diversity and Inclusion Award, Institutions of Higher Learning, February 2020
• External Review Panel, HRSA-18-030: Rural health care services outreach. January 2018. 
• External Review Panel, Advanced Nursing Education Workforce (ANEW), HRSA. February 2019.
• External Review Panel, Oral Health Infrastructure, HRSA. July 2019 
• External Review Panel, Rural Health Development Network Program, HRSA, March 2020.

Presentations

• Mayfield-Johnson S. Community research fellows training program. Oral presentation at the Gulf States Health Policy Center; April 2017; Mobile, AL.
• Mayfield-Johnson S. Improving women’s health along the Mississippi gulf coast: findings from focus groups on women’s preventative and reproductive health. Oral presentation at the American Public Health Association Annual Meeting and Exposition; November 2016; Denver, CO.
• Mayfield-Johnson S. Improving Knowledge and Behavioral Intentions Associated with Determinants of Infant Mortality in Southern Mississippi: Let’s Start with Head Start Families. Oral presentation at the American Public Health Association Annual Meeting and Exposition; November 2016; Denver, CO.
• Mayfield-Johnson S. Increasing Research Capacity in Mississippi Communities: Evaluation of the Community Fellows Research Training Program. Oral presentation at the American Public Health Association Annual Meeting and Exposition; November 2016; Denver, CO.
• Mayfield-Johnson S. Photovoice training for 45 tobacco control directors. Oral presentation at the Mississippi State Department of Health; November 2016; Jackson, MS.
• Mayfield-Johnson S. Comprehensive core skills in outreach and chronic disease training. Oral presentation at the Delta Health Alliance; January 2017; Ridgeland, MS.
• Mayfield-Johnson S, Fastring D, Keel K, Colby D, Conner M. Nutritional and physical activity intervention for Head Start Centers in South Mississippi: A comprehensive evaluation. Oral Presentation at the American Public Health Association Annual Meeting and Exposition; November 2017; Atlanta, GA.
• Mayfield-Johnson S, Fastring D. Mississippi community health worker needs assessment. Oral presentation at the Delta-Area CHW Symposium: Mississippi Delta Health Collaborative; November 2017; Stoneville, MS.
• Mayfield-Johnson S. Photovoice. Oral presentation at the Community Research Fellows Training Program.; April 2018; Mobile, AL.
• Mayfield-Johnson S. Community research fellows training program: Reducing mistrust of research and researchers among participants. Poster session at the American Public Health Association Annual Meeting and Exposition; November 2017; Atlanta, GA.
• Mayfield-Johnson S. We make the road by walking: An overview of national CHW activity. Oral presentation at the Delta-Area CHW Symposium: Mississippi Delta Health Collaborative; November 2017; Stoneville, MS.
• Mayfield-Johnson S, Bright C, Manzella B, McKenzie A, Archer S. Health policy affects health outcomes, community determinants of health. Oral presentation at the Gulf States Health Policy Center Symposium; April 2018; Washington, DC.
• Mayfield-Johnson S, St. John J, Hernandez W, Fastring D. Results from a national CHW survey. Scientific breakout session at the American Public Health Association Annual Meeting and Exposition; November 2017; Atlanta, GA.
• Mayfield-Johnson S. Effectiveness of community health workers in reducing cardiovascular disease in the Mississippi Delta. Oral presentation at the COBRE-MCCTR Joint Meeting; January 2018; Jackson, MS.
• Mayfield-Johnson S. Comprehensive core skills in outreach and motivational interviewing training. Training workshop at the Mississippi Delta Health Collaborative; July 2018; Stoneville, MS.
• Mayfield-Johnson S. Le D, Fastring D, Nguyen J. Measuring Vulnerability and developing resiliency among the Vietnamese population on the Mississippi Gulf Coast through Photovoice. Oral presentation at the Mississippi IDeA Conference; July 2018; Jackson, MS.
• Mayfield-Johnson S. Comprehensive core skills in outreach and motivational interviewing training. Training workshop; June 2018; Greenwood, MS.
• Mayfield-Johnson S, Le D, Fastring D, Nguyen J. Describing vulnerability and resiliency of Vietnamese Mississippi Gulf Coast residents through Photovoice. Oral presentation at the Second Conference on Bioethics Issues in Minority Health and Health Disparities Research, Morehouse School of Medicine; January 2019; Opelika, AL.
• Mayfield-Johnson S, Manzella B, McKenzie-Skipper A, Sanders E. Health policy affects health outcomes. Oral presentation at the Gulf States Health Policy Center Symposium; April 2019; Washington, DC.
• Mayfield-Johnson S, Le D, Nguyen J. Vulnerability and resiliency among the Vietnamese population on the Mississippi Gulf Coast through Photovoice. Oral presentation at the 20th Anniversary of the National Conference for and About CHWs; April 2019; Las Vegas, NV.
• Mayfield-Johnson S. Roles of community health advisors in CEnR. Oral presentation at the Community-Engaged Research Summer Institute; June 2018; Tougaloo, MS.
• Mayfield-Johnson S. Community-engaged research, foundations, principles, and practices. Oral presentation at the Community-Engaged Research Summer Institute; June 2018; Tougaloo, MS.
• Mayfield-Johnson S. What is a community health worker? Oral presentation at the Prematurity and Breastfeeding Summit; June 2019; Jackson, MS
• Mayfield-Johnson S. Effectiveness of community health workers in reducing cardiovascular disease in the Mississippi Delta. Poster presentation at the National Rural Health Association’s Annual Meeting; May 2019; Atlanta, GA.
• Mayfield-Johnson S, Le D, Nguyen J. Developing resiliency among the Vietnamese population on the Mississippi Gulf Coast. Poster session at the National Rural Health Association’s Health Equity Conference; May 2019; Atlanta, GA.
• Mayfield-Johnson S. Partnering with CHWs in population health. Panel presentation at the Mississippi Public Health Association; October 2019; Jackson, MS.
• Mayfield-Johnson S, Le D, Fastring D, Nguyen J. Describing vulnerability and resiliency through photovoice: Generational perspective from Mississippi Gulf Coast Vietnamese Community. Poster session at the American Public Health Association Annual Meeting and Exposition; November 2019; Philadelphia, PA.

Pubmed

Xiuquan Wang, PhD

Professor, Mathematics
Tougaloo College

Uncovering and Understanding Population Differences with Topological Methods

Dr. Wang's pilot project uses topological data analysis and analytic tools to generate information for analysis to better describe the mechanisms of disease in the study population (JHS participants). The same disease may come from many different mechanisms but the underlying mechanism of the disease may determine the best treatment. The goal of the analysis is to break populations with complex diseases into mechanistically consistent subpopulations and propose treatments based on the mechanism.

Obesity, hypertension, renal disease, and a combination of the three are the result of distinct etiologies within the study participants. By analyzing aptamer, metabolic, and clinical data alone or in tandem, differences between populations will explain these etiologies.

Honors and Awards

• External Peer Review Panel: American Journal of Bioinformatics Research; Scientific and Academic Publishing; September 2019.

Presentations

• Wang X. ““Understanding and uncovering population differences with topological methods.” Oral presentation at the 2019 MCCTR Annual Retreat and EAC Meeting; May 2019; Jackson, MS.
• Wang, X. “Understanding and uncovering population differences with topological methods.” Oral presentation at the 2020 Joint Mathematical Meeting; May 2020; Denver, CO.

Andrew Smith, MD, PhD

Director, Radiology Research
Body and Oncologic Radiologist

Comparative Effectiveness of Noninvasive Tests for Staging Chronic Liver Disease

Dr. Smith's research focuses on identifying methods to non-invasively stage chronic liver disease in lean and obese patients. Chronic liver disease is clinically silent and can progress to irreversible cirrhosis which can in turn lead to liver cancer, liver failure and death. Chronic liver disease is more common, more severe, and more difficult to stage in obese patients. Treatment is based on the cause and stage of disease, and the reference standard for staging chronic liver disease is liver biopsy, though problems with the procedure include the invasive approach, sampling errors, subjectivity in pathologic staging, and complications such as pain, bleeding, infection and rarely death.

Dr. Smith is conducting a comparative effectiveness study whereby his team will prospectively compare the accuracy and technical success rate of several different noninvasive imaging techniques that can be used to stage chronic liver disease including ultrasound elastography, magnetic resonance elastograpy, and a computed tomography (CT) liver surface nodularity score. He hypothesizes that the CT liver surface nodularity score will have similar accuracy but a high technical success rate than competing noninvasive imaging techniques, especially in obese patients.

Marcus Zachariah, MD, PhD

Assistant Professor, Neurosurgury
UMMC

Modeling Leptomeningeal Metastasis using Breast Circulating Tumor Cell Xenografts

Leptomeningeal metastasis (LMD) occurs in up to 10% of solid tumors and 15% of hematologic malignancies, with an expected median survival of 3-16 weeks. Despite overwhelming associated morbidity and mortality, major gaps exist in the understanding of LMD, and therapeutic options are limited. In this 1- year pilot proposal, we will develop a circulating tumor cell (CTC)-based patient-derived xenograft (PDX) model of LMD in zebrafish. PDX models in zebrafish offer the benefit of high throughput, low cost, and the requirement for fewer input cells compared to other model systems. We will focus our efforts on 2 specific aims. First, using breast CTC isolates (BRx-42 and BRx-29, both derived from the peripheral blood of women with intracranial metastasis) that we have previously established and engineered to express luciferase and green fluorescent protein, we will perform intraventricular brain injections in zebrafish embryos 2 days post-fertilization. Subsequently, we will evaluate tumor cell growth and invasion in the zebrafish embryos, which are translucent, using fluorescence microscopy. Second, we will collect CTCs directly from the cerebrospinal fluid (CSF) of breast and lung cancer patients with LMD. Of note, CTCs from the CSF are routinely collected during clinical care of patients with LMD. Any excess CTCs will be labeled fluorescently with Dil and injected intraventricularly in zebrafish embryo brains 2 days post-fertilization. We anticipate obtaining CTCs from 5-10 patients during the 1-year pilot period. Tumor cell growth and invasion will be evaluated using fluorescence microscopy. During the 1-year funding period, we expect to achieve the development of these two systems as robust models of studying LMD. In follow-up studies, we will employ these models to 1) explore molecular pathways associated with the development of LMD using CRISPR/CAS9 whole-genome screening and 2) evaluate candidate therapeutics for LMD. We anticipate these studies will lead to high-profile publications and funded grant applications.

Pubmed