Collaborative Bioinformatics Research with H-SC Student Taylor J. McGee ’23 Highlights New Biomarkers of Melanoma Patient Response to Immunotherapy
Elliott Associate Professor of Biology Dr. Kristian M. Hargadon ’01 recently published an article entitled “Genomic and Transcriptional Changes in IFNg Pathway Genes are Putative Biomarkers of Response to Ipilimumab Immunotherapy in Melanoma Patients” in the journal Expert Review of Clinical Immunology. This invited article is a Key Paper Evaluation highlighting a seminal paper in the field of tumor immunology from the laboratory of Nobel Laureate Dr. James Allison, who developed the first FDA-approved immunotherapeutic for a cancer treatment strategy known as immune checkpoint blockade. Since the approval of ipilimumab in 2011, ipilimumab’s success as a therapeutic has spearheaded the development of several other now-approved immune checkpoint inhibitors, all of which function by “unleashing” anti-tumor immune responses that are otherwise restrained in cancer patients. Though the success of these therapies has led to unprecedented clinical outcomes for many cancer patients, there remain others who either fail to respond to therapy or exhibit disease recurrence after a short response. The work from Dr. Allison’s group highlighted in Dr. Hargadon’s Key Paper Evaluation was the first to describe defects in genes associated with the IFNg pathway as a mechanism of tumor escape from ipilimumab-associated immune responses. Specifically, mutations and other alterations to genes that control this pathway in tumor cells were found to drive tumor resistance to therapy-induced immune responses.
As part of his evaluation of this seminal work, through the College’s Faculty Fellowship Program this past summer Dr. Hargadon conducted additional bioinformatics research with Hampden-Sydney student, Taylor J. McGee ’23, to assess whether non-genomic alterations to the IFNg pathway also correlated with patient response to ipilimumab. Using clinical data from melanoma patients catalogued in The Cancer Genome Atlas, Dr. Hargadon and Taylor found that RNA levels for several IFNg pathway genes also correlate with patient response to ipilimumab. These new data indicate that not only are direct changes to IFNg pathway genes associated with tumor resistance to therapy, but so too are alterations in IFNg pathway gene expression levels. These findings further highlight the significance of the IFNg pathway as a determinant of anti-tumor immune efficacy as first described by Dr. Allison’s group at MD Anderson Cancer Center, and they reveal the potential utility of RNA-level biomarkers associated with this pathway that could be used to predict patient response to immunotherapy in the future.
Taylor McGee, a co-author on this article, is a sophomore at Hampden-Sydney College and plans to pursue his Ph.D. in computational biology following his graduation in 2023. His ultimate career goal is to apply novel computational models to the study of problems in the field of HIV research.
The article authored by Dr. Hargadon and Taylor can be found at: https://www.tandfonline.com/doi/full/10.1080/1744666X.2021.1847644?scroll=top&needAccess=true
Elliott Associate Professor of Biology Dr. Kristian M. Hargadon ’01 recently published a major review article entitled “Tumor Microenvironmental Influences on Dendritic Cell and T Cell Function: A Focus on Clinically Relevant Immunologic and Metabolic Checkpoints” in the journal Clinical and Translational Medicine. An invited review commissioned by the journal’s Editor-in-Chief Dr. Xiangdong Wang, Distinguished Professor of Medicine and Director of the Shanghai Institute of Clinical Bioinformatics at the prestigious Fudan University in China, Dr. Hargadon’s article highlights recent advances in immunotherapy and targeted therapy as cutting-edge treatments for cancer. His review discusses in particular the role of key checkpoints that inherently limit the immune and metabolic functions of dendritic cells and T cells within the tumor microenvironment, and it emphasizes how insights into these suppressive pathways have led to the identification of novel targets for therapies designed to enhance the anti-tumor immune functions of these important cell populations. Dr. Hargadon’s article also discusses the potential for combinatorial therapies that target these diverse checkpoints to enhance patient outcome by increasing the percentage of patients likely to benefit from immunotherapy and by overcoming tumor cell resistance to immunotherapy in patients who normally do respond but then ultimately relapse.
Published by John Wiley and Sons (Wiley), Clinical and Translational Medicine is an international, peer-reviewed, and open access journal with aims at 1) promoting and accelerating the translation of preclinical research to a clinical application and 2) enhancing communication between basic and clinical scientists. Dr. Hargadon’s article can be accessed at: https://onlinelibrary.wiley.com/doi/full/10.1002/ctm2.37
Elliott Associate Professor of Biology Dr. Kristian M. Hargadon ’01 has recently published research on the function of the FOXC2 transcription factor in melanoma in Frontiers in Oncology, one of the most cited and highly ranked journals in the field of Oncology. The article, entitled “RNA-seq Analysis of Wild-Type vs. FOXC2-Deficient Melanoma Cells Reveals a Role for the FOXC2 Transcription Factor in the Regulation of Multiple Oncogenic Pathways,” employs genomic and bioinformatic analyses of a novel CRISPR-Cas9 gene-edited melanoma cell line engineered by Dr. Hargadon at Hampden-Sydney College. The study provides important mechanistic insights into FOXC2’s role in the regulation of melanoma cell proliferation, invasion, metabolism, drug resistance, and immune escape, all of which are key hallmarks of cancer progression. Together with previous research published by Dr. Hargadon in Cancer Genomics and Proteomics in late 2019, these data highlight the FOXC2 transcription factor as a major oncogenic driver in melanoma.
Of note, former H-SC student Corey J. Williams ’19 is a co-author on the Frontiers in Oncology article with Dr. Hargadon. Corey is currently enrolled as a medical student at the VCU School of Medicine. Dr. Hargadon, Corey, and pathologists at VCU are currently planning collaborative studies that will extend the in vitro and animal studies at H-SC into a clinical setting. This work will involve analyses of FOXC2 expression in melanoma cells from patient biopsies and will assess whether FOXC2 is a useful prognostic factor for predicting tumor progression and survival in melanoma patients. Such information may ultimately be useful in determining optimal treatment strategies for patients based on FOXC2 expression levels in their tumors at the time of diagnosis.
Dr. Hargadon’s Frontiers in Oncology article can be accessed at:
Dr. Kristin Fischer, Andrew Howell ’20, and Brahm Dean ’21 recently traveled to Philadelphia to present their research at the Biomedical Engineering Society Annual meeting. Andrew presented his work with Dr. Fischer on fabricating a 3D printed uniaxial stretch bioreactor. This work is supported by a grant Dr. Fischer received from the Virginia Academy of Sciences. Brahm presented his work with Dr. Fischer, Dr. Paul Mueller in Chemistry, and Dr. Trey Thurman in Physics on incorporating zinc into hydrogels to make them conductive for soft tissue regeneration like skeletal muscle.
The latest issue of the journal Cancer Genomics and Proteomics features new research published by Elliott Associate Professor of Biology Dr. Kristian M. Hargadon ’01. Dr. Hargadon’s latest work describes a novel role for the FOXC2 transcription factor as a driver of melanoma progression, and his study represents the first to investigate FOXC2 function in the context of this particular type of cancer. Dr. Hargadon began investigating FOXC2’s role in melanoma progression in 2015, after previous work in his laboratory demonstrated elevated FOXC2 gene expression in a highly aggressive mouse melanoma model. Over the last 4 years, Dr. Hargadon has involved several Hampden-Sydney College students in projects designed to understand FOXC2 function in melanoma cells. This work included the use of CRISPR-Cas9 gene-editing technology to engineer a novel FOXC2-deficient melanoma cell line that exhibited delayed outgrowth in experimental animals. Subsequent gene expression analyses using this novel cell line demonstrated that FOXC2 regulates several oncogenic pathways in melanoma cells, including drug resistance and responsiveness to important components of the immune system. The significance of this work in the mouse model is highlighted by similar findings in tumor biopsies of melanoma patients. Dr. Hargadon and his students analyzed patient data from The Cancer Genome Atlas and found that high FOXC2 gene expression correlates with poor patient survival following treatment with either chemotherapy or immunotherapy. These findings suggest that FOXC2 might serve as a useful biomarker in predicting melanoma patient response to these therapeutic modalities, and they also highlight the utility of Dr. Hargadon’s mouse model for investigating how FOXC2 promotes drug and immune resistance in melanoma cells in future studies.
This multi-year project included contributions from 6 H-SC students, all of whom worked with Dr. Hargadon through either Hampden-Sydney College’s Summer Research Program or its Honors Capstone Program. These students are included as co-authors on the research paper in Cancer Genomics and Proteomics and are listed below:
Jefferson Thompson ’16 – attending Arkansas College of Osteopathic Medicine
Coleman Johnson ’19 – attending Virginia Commonwealth University School of Medicine
Corey Williams ’19 – attending Virginia Commonwealth University School of Medicine
David Bushhouse ’19 – attending Northwestern University Interdisciplinary Biological Sciences Ph.D. Program
Eli Strong ’20 – will attend George Washington University School of Medicine in 2020
Brian Tarnai ’20 – will attend George Washington University School of Medicine in 2020
Dr. Hargadon’s research article is available at: http://cgp.iiarjournals.org/content/16/6/491.full.pdf+html
Elliott Associate Professor of Biology Dr. Kristian M. Hargadon ’01 was recently named a recipient of the Virginia Academy of Science’s Mary Louise Andrews Award for Cancer Research. This award, in the form of a $3,000 research grant, will support a project entitled “The Role of Tumor-associated Chemokine Receptors in Lymph Node Invasion by Melanoma.” An expert in tumor immunology, Dr. Hargadon has focused his recent efforts on melanoma, an aggressive type of skin cancer that frequently metastasizes throughout the body. This project will address factors that promote melanoma spread to regional lymph nodes, a poor prognostic factor in cancer patients. Insights into lymph node invasion by melanoma may yield novel targets for therapies that aim to delay melanoma progression. Such approaches might also lead to improved responses to immunotherapy regimens, particularly those that target immune cells within lymph nodes and which might otherwise be compromised by tumor cells that have already spread to these organs prior to treatment. Preliminary work to support this award application began in 2018, when Dr. Hargadon mentored Goldwater Award recipient David Bushhouse ’19, who presented the lab’s findings at the Annual Meeting of the American Association for Cancer Research in Atlanta, Georgia. David is currently pursuing his Ph.D. in the Interdisciplinary Biological Sciences Graduate Program at Northwestern University.
Elliott Associate Professor of Biology Dr. Kristian M. Hargadon ’01 and two of his research students (Corey Williams ’19 and Coleman Johnson ’19) recently published a review article on cancer immunotherapy in the journal International Immunopharmacology. The article, entitled “Immune Checkpoint Blockade Therapy for Cancer: An Overview of FDA-approved Immune Checkpoint Inhibitors,” highlights the emerging field of checkpoint blockade therapy that has revolutionized the treatment of many cancer types in recent years. Designed to “release the brakes” that inherently limit the strength and duration of natural immune responses, checkpoint blockade therapy enables many patients to achieve long-term anti-tumor immune responses capable of eradicating their disease. An expert in tumor immunology. Dr. Hargadon was invited by editors of the journal to contribute an article on cancer immunotherapy, and he used this opportunity to engage two of his pre-medical research students in the analysis of clinical trial outcomes for immune checkpoint inhibitors. Corey Williams and Coleman Johnson have been doing melanoma research in Dr. Hargadon’s laboratory since the summer of 2017. Rising seniors, they will continue their work on factors that promote tumor immune evasion during their senior year. Both have already been accepted to Virginia Commonwealth University’s School of Medicine.
The Hargadon et al. article may be accessed here: https://authors.elsevier.com/a/1XJoR5aRFnNvyw
In addition to appearing in a regular issue of the journal, Dr. Hargadon’s article will also be featured in a Special Issue on “Cellular Therapeutics in the Context of Immunopharmacology.”
5 outstanding Hampden-Sydney College sophomore students were recently accepted into prestigious medical schools through early assurance articulation agreements established at the College. David Fluharty ’20, Khoa Tran ’20, and Jared Dunlap ’20 were all accepted to the Virginia Commonwealth University School of Medicine, and Eli Strong ’20 and Brian Tarnai ’20 were both accepted to the George Washington University School of Medicine. These students will complete their 4 years of undergraduate work at Hampden-Sydney College and will then enroll in medical school in the summer of 2020!
On Thursday, May 24, three Hampden-Sydney students working in the laboratory of Elliott Associate Professor of Biology Dr. Kristian M. Hargadon ’01 delivered oral presentations of their melanoma research. Corey Williams ’19, Coleman Johnson ’19, and recently named Goldwater Scholar David Bushhouse ’19 presented their work on the role of FOXC2 in melanoma progression. While Coleman has been investigating how FOXC2 regulates melanoma cell adhesion to the extracellular matrix and lymphatic endothelial cells, Corey has been studying how FOXC2 influences the expression of integrins and other cell adhesion molecules involved in these processes. In related work, David Bushhouse has been optimizing a chromatin immunoprecipitation assay for identifying target genes directly regulated by the FOXC2 transcription factor. Coleman and Corey have already been accepted to medical school at Virginia Commonwealth University, and David will be applying to graduate schools to pursue his Ph.D.
Also at this conference, Dr. Hargadon presented his work on the ways he is introducing his cancer research into the classroom as a means of exposing more students to the research process and as a tool for enabling students to investigate and better understand the process of gene expression.