Mitchell J. Frederick, PhD, BS
Present Title & Affiliation
FIVE MOST IMPORTANT CONTRIBUTIONS
1. First scientist to discover and publish functions for the novel human chemokine, BRAK.
2. Key scientist in the discovery of the novel Serpin, Headpin, and its functions.
3. First scientist to profile the phosphoproteome of Head and Neck Squamous Cell Carcinom HNSCC, and report frequent activation of PKC iota, a potential oncogene in this type of cancer
4. A team leader of a multi-instiutional effort to comprehensively characterize genomic abnormalities in HNSCC. This study was recently published in SCIENCE and included the identification of inactivating mutations in NOTCH 1 that occur in primary HNSCC, implicating this gene as a tumor suppressor.
5. Mentored, trained, and educated numerous research fellows , graduate students, and research assistants resulting in many co-authored publications. Clinical fellows , students, and research assistants have included: Dr. Tom Shellenberger, Dr. Hernan Gonzalez, Dr. Manu Gujrati, Dr. Chad Galer, Dr. Maria Gule , Dr. Genevieve Andrews, Dr. Kenji Mitsudo, Maria Sciuto, Mayur Gadhikar, Shhaym Moorthy, and David Fooshee.
Head and neck squamous cell carcinoma (HNSCC) causes roughly 300,000 deaths worldwide each year, and remains a challenge to treat despite advances in surgery, chemotherapy, and radiation. A better understanding of the signaling abnormalities and genomic alterations driving this disease has been the major goal and focus of my research as an Assistant Professor. I have been utilizing discovery-based research strategies to identify important molecular changes in primary HNSCC from patients and I have been working towards understanding the function of these molecules as they are discovered. This endeavor has gone through many evolutions and has led to the discovery of novel molecules and their functions. More recently, the approaches have culminated in a first- author publication in Science, in which we report the comprehensive characterization of the mutation spectra and gene copy number variations (CNV) found in primary HNSCC. I will now elaborate in chronological order some of the milestones of my research career and how it has impacted the scientific field.
In my earlier years, I collaborated with Dr. Gary Clayman to build a gene discovery lab and establish the techniques necessary to identify and analyze genes differentially expressed between primary HNSCC and their matching normal tissue from patients. Although some of this work pre-dates the widespread use of mRNA expression arrays and my appointment as Assistant Professor, it provides necessary context for the subsequent work and follow-up studies which did occur during my current appointment. Through our gene discovery efforts, I was one of the first scientists to clone and identify a novel human chemokine, BRAK (CXCl14), which is abundantly expressed in normal squamous mucosa but conspicuously absent in primary HNSCC tumors and virtually all established HNSCC tumor cell lines. This was before the completion of the Human Genome Project when there were still many unknown human genes. I spent several years in the laboratory successfully developing research tools to study the function of this novel chemokine, including recombinant human BRAK protein, antibodies that would work in multiple applications (i.e, ELISA, western blotting, immunohistochemistry), as well as engineering cDNA constructs and HNSCC lines stably re-expressing the BRAK gene. These research tools and reagents enabled me to be the first scientist to discover some of the important functions of BRAK, including its ability to attract immature human dendritic cells as well as inhibit angiogenesis. I was the senior and corresponding author on the published manuscript that communicated these findings (i.e, Shellenberger et al. 2004). Together, this paper and my original earlier publication on BRAK (i.e, Frederick et al. 2000) have been cited at least 125 times in the scientific literature. Although I no longer actively work on BRAK, I am still recognized by the scientific community as an expert on the molecule because of my work and I am occasionally solicited to review papers on the subject. In addition, the reagents I established have been used globally by leading scientists who have collaborated with me to publish papers on BRAK function in high impact journals, including PNAS and the Journal of Immunology. These latter international collaborations have uncovered novel functions for BRAK, including an anti-microbial activity. My research on BRAK has been funded by two consecutive developmental project awards from the University of Texas M.D Anderson Cancer Center Head and Neck SPORE, in which I was the Principal Investigator.
I have also played a very crucial role in the discovery of other genes and their functions. Working together with a research fellow whom I trained and mentored, we discovered and cloned another previously unknown gene that we named headpin (SERPINB13). Headpin is also abundantly expressed in normal squamous mucosa, but poorly expressed in primary HNSCC and established HNSCC tumor cell lines. I was one of the key investigators in a team of researchers who were the first to determine a biologic function for headpin, which turns out to be an inhibitor of cathepsins K and L (Jayakumar et al. 2003). As a further expansion of our gene discovery efforts, I worked together with several more research fellows to identify and publish additional genes differentially expressed in HNSCC tumors, including LEKTI which had no known function at the time (Gonzalez et al. 2003). Subsequently, I was a key collaborator and co-author on the first paper to demonstrate a function for LEKTI (Mitsudo et al. 2003), which turns out to be an inhibitor of plasmin, elastase, and kalikrein 5.
After identifying a number of genes differentially expressed in HNSCC and their functions, I later became interested in the aberrant signaling pathways in these tumors. Many proteins and cellular processes are regulated by protein phosphorylation and the majority of experimental cancer drugs target protein kinases. In order to examine the head and neck cancer phosphoproteome, I took a 9-month sabbatical to work and train at the Center for Applied Proteomics at George Mason University, in Manassas Virginia. While there, I worked closely with Lance Liotta and Emanual Petricoin, who are world renowned leaders in the field of proteomics.
During the sabbatical, I performed laser capture microdissection on clinical samples from patients with HNSCC , to enrich for either tumor or matched non-malignant squamous mucosa. I subsequently examined expression levels of 60 proteins (predominantly phosphoproteins) in 23 pairs of matched samples using state of the art reverse phase protein microarrays. This generated 2760 protein endpoints for analysis. Back at M.D. Anderson I worked closely with our department of Bioinformatics to come up with a meaningful way to analyze the large data set. As there are no standard ways to analyze this type of data, I developed some novel approaches that were subsequently incorporated into a manuscript detailing our findings (Frederick et al. 2011). The manuscript which appeared in the American Journal of Pathology has generated interest in the scientific community, as I was recently solicited to write a Book Chapter in the Methods in Molecular Biology series, with a chapter title of “Protein arrays: looking for new targets”. I also received funding as a principal investigator from the Thyroid Head and Neck Cancer(THANC) foundation to support this work, in the form of a Young Investigator award.
Our phosphoproteomic analysis demonstrated 18 protein analytes to be globally elevated in HNSCC, and 17 that were decreased compared to normal squamous mucosa. The key findings reported in our paper were that HNSCC tumors have elevated phosphorylation of checkpoint kinases (despite no prior chemoradiation), and elevated phosphorylation of PKC iota and MEK 1/2, as well as elevated levels of total PKC iota. I am currently collaborating with Dr. Jeffrey Meyers and co-mentoring one of his graduate students on a project that employs checkpoint kinase inhibitors in HNSCC, and this effort has grown partly from our original observations that HNSCC tumors have activated checkpoint kinase pathways. Our paper was the first to report that PKC iota is overexpressed and appears activated in many HNSCC, and this is highly significant because the molecule is an oncogene in lung cancer. We further demonstrated that the PKC iota locus is amplified in several HNSCC lines, and more recently we have found the locus to be amplified in a number of primary HNSCC tumor samples as reported in our recent genomics paper published in Science (Agarwal, et al. 2011). Interestingly, we found that phosphorylation of MEK and its downstream target ERK had an unexpected inverse relationship, which has implications for targeted therapy of HNSCC using MEK inhibitors.
In 2009 I was the recipient and principal investigator of an extramural grant from AstraZeneca to study the effect of their experimental drugs on the growth and signaling pathways of colon cancer stem cells. Although this was somewhat tangential to my work with HNSCC, it provided an opportunity for me to continue my collaborations with the Proteomics Group at George Mason University, as well as expand my research to collaborate at the international level with Ruggero De Maria (Rome, Italy) who is one of the world’s leading experts in cancer stem cell research. This project is nearly complete and we are currently preparing a manuscript that describes our findings after screening more than 60 AstraZeneca drugs using established colon cancer stem cell lines.
Recognizing the technical limitations inherent in studying mRNA and only a subset of the proteome to understand cancer, I began to search for a more comprehensive strategy. Aware of recent technical advances in high throughput genomics platforms I initiated collaboration with Dr. Jeffrey Myers in order to comprehensively examine the genomic and epigenomic alterations present in HNSCC. Together, we successfully wrote and obtained 2 extra-mural grants totaling more than $4 millon dollars from the NIH and Cancer Prevention Institute of Texas (CPRIT) to completely characterize the genetic and epigenetic alterations in HNSCC. Dr. Myers is the principal investigator on these grants, and I am a Co-Investigator on both. I played a key role in the architecture of these grants and helped bring together our various collaborators on the project, including David Wheeler from the Baylor College of Medicine Human Genome Sequencing Center. Our specific aims for these projects include whole exome sequencing to identify somatic mutations in an unbiased fashion, analysis of gene copy number variations, analysis of chromosomal structural alterations, profiling mRNA and miRNA, and genome-wide analysis of DNA methylation. I am currently one of the principal hands on investigators for these funded projects and have been involved in nearly every step of the research from bench top, to data analysis, to presenting our findings at scientific meetings and in writing our recent Science paper.
Although our work is far from complete our group has found that primary HNSCC tumors frequently contain inactivating mutations in NOTCH1. This provides strong genetic evidence that NOTCH1 functions as a tumor suppressor in this cancer type. Previously, knockout studies in mice had linked loss of NOTCH1 function to development of murine skin cancers, but prior to our work there was no evidence that NOTCH1 played a role in the development of any human solid tumors. Our sequencing paper also re-confirmed that somatic mutations in p53 and p16 frequently occur in primary HNSCC, and that activating mutations in PI3K and HRAS also occur in a significant fraction of patients, albeit at much lower frequencies. The presence of PI3K and HRAS mutations has therapeutic implications, because some experimental drugs can directly or indirectly target these pathways. Currently, we are performing an integrated analysis using data from all of our genomic and epigenomic platforms to better understand alterations at the pathway level as well as potential interactions.
FUTURE PLANS AND PENDING GRANTS
I plan to continue working with our multiple high throughput platforms to comprehensively characterize genomic and epigenomic alterations in HNSCC, as well as complete the integrated multi-platform analysis. This is needed to gain a better understanding of all the alterations and common pathways disrupted in HNSCC. I recently submitted a letter of intent to apply for a grant, as a principal investigator, to an RFA announced by the Cancer Prevention and Research Institute of TEXAS (CPRIT) The grant title is “Bridging the Biomarker Gap in Cancer: Targeted re-sequencing of genes frequently altered in head and neck and lung cancers,” and the major objective is to develop a cost-effective and sensitive assay easily run on clinical specimens, which will allow targeted re-sequencing of genes frequently altered in HNSCC and lung cancer and to determine the potentially utility of the identified sequence abnormalities as prognostic and/or predictive biomarkers. I am also currently examining the mechanism whereby NOTCH1 behaves as a tumor suppressor gene in HNSCC, and this will serve as the basis of an NIH RO1 grant submission in the near future.
1. Patient Care-N/A
2. Research -73% time. My research is laboratory based, but very often involves use of patient samples and preclinical models. Therefore it is a mix of basic science and translational in nature.
3. Instructional Activities-25% time. I have had the privilege to train, educate, and mentor many clinical research fellows, graduate students, and research assistants. This includes teaching general knowledge, experimental design, data analysis, and laboratory techniques.
4. Other Sponsored Activities & Other Institutional Activities.- 2% time. I have occasionally reviewed manuscripts for various scientific journals that are being considered for publication, and grant applications for the MD Anderson AstraZeneca Alliance.
5. Administrative. N/A
1. Understanding genomic and signal pathway abnormalities in head and neck cancer
1. Testing of anti-cancer pharmaceuticals
2. Mechanisms of drug resistance
3. Pharmaceutical pathways specific for head and neck cancer
1515 Holcombe Blvd. - Unit 123
Unit Number: Unit 123
Houston, TX 77030
Room Number: T5.3908
Education & Training
|1995||The University of Texas Health Science Center, Graduate School of Biomedical Science, Houston, TX, PHD, Cancer Biology|
|1985||University of Michigan, Ann Arbor, MI, BS, Cellular and Molecular Biology|
|2/1996-5/1996||Project Investigator Elizabeth A. Grimm, Ph.D, The University of Texas MD Anderson Cancer Center Department of Tumor Biology, Houston, TX|
Peer-Reviewed Original Research Articles
|1.||Henderson YC, Frederick MJ, Wang MT, Hollier LM, Clayman GL. LBP-1b, LBP-9, and LBP-32/MGR detected in syncytiotrophoblasts from first-trimester human placental tissue and their transcriptional regulation. DNA Cell Biol 27(2):71-9, 2/2008. PMID: 18004979.|
|2.||Jayakumar A, Kang Y, Henderson Y, Mitsudo K, Liu X, Briggs K, Wang M, Frederick MJ, El-Naggar AK, Bebök Z, Clayman GL. Consequences of C-terminal domains and N-terminal signal peptide deletions on LEKTI secretion, stability, and subcellular distribution. Arch Biochem Biophys 435(1):89-102, 3/2005. PMID: 15680911.|
|1.||Frederick MJ, Grimm EA. Tumor target contact induces lymphokine activated killer protein phosphorylation. Proceedings of the American Association for Cancer Research 34:444, 1993.|
Grant & Contract Support
|Title:||NOTCH Pathway Dysfunction in Head and Neck Cancer; Mechanisms and Consequences|
|Duration:||1/1/2012 - 8/31/2013|
|Title:||Comprehensive analysis of genetic and epigenetic changes in oral cancer|
|Funding Source:||Cancer Prevention & Research Institute of Texas (CPRIT)|
|Principal Investigator:||Jeffrey N. Myers|
|Duration:||8/1/2010 - 7/31/2013|
|Title:||Comprehensive Analysis of Genetic Alterations in Squamous Cell Carcinoma of the Oral Tongue|
|Principal Investigator:||Jeffrey N. Myers|
|Duration:||9/25/2009 - 8/31/2012|
|Title:||Effect of AstraZeneca Experimental Drugs on the Growth and Signaling Pathways of Colon Cancer Stem Cells|
|Duration:||6/15/2009 - 6/14/2010|
|Title:||Profiling Pathways that Regulate Tumor Survival in Patients with Head and Neck Cancer|
|Duration:||1/1/2008 - 12/31/2008|
|Title:||Preclinical Studies with the Novel Angiogenesis Inhibitor BRAK|
|Title:||Function of BRAK, a Novel Chemokine Lost in Head and Neck Cancer|
Last updated: 8/27/2013
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