IOTF Mentors: Track 3 and Track 4

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While at FDA, fellows will each be assigned a mentor who will be a senior member of FDA scientific review staff. Fellows will be matched with one of 23 mentors from the list below through a process of mutual selection. Mentors are listed in alphabetical order by last name.


Steven R. Bauer, Ph.D.

Biologist, Laboratory of Stem Cell Biology, Division of Cell and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration
steven.bauer@fda.hhs.gov
301-827-0684

Program

Safety and efficacy of ex-vivo cell and gene therapy

Project Summary

We have established a model system to study the multipstep process of virally mediated tumorigenesis 1 with the ultimate goal of assuring safer combination cellular and gene therapies. The combination of cell plus gene therapies holds tremendous potential for the treatment or cure of cancer. Many cell therapies rely on ex vivo gene transduction followed by selection and expansion to achieve the desired number of cells with the desired therapeutic properties. Unfortunately, three out of eleven patients in a SCID gene therapy trial received retrovirally-transduced hematopoietic stem cells and subsequently came down with T cell leukemia. This illustrates the importance of understanding mechanisms of tumorigenesis when considering risks and benefits of combined cellular and gene therapy.

Proposed Project for IOTF Fellow

In this lab, fellows would utilize a model system that we have established to increase our understanding of the multistep transformation1 process with the ultimate goal of assuring safer combination cellular and gene therapies. Our lab uses normal mouse precursor B-cells cultured with recombinant IL-7 and bone-marrow stroma. These cells are normal but proliferate indefinitely in the presence of IL-7 and the stromal cells. We have demonstrated that these pre-B cells can be infected and transformed in vitro by dual oncogene retroviruses carrying c-myc with either v-abl or v-raf1. We have used this model to study some of the important steps that lead to leukemia including mechanisms that lead to constitutive activation of growth factor signal transduction pathways1 and mechanisms that lead to loss of sensitivity to growth inhibition factors, specifically TGF-beta. However, many questions remain and more global approaches such as micro array and proteomics techniques could be used by IOTF fellows to compare and contrast the effects of different oncogenes introduced into normal cells using oncogenic retroviruses. We expect that knowledge gained will ultimately enhance our ability to safely use vector-transduced precursor cell populations for use in treatment of a variety of human diseases. We also expect that a better understanding of oncogenic subversion of growth pathway signaling will lead to safer and a greater range of therapeutic approaches to lymphoid lineage pathologies and tumors in general.

Regulatory Activity

The PI has extensive experience in regulation of cellular and gene therapies (since 1991) and will mentor the fellow in the investigational new drug (IND) review process in the areas of cell and gene therapies, especially those related to cancer (e.g., gene-transduced stem cells, allogeneic stem cells for hematopoietic reconstitution). The fellow will gradually accumulate experience and spend up to 50% of their time in reviewing manufacturing, production, and characterization of cell or gene therapy products. M.D.s can also spend a portion of their time learning and performing clinical reviews within the clinical/pharmacology/toxicology review division.


Serge L. Beaucage, Ph.D.

Acting Chief of the Laboratory of Chemistry (LC), Division of Therapeutic Proteins (DTP), Office of Biotechnology Products, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research
serge.beaucage@fda.hhs.gov
301-827-5162

Program

Chemical synthesis of oligonucleotides for synthetic biology applications.

Project Summary

This project has important implications for both the detection and treatment of infectious diseases and cancers. Indeed, antisense DNA oligonucleotides, aptamers, and small interfering RNA oligonucleotides (siRNA) have been used in vivo to treat certain types of cancers by altering the expression of cancer-related genes. Although our research group has engineered a novel class of heat-sensitive DNA therapeutic oligonucleotides that are activated in vivo through the heat-induced loss of thermolabile protecting groups, our research program has also been focused on the development of a technology that will enable the chemical synthesis of ultra-long DNA oligonucleotides (>1 kb). First and foremost, the aim of this project is to fulfill the high demand for synthetic genes, which will be used in a variety of synthetic biology applications including genetic engineering and chromosome construction.

Proposed Project for IOTF Fellow

The main objectives of the project are to carry out the automated synthesis an assembly of an edited form of an oncogene using a new technology developed in our laboratory. Basic organic chemistry skills are required for this project given that modification of standard nucleic acid protecting groups may be necessary to overcome solubility problems and DNA chain extension kinetic issues. Molecular cloning skills will also be required to assemble ultra-long DNA sequences into the edited oncogene of interest. If successful, the outcomes of this project should have far-reaching implications in gene therapy applications and chromosomal manipulations. An optional project, the IOTF fellow might consider working on, is the development of short, trans-acting, positively charged nucleic acid sequences for enhancing the cellular delivery of siRNAs aimed at silencing the expression of target oncogenic proteins.

Regulatory Activity

The review of incoming pre-Investigational New Drugs (pINDS) and Investigational New Drugs (INDS) submissions, and of the amendments of the currently active INDs, is the responsibility of the LC. More than 400 active INDs are under review in the LC; these INDs relate to a plethora of enzymes including pancreatic, PEGylated and unPEGylated enzymes. In addition, PEGylated and unPEGylated growth factors, erythropoetin-derived products, immunoconjugates, fibroblast and epidermal growth factors, thrombolytic and toxin-fusion proteins are among the active INDs under the jurisdiction of the LC. The fellow will participate in the regulatory review of pIND and IND submissions. These activities will provide the fellow with a solid regulatory training under the tutelage of review teams dedicated to assess the quality attributes of therapeutic proteins and enzymes, through a science-based approach.


Mona S. Calvo, Ph.D.

Expert Regulatory Review Scientist, Nutritionist Division of Toxicology, Office of Applied Research and Safety Assessment (OARSA), Center for Food Safety and Applied Nutrition (CFSAN), FDA
mona.calvo@fda.hhs.gov
301-210-7581

Program

Programs: 1) Edible Mushrooms and Mammary Tumors; 2)Vitamin D status and cancer risk: Use of the NHANES survey data to determine nutrient-cancer relationships

Project Summary

1. Optimizing vitamin D and ergosterol content of white button and portabella mushrooms (Agaricus bisporus): Effects on innate immune response and mammary tumor development in rodents. The IOFT Fellow's activity would in part be involved with a proposed study which examines the effects of commonly consumed mushrooms on breast tumor growth and development. Since ancient times many world cultures have prized mushrooms for their exotic taste and medicinal value. Mushrooms are nutritious containing 19-35% high biological quality protein and significant levels of fiber, thiamin, riboflavin, ascorbic acid, vitamin D2 and trace minerals .Mushrooms also contain non-nutritive substances such as ?-glucan, ergosterol, and chitin that have been shown to have anti-tumor, anti-angiogenic and immune response enhancing properties that promote health by preventing chronic diseases such as cancer. Mushrooms are the only natural dietary source of vitamin D2 commonly consumed in the US and Canada and they also contain a high amount of ergosterol or pre-vitamin D2, which when isolated from mushrooms has been shown to have anti-tumor actions. An adequate vitamin D intake is important to the prevention of cancer, infections and other chronic diseases, and this knowledge has been strengthened by several recent cross-sectional or longitudinal studies which demonstrate a significant association between estimates of vitamin D intake and reduction in cancer or other disease risk. Given these findings, vitamin D merits consideration for inclusion in the list of nutrients that could qualify a fruit, vegetable or grain product for a cancer health claim on its label. Moreover, several recent studies have identified a surprisingly high prevalence of vitamin D insufficiency in otherwise healthy adults in North America, which establishes a clear need for more vitamin D rich food sources.

The specific aim of this study is to ascertain if feeding white button mushrooms with optimized vitamin D2 content during early life and through sexual maturity is protective against the development and growth of mammary tumors in a rat model for carcinogen induced mammary cancer. The focus of this study is on the vitamin D2 and ergosterol content of mushrooms and involves exposing the mushrooms to short periods of ultraviolet light (UVB) or sunlight during harvesting to maximize the amount of vitamin D2 and ergosterol content, which is analogous to what happens in human skin upon exposure to sufficient UVB light. Circulating levels of 25(OH)D, the main indicator of vitamin D status, reflect contributions from dietary sources, both natural foods such as fungi (D2) and vitamin D3 from fatty fish and organ meats and vitamin D2 and D3 from fortified foods, and contributions from endogenous synthesis in the skin (D3). In most individuals the largest contributors to circulating 25(0H)D levels is from cutaneous synthesis, however environmental, seasonal, physiologic and behavioral factors are increasingly impairing the amount of vitamin D3 we can make through solar exposure. We have only recently recognized the significant need for more vitamin D rich foods in the US and Canadian food supply in order to maintain adequate serum levels of 25(OH )D to help prevent the development of chronic disease.

Proposed Project for IOTF Fellow

The main objectives of the project are to carry out the automated synthesis an assembly of an edited form of an oncogene using a new technology developed in our laboratory. Basic organic chemistry skills are required for this project given that modification of standard nucleic acid protecting groups may be necessary to overcome solubility problems and DNA chain extension kinetic issues. Molecular cloning skills will also be required to assemble ultra-long DNA sequences into the edited oncogene of interest. If successful, the outcomes of this project should have far-reaching implications in gene therapy applications and chromosomal manipulations. An optional project, the IOTF fellow might consider working on, is the development of short, trans-acting, positively charged nucleic acid sequences for enhancing the cellular delivery of siRNAs aimed at silencing the expression of target oncogenic proteins.

2. Use of NHANES survey data to explore the relationship between vitamin D status and intake and the risk of cancer. The IOFT Fellow's activity would also involve participation in an on-going study to examine the association between vitamin D status indicators and dietary intake and the serum levels of specific biomarkers for cancer.

Regulatory Activity

Fellows would gain both applied epidemiological and test animal experimental experience in gathering the type of data needed by CFSAN regulatory review scientists to make a decision to allow a cancer-nutrient Health Claim on a qualified food or dietary supplement. The findings might indicate a strong relationship that would allow "Vitamin D and Cancer Health Claims" and "excellent or good source" content claim for mushrooms with respect to vitamin D content. The mentor would council the Fellow at all stages of the research both in survey data exploration and in their hands-on involvement in testing the efficacy and safety of mushrooms in preventing tumor growth. The Fellow would also participate in all aspects of regulatory action(s ) that could be initiated with the given results. The applicant for this mentorship has previous experience mentoring medical students in nutrition /endocrine research, over 18 years of experience as a regulatory review scientist, authored the Calcium Osteoporosis Health Claim (one of the original 10 Health Claims for which a review was mandated by Congress), has reviewed several industry submitted health claims, has kept active and current in her field of research and expertise, has participated in the analyses of all calcium and vitamin D related data from the NHANES surveys and is recognized as CFSAN's expert in calcium, phosphorus and vitamin D. Establishing the importance of mushroom consumption to preventing cancer would merit being highlighted by the National Cancer Institutes' Five-A-Day Program that encourages the consumption of fruits and vegetables as a cancer preventive action and such positive findings about mushrooms would allow specific message about the importance of adequate intakes of vitamin D in the 2005 Dietary Guidelines for Americans to specifically draw attention to mushrooms as being a low fat healthy source of vitamin D.


Rosalie K. Elespuru, Ph.D.

Principal Investigator, Genetic Toxicology Lab, OSEL, Division of Biology, Chemistry and Materials Science (DBCMS) CDRH
rosalie.elespuru@fda.hhs.gov
301-796-0237

Program

Genetic Alterations, Cancer Risk, and Translational Diagnostics

Project Summary

Genetic alterations are implicated in the causation of cancer and recently have been used as biomarkers for diagnosis of cancer, stratification of patients into treatment groups, and monitors of therapy outcome. In the area of safety assessment (cancer prevention), we assess the capability for DNA interactions of new drugs, device materials, and food additives. In the area of cancer diagnosis and therapy, CDRH regulates genetic and genomic diagnostic devices, expected to be developed for the advent of "personalized medicine". Early diagnosis is a central goal in the prevention of metastatic tumor development (cf. “Moonshot”). In both aspects a central theme is the analytical capability for detection of rare mutant DNA within a background of normal DNA.

Proposed Project for IOTF Fellow

Diagnostics for early cancer detection and therapy monitoring. Detection of mutant DNA in blood and/or exosome RNA in urine or saliva would be the focus. K-RAS codon 12 mutations are a common biomarker for lung and pancreas cancers, and a good model for assessment of diagnostic tools, limits of detection, and human application. Exosomes are a new source of stable nucleic acid biomarkers and can be resourced from less invasive human compartments such as urine and saliva. The fellow would experiment with a choice of molecular diagnostic techniques and instruments (lab equipment or a battery operated PCR instrument), depending on his/her particular interests and goals. Experiments would be designed with spiked-in surrogate nucleic acids to determine limits of detection. Adequate systems development would be followed by acquisition of human or more relevant and realistic samples for analysis. Adaption of a diagnostic system to the battery operated instrument could be used for point of care diagnostics assessment. As a corollary, this project would define the technical factors affecting detection of rare mutant DNA and/or RNA biomarkers in blood and other tissues, relevant to review standards for genetically based diagnostic tests.

Regulatory Activity

The PI has 20 years of FDA experience in the application of genetic analyses to cancer risk assessment of regulated products and is involved in the broader scientific community as past President of the US society of genetic toxicologists. The fellow would follow product reviews relative to cancer risk (device safety assessment) or nucleic acid-based (NAAT) diagnostics, involving the Office of Device Evaluation or the Office of InVitro Diagnostics, respectively. The latter group also reviews genetic tests used in personalized medicine.


Brandon D. Gallas, Ph.D.

Mathematician, Division of Imaging and Applied Mathematics (DIAM), Office of Science and Engineering Laboratories (OSEL), Center for Devices and Radiological Health (CDRH), FDA
brandon.gallas@fda.hhs.gov
301-796-2531

Program

Improving Clinical Trials for Imaging Devices

Project Summary

Imaging devices, image processing tools, computer-assist products, visualization packages, and display devices represent a large regulatory portfolio in CDRH that is continuing to expand.  CDRH is in perpetual need of new paradigms for the evaluation of these products using reader studies, standardized databases, and modeling. These evaluations must be statistically interpretable, relevant for their intended use, and at reasonable cost. This project will investigate new, improved clinical trial designs and statistical methods, as well as develop and validate data analysis tools, which will lead to more powerful clinical studies of the efficacy of imaging devices for fewer resources.

Proposed Project for IOTF Fellow

Depending on the skills and interests of the fellow, a project will be developed in any of the following areas

  • developing mathematical and simulation demonstrations of potential to increase statistical power with new clinical trial designs and analysis methods
  • writing software interface for image display and reader interpretation
  • designing reader study protocols and analyses and executing them with novice readers and simulated images to demonstrate
  • proof-of-concept under a controlled setting
  • designing and executing reader studies with expert readers to tailor methods to the clinical environment

Regulatory Activity

Training courses will be offered to the Fellow on the premarket and postmarket functions of CDRH, the importance of risk management in evaluating the safety of new medical products, how to conduct meetings, technical writing, and writing for sponsors. The Fellow will gain experience with the device approval process used in CDRH through exposure to actual submissions of imaging devices, computer-aided diagnostic (CAD) devices, and others. The fellow will assist in all aspects: the planning of trials, the review process, meeting with sponsors, writing letters to sponsors, and preparing/attending panel meetings.


Indira Hewlett, Ph.D.

Chief, Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration
indira.hewlett@fda.hhs.gov
240-402-9587

Program

Nanotechnology diagnostics — Point-of-care and Benchtop assays

Project Summary

A primary goal of FDA is to bring new technologies including better methods that are rapid, more accurate, and less expensive to disease screening and diagnosis. We have used nanomaterials to improve the performance of assays for detection of proteins and nucleic acids. Our lab has successfully developed highly sensitive antigen /antibody and nucleic acid assays for the detection of HIV and influenza viruses as well as for the major biodefense pathogens using fluorescent Europium particles for protein and metal gold/silver nanoparticles for nucleic acid detection. With additional funding we have initiated development of microfluidics based point-of-care platforms. We intend to extend this technique to other pathogens of relevance to FDA's public health mission including West Nile virus (WNV), Hepatitis B virus (HBV), hepatitis C virus (HCV), Ebola, a biodefense pathogen and M. tuberculosis, a significant co-infection in AIDS. The technology can be used to detect cancer biomarkers. We will evaluate the feasibility of developing a multiplex assay to simultaneously detect these pathogens in a single sample. The proposed project will benefit FDA in the following ways: 1) it will give FDA scientists involved in regulating diagnostics hands-on expertise and knowledge of how to regulate related products 2) laboratory experience with the nanoscale technology to develop review criteria and standards for effective regulation of product applications of future nano-scale assays for detection of biomarkers of diseases.

Proposed Project for IOTF Fellow

The fellow will be involved with development and optimization of the nanoparticle-based assays for detection of biomarkers of HIV and other pathogens. In addition, the nanoparticle-based assay technology will be extended to detection of serum biomarkers using single and multiplexed diagnostic assays for early detection of AIDS related pathogens.

Regulatory Activity

Review of in vitro diagnostics for retroviral agents and blood borne/biodefense pathogens.


Deborah A. Hursh, Ph.D.

Principal Investigator, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research (CBER), FDA
deborah.hursh@fda.hhs.gov
240-402-9597

Program

Developing markers to assess genome stability of stem cell-based medical products

Project Summary

Cell-based medical products represent therapeutic source material with tremendous promise for the treatment of degenerative disorders as well as cancer. However, deriving and manufacturing cellular products for clinical use often requires expansion and manipulation in vitro, which may introduce risk factors for genome instability and subsequent tumor formation. These risk factors remain incompletely understood and current research is limited by inadequate tools to identify and investigate the sources of genomic instability in culture. The Hursh lab is investigating potential epigenetic markers for genome stability in cell-based products. Our goal is to further develop effective tools to identify cell culture-related risk factors for genome stability and identify potential genomic regions susceptible to damage during cellular manufacturing. In recent years, evidence has emerged linking specialized chromatin structures to DNA replication as well as DNA damage response (DDR). These structures include histone variants and unique post-translational modifications (PTM) of histones, which facilitate faithful replication of the genome and repair of damaged DNA resulting from replication errors or spontaneous double-strand breaks. In response to double-strand breaks, the histone variant H2A.X is phosphorylated around the break site to generate gamma-H2A.X, which marks the damage location and coordinates the DDR. Notably, evidence in yeast and mammalian cells suggests genomic gamma-H2A.X preferentially occurs at proposed fragile sites in the genome, which may be vulnerable to damage during cellular manufacturing processes. Additionally, other histone PTMs have been identified that mark damage locations and influence their resolution. We are actively investigating the utility of these structures as leading indicators of genome instability in cell-based products with the potential to serve as markers of quality assurance in cell-based medical products.

Proposed Project for IOTF Fellow

An IOTF fellow will investigate the effect of culture conditions, including chemical differentiation, of human multipotent and pluripotent stem cells in vitro on epigenomic and genomic stability. The fellow will be responsible for developing appropriate cell culture protocols to explore potential dynamic chromatin structures associated with DNA damage events upon in vitro manipulation. Available tools for this project include spectral karyotyping, confocal microscopy, flow cytometry, chromatin immunoprecipitation, and quantitative real-time PCR.

Regulatory Activity

At the FDA, Dr. Hursh is a product reviewer who regulates clinical trials in cell therapy, gene therapy, and devices. Many of these are for the treatment of cancer. Under the mentorship of Dr. Hursh, fellows will undertake research on human stem cells, and receive mentorship in the review of investigational new drug applications for cell and gene therapy medical products.


Gibbes Johnson, Ph.D. and Ying-Xin Fan, Ph.D.

Gibbes Johnson, Ph.D., Chief and Ying-Xin Fan, Ph.D., Senior Research Chemist, Laboratory of Chemistry, Division of Therapeutic Proteins, Office of Biotechnology Products, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research (CDER), FDA
gibbes.johnson@fda.hhs.gov, (301) 827-1770
ying-xin.fan@fda.hhs.gov, (301) 827-1763

Program

Evaluation of the adverse effects of EGF receptor kinase inihibition using kinase-inactive EGF receptor knock-in mice

Project Summary

Dysregulation of ErbB receptor activity, especially the epidermal growth factor receptor (EGFR) and ErbB2 (HER2), has been implicated in various human cancers. Accordingly, these receptors are studied to understand their importance in cancer biology and as therapeutic targets. To date, several small molecule inhibitors of the EGFR and ErbB2 tyrosine kinases, such as gefitinib, erlotinib and lapatinib have been approved by the FDA for treatment of patients with lung or breast cancers. To identify and study the potential adverse effects of these kinase inhibitors, we have generated knock-in mice in which we have replaced wild type EGFR with full length kinase-inactive EGFR. Interestingly, these EGFR-KI mice are viable and can live up to 6 months. We propose to use this mouse model to predict clinical safety concerns and risks which specifically arise from therapies that inhibit the EGFR tyrosine kinase. In addition, these studies will provide insight into the physiological role of the EGFR catalytic activity.

Proposed Project for IOTF Fellow

The fellow’s primary research will be focused on the detailed analysis of the EGFR-KI mice and elucidation of the molecular mechanism of the phenotype. In addition, the fellow will also have the opportunity to participate in ongoing research in the lab on the oncogenic and signaling mechanisms of EGFR and ErbB2 cancer mutants and drugs targeted to the mutants.

Regulatory Activity

The Division of Therapeutic Proteins regulates a wide range of therapeutic proteins for the treatment of cancer. Drs. Johnson and Fan have extensive regulatory experience and the Lab of Chemistry has primary chemistry, manufacturing and controls review responsibilities for therapeutic enzymes used for oncology indications. Under the mentorship of Drs. Johnson and Fan, the Fellow will gain experience by participating in the quality review of drug applications as part of an interdisciplinary team to evaluate potential protein drugs for cancer.


Kathryn E. King, Ph.D.

Staff Scientist, Laboratory of Molecular Oncology, Division of Monoclonal Antibodies, Office of Biotechnology Products (OBP), Center for Drug Evaluation and Research (CDER), FDA
kathryn.kingk@fda.hhs.gov
(301) 827-0794 - lab

(301) 827-0664 - office

Project

Molecular mechanisms of epithelial neoplasia

Project Summary

The development of monoclonal antibodies for the targeted treatment of solid tumors is a major focus of efforts in the pharmaceutical arena as is evidenced by the recent approvals of Perjeta and Kadcyla. An understanding of the molecular mechanisms underlying cancer pathogenesis is critical for the development and regulatory review of such therapies. In the Weinberg laboratory it is our aim to understand the molecular mechanisms involved in cancer pathogenesis by using the murine epidermis as a model system for the study of epithelial cancers. In particular the lab is focused on the p53 family, comprised of p53/p63/p73, which are expressed as multiple protein isoforms. These isoforms can mimic or interfere with one another, and their balance ultimately determines biological outcome in a context-dependent manner. Unlike p53 which is commonly mutated in human tumors, p63, and in particular the ?Np63 subclass, is often overexpressed in human squamous cell cancers. However, normal levels of p63 expression are critical for normal epidermal development and homeostasis. The aim of the research is to understand the biological impact of dysregulated p63 expression and the molecular mechanisms of action underlying this impact using murine squamous epithelium in both in vitro and in vivo models.

Proposed Project for IOTF Fellow

Fellow will work on a project relating to the characterization of upstream interactions between the p63 and c-Rel pathways, mediation of downstream events, or targets impacted by the overexpression of ?Np63? that are c-Rel dependent. This work will contribute to the overall research program of the Weinberg lab, which is focused on p63 and interacting pathways in epithelial biology and neoplasia. The fellow should have a good understanding of cancer, cellular and molecular biology. Candidates must have a Ph.D. and/or a M.D. and experience in cellular/molecular biology. Initially, the position will be located on the main NIH campus in Bethesda, MD until the FDA moves to the White Oak Campus in Silver Spring, MD in 2014. Opportunities to participate in journal clubs and data sharing meetings exist.

Regulatory Activity

Over nearly 30 years monoclonal antibodies have transformed from being solely a research tool to therapeutic agents for treating human disease. Today development of monoclonal antibodies is a major focus of pharmaceutical manufacturers. The Division of Monoclonal Antibodies is responsible for product quality review of antibodies, antibody conjugates, Ig-linked fusion proteins, ScFv, Fab’s and other antibody related proteins including those currently under development for the detection and treatment of solid tumors. The Fellow will be mentored to participate in regulatory responsibilities which may range from pre-IND meeting guidance to Sponsors through the review of licensing applications and post-marketing manufacturing changes. The mentor has a strong interest in cell substrate characterization issues as they relate to biologics manufacturing and the use of emerging molecular methods for virus detection in biologics. Ample additional opportunities for reviewer training are available both at the divisional and office level.


Andrew M. Lewis Jr., M.D.

Research Reviewer, Laboratory of DNA Viruses, Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, FDA
andrew.lewis@fda.hhs.gov

301-827-0650

Program

Possible risks associated with genomic instability of neoplastic cells represented by the evolution of the neoplastic phenotype from non-tumorigenic to tumorigenic in the VERO and MDCK cell models.

Project Summary

VERO cells are known to evolve from an immortalized non-tumorigenic state to a phenotype that expresses the capacity to form tumors in nude mice. We have found that this process can be associated with in vitro correlates of cell mobility (wound healing assays) and cell invasion (Matrigel invasion) assays and the over-expression of at least 4 different microRNAs (miRNAs). Studies are underway to confirm and extend these results (using cells at intermediate passage levels to those cells studied to date) to determine the relationship of passage level to the expression of characteristics attributable to the evolution of the neoplastic processes that occurs during serial passage in tissue culture. Similar studies are underway using dog kidney cells (MDCK and other canine cell lines under development). In addition, studies are underway to evaluate the complexities of the variety of tumorigenic phenotypes that appear to be expressed by MDCK cells.

Proposed Project for IOTF Fellow

The directions that the above studies are taking indicate that there are multiple projects for an IOTF Fellow to consider. A new Fellow would be invited to participate one of the projects noted above. However, to ensure (to the extent possible) a successful Fellowship, given the vagaries of research, I prefer to have Fellows involved in several projects that are mutually agreed upon.

Regulatory Activity

Our research is directed toward understanding neoplastic processes from the perspective of addressing possible risks posed by neoplastic cells being used in the manufacture of viral vaccines. Those participating in these projects will be exposed to the variety of issues associated with neoplastic cell substrates and the vaccines being manufactured in them. In addition, our staff is involved in the regulation of papillomavirus vaccines.


Marian Major, Ph.D.

Acting Chief, Laboratory of Hepatitis Viruses. Office of Vaccine Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration
marian.major@fda.hhs.gov

301-827-1881

Program

Studies on hepatitis virus pathogenesis and prevention

Project Summary

Our research program is focused on learning more about the way hepatitis C virus (HCV) causes disease in humans and how the immune system responds to this virus. An estimated 3.2 million Americans have chronic HCV infection and over 200 million people worldwide are infected. In addition, 85% of people infected with the virus develop persistent infections that can eventually cause severe liver problems, such as cirrhosis and liver cancer (hepatocellular carcinoma, or HCC). HCV infection is considered one of the major risk factors for primary liver cancer in the US, Europe and Japan. Furthermore, HCC is one of the few cancers that is increasing in frequency and rate of mortality in the US. Despite these alarming statistics, there is as yet no vaccine to prevent HCV infection. Therapy for HCV has improved over the past five years. Yet for most of the world daily treatment with these drugs is not an option because they are expensive and must be administered carefully due to their toxicity. Two options that hold promise for reducing the rates of infection, disease, and death due to HCV are vaccines and immunotherapy.

Proposed Project for IOTF Fellow

This work will study systems and approaches that can prevent or inhibit HCV infection in vitro using cell culture cells and in vivo using a chimeric mouse model for HCV infection.

Regulatory Activity

Review of all BLA and IND applications for hepatitis virus vaccines. Participation in pre-IND and pr-BLA meetings with sponsors provides guidance on potential clinical trials and licensure of hepatitis virus vaccines.


Kyle J. Myers, Ph.D.

Director, Division of Imaging, Diagnostics, and Software Reliability (DIDSR), Office of Science and Engineering Laboratories (OSEL), Center for Devices and Radiological Health (CDRH), FDA
kyle.myers@fda.hhs.gov

301-796-2533

Program

Quantitative Imaging and Computer-Aided Diagnosis

Project Summary

The imaging program in the Division of Imaging, Diagnostics, and Software Reliability (DIDSR), Office of Science and Engineering Laboratories (OSEL), Center for Devices and Radiological Health (CDRH), FDA, has a well-established reputation in the field of performance assessment of medical imaging systems and ancillary devices such as computer-aided diagnostic algorithms. It is also fully integrated within the Center regulatory review process for these devices. Medical images contain considerably more information than what clinicians currently use as part of their routine evaluation. Carefully-designed image acquisition/analysis techniques to better collect and extract quantitative information, and pattern recognition/statistical learning techniques to intelligently aggregate the extracted information hold the promise to enable the clinician exploit this information for improved patient care. Example areas of application include imaging biomarkers to quantify response to therapy, prognostics, and computer-aided detection/diagnosis systems such as those used in screening radiology, malignant/benign tissue discrimination in medical images, and digital pathology.

Our research program impacts the regulatory assessment of a wide variety of systems that either extract quantitative imaging biomarkers or use extracted image features in computer-aided diagnosis devices. Findings from the quantitative imaging component of our project will be helpful for recommendations for appropriate study designs and endpoints for CDRH and CDER submissions, guidance to developers, and in the process of qualification of imaging biomarkers. Findings from the computer-aided diagnosis component of our project will be helpful in evaluation of claims for devices utilizing quantitative imaging features, identifying the extent to which synthetic/blended image data may be useful in this context, and in reducing the data size/number of clinical trials for these devices.

Proposed Project for IOTF Fellow

The Fellow will collaborate with DIDSR scientists on the investigation of current barriers to quantitative imaging, including issues related to image acquisition and the development of imaging standards and/or calibration methods, image analysis methods for the extraction of quantitative information from images related to disease state, image display requirements for furthering quantitative image analysis, and methods for the assessment of quantitative tools. The project will involve collaboration with the RSNA (Radiological Society of North America) Quantitative Imaging Biomarker Alliance.

Regulatory Activity

The Fellow will gain experience with the device approval process used in CDRH and the drug approval process in CDER through exposure to imaging and computer-aided diagnosis (CAD) device applications in CDRH and drug applications in CDER. This will involve understanding how CDRH and CDER perform their premarket and postmarket functions and the importance of risk management in evaluating the safety of new medical products.


Akhilesh K. Nagaich, Ph.D.

Senior Staff Fellow, Laboratory of Chemistry, Division of Therapeutic Proteins, Office of Biotechnology Products, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research, FDA
akhilesh.nagaich@fda.hhs.gov
(301) 827-1780

Program

Epigenetic Mechanisms in Cancer Development

Project Summary

Epigenetic mechanisms play a central role in the genesis of most, if not all cancers. Several recent studies have implicated aberrant chromatin remodeling activity in the development of human cancer. Evidence has emerged that perturbation of complexes that remodel chromatin by mobilizing nucleosomes may have a central role in tumor suppression and oncogenic transformation. Our lab is investigating the mechanism of action of ATP dependent chromatin remodeling enzymes and how they cooperate with p53 and steroid nuclear receptors to prevent oncogenic transformation.

Proposed Project for IOTF Fellow

The fellow will have the opportunity to pursue one of the several projects to study the mechanism of action of chromatin remodeling enzymes and their role in genome function. Exciting projects include studies on: (i) the role of ATP-dependent chromatin remodeling complexes in p53-mediated transcriptional regulation; (ii) the enzymology of ATP-dependent chromatin remodeling proteins, and (iii) the role of chromatin architectural proteins in transcription and higher order chromatin organization. The laboratory is located on the main NIH campus in Bethesda and has access to excellent core facilities and the NIH library.

Regulatory Activity

The fellow will perform the regulatory review of therapeutic enzymes and other oncology products as part of an inter-disciplinary team to assess the potential efficacy and safety of the drugs, and communicate directly with product sponsors.


Michael O’Hara, Ph.D.

Deputy Director, Division of Radiological Health, Office of In Vitro Diagnostics and Radiological Health (OIR), Center for Devices and Radiological Health (CDRH), Food and Drug Administration (FDA)
michael.ohara@fda.hhs.gov

301-796-0294

Program

Regulatory Requirements for Radiation Oncology (RO)

Project Summary

Like all medical treatments, radiation therapy treatments present both benefits and risk. Approximately 70% of all cancer patients will receive radiation therapy in one form or another. Of these patients, 60% will be treated with curative intent. This therapeutic modality has led to improvements in the treatment of numerous types of cancer. At the same time, it exposes patients to high doses of ionizing radiation (hereafter “radiation”), which elevates a person’s lifetime risk of developing cancer and can cause substantial morbidity. A balanced public health approach seeks to support the benefits of radiation therapy while minimizing the risk.

Patients should receive an optimal radiation dose, with the desired treatment effect on the tumor and sparing of normal tissue. FDA can advance this goal by using our regulatory authority judiciously while also collaborating with the healthcare profession community. FDA and our partners will take steps to:

  • Identify weaknesses in pre-market regulatory review that affect cleared medical devices;
  • Increase the level of post-market device failure reporting;
  • Develop methods to analyze device failure databases;
  • Promote safe use of radiation therapy devices.

By coordinating these efforts, we can optimize patient exposure to radiation, prevent treatment errors, and thereby reduce radiation-related risk while maximizing the benefits of RO treatment.

Proposed Project for IOTF Fellow

Conduct scientific reviews of radiation therapy devices to determine if changes in pre-market requirements or new post-market programs are necessary to maximize the benefits of radiation therapy with as low as reasonably achievable radiation doses. These reviews will include pre-market assessment of the regulatory data currently necessary to clear radiation therapy devices for clinical markets. The project will review post-market and compliance data from marketed radiation oncology devices to determine if the post-market and compliance issues with these devices can help predict the need for changes in regulatory scrutiny during pre-market evaluation. This project will provide input and direction for the implementation of FDA’s initiative to reduce exposure to radiation through dose reduction efforts related to equipment design and labeling. Regulatory activities related to radiation therapy treatments and regulatory changes for radiopharmaceuticals or chemotherapeutic drugs at FDA’s Center for Drug Evaluation and Research (CDER) will be assessed for impact on clearance of radiation therapy devices and our dose check program. This project will involve working with a team of interdisciplinary scientists to better regulate medical devices for radiation therapy. Also, the Fellow will provide input and direction in the implementation of FDA’s goal of reducing errors in radiation therapy through efforts related to training, equipment design and labeling, and education.

Regulatory Activity

Expected 1 year accomplishments: Learn FDA’s pre-market, post-market and compliance review program for radiation therapy products. Assist in developing and guiding implementation of all aspects of FDA’s action plan for radiation therapy devices, as described above. Develop a monitoring plan and metrics to measure longer term outcomes of FDA’s action plan.


Keith Peden, Ph.D.

Chief, Laboratory of DNA Viruses, Division of Viral Products, Office of Vaccines Research and Review, CBER, FDA
keith.peden@fda.hhs.gov

240-402-7312

Program

Evaluation of the safety of neoplastic cell substrates for viral vaccine production: Development of assays to assess tumorigenicity and oncogenicity

Project Summary

Vaccines have proven to be the best way to control infectious diseases. Vaccines are needed against such diseases as HIV/AIDS, pandemic influenza, MERS, Ebola virus, and Zika virus. Unfortunately, the current repertoire of cell substrates used to produce vaccines is inadequate and additional cells are needed. The types of cells required to manufacture these new vaccines are always immortal, some are tumorigenic and some are derived from human tumors. The use of such cells presents regulatory hurdles such as the perceived risks of using cells that were derived from a human cancer to make vaccines for infants and children. Our research attempts to address these concerns.

Proposed Project for IOTF Fellow

While specific projects change depending on progress being made, the general areas of research will be in evaluation of virus detection methodologies, understanding how cells become tumorigenic (which will involve investigating the contribution of epigenetics to tumorigenicity), and evaluating the oncogenicity of DNA in animal models.

Regulatory Activity

Our area of regulation is in viral vaccines against HIV, influenza, Ebola virus, Zika virus, and other viral diseases; our specific areas of responsibility are in product safety and manufacturing.


Ashutosh Rao, R.Ph., Ph.D.

Principal Investigator, Laboratory of Biochemistry, Division of Therapeutic Proteins, Office of Biotechnology Products, Office of Pharmaceutical Science, Center for Drug Evaluation and Research (CDER), FDA
ashutosh.rao@fda.hhs.gov

301-827-4487

Program

Molecular mechanisms of cancer chemotherapy and cardiotoxicity

Project Summary

Our goal is to understand the mechanisms of oxidative stress and DNA damage in the context of cancer chemotherapy and cardiotoxicity. The DNA damaging anthracycline doxorubicin is a critical front-line treatment for primary breast cancer. Unfortunately, doxorubicin also causes dose-limiting cardiotoxicity. The cardiac damage is thought to result from mitochondrial oxidative stress that causes free radical damage to heart muscle. Previous combination therapies aimed at cardioprotection have used non-specific antioxidants that have failed to show clinical benefit. Our previous findings on iron chelators and cancer chemotherapy have provided preliminary insight into the complex nature of these agents. Using cellular and animal models, we aim to characterize the molecular pathways by which oxidants and anti-oxidants effect cardiac and tumor biology. Towards this overall goal we have two ongoing projects: (1) elucidate the mechanisms of cell death and autophagy by mitochondrially-targeted redox agents, and (2) the validation and applications of a syngeneic animal model for studying cardiotoxicity and antitumor efficacy.

Proposed Project for IOTF Fellow

The fellow will have the opportunity to pursue one of several research projects based on his/her interest within the context of cancer chemotherapy. Candidates must have a good understanding of cancer biology and molecular biology. Position is located on the NIH campus in Bethesda, MD. The fellow will also have opportunities to interact and collaborate with NCI laboratories on specific joint projects. The Fellow will also be expected to participate in regular research meetings and seminars.

Regulatory Activity

The Division of Therapeutic Proteins regulates a broad range of therapeutic agents including, but not limited to, oncology products. The fellow will actively participate in the team-based review of investigational drug applications. The fellow will be expected to attend regulatory training sessions and participate in regulatory meetings.


Jakob Reiser, Ph.D.

Principal Investigator, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration
Jakob.Reiser@fda.hhs.gov

240-402-7340

Program

Cell-specific targeting of gene therapy vectors

Project Summary

Our laboratory uses genetic engineering methods to improve the safety of HIV-1-based lentiviral vectors. The ability to use lentiviral vectors to genetically modify cells ex vivo (e.g., hematopoietic stem/progenitor cells and T cells), and in vivo (e.g., therapeutic cancer vaccines) has resulted in new treatment options for a number of acquired and inherited diseases. While these vectors are promising, they pose risks in the context of in vivo applications in that the tissue tropism of the currently available lentiviral vectors is broad, potentially resulting in the transduction of off-target tissues. This illustrates the need for improved strategies allowing targeted vector delivery. Vector targeting offers advantages of enhanced therapeutic effects and reduced side effects.

Proposed Project for IOTF Fellow

Fellows will help develop strategies to target lentiviral vector transduction to specific cells in vivo in the context of mouse-based orthotopic models of human lung and breast cancer using vector particles displaying cell-specific ligands. The main objectives are to identify useful strategies for lentiviral vector targeting and to determine the robustness, specificity, and scalability of these approaches. The human interleukin-13 receptor a2 (IL-13Ra2) will be used as a model receptor in the context of lentiviral vectors displaying human interleukin-13 (IL-13) or RNA-based aptamers directed against IL-13Ra2. Human IL-13Ra2 is an appealing target because it is uniquely overexpressed in many different human tumors, making it an attractive target for tumor therapy.

Regulatory Activity

The PI has experience in reviewing gene therapy files (since 2008) and will mentor the fellow in the investigational new drug (IND) review process in the areas of cell and gene therapies, especially those related to cancer (e.g., CAR T cells). The fellow will spend up to 50% of their time in reviewing manufacturing, production, and characterization of gene therapy products related to cancer.


Jan Simak, Ph.D.

Visiting Scientist, Laboratory of Cellular Hematology, Division of Hematology, Office of Blood Research and Review (OBRR), Center for Biologics Evaluation and Research (CBER), FDA
jan.simak@fda.hhs.gov

301-827-3978

Program

Cell Membrane Microparticles In Plasma As Biomarkers In Cancer

Project Summary

Cell membrane microparticles (MPs) in blood, 0.1-1.5 m in size, are released from platelets, blood cells, endothelial cells, and some other cell types including cancer cells. MPs are present in circulating blood of healthy donors and their elevated counts have been reported in various pathologies. In addition, it has been documented that MPs exhibit various biological activities and thus may play significant role in many physiological and pathophysiological processes including hemostasis and thrombosis, inflammation, modulation of vascular tone, angiogenesis, stem cell engraftment, or tumor metastasis. Development and validation of immunodetection and functional assays for MP analysis in blood is essential. Screening of MP phenotypes for diagnostic value is needed. We have designed an original three-color flow cytometry assay for the analysis of MPs in plasma and demonstrated the presence of several different phenotypes of MPs in plasma of healthy blood donors. We have done initial studies in patients with paroxysmal nocturnal hemoglobinuria (PNH), sickle cell disease (SCD), and acute ischemic stroke. Correlations have been found between plasma counts of certain MP phenotypes and severity of the disease.

Proposed Project for IOTF Fellow

The project will focus on studies of MPs derived from platelets, blood cells and endothelial cells, as well as MPs derived from cancer cells, in plasma of cancer patients. Different immunodetection and functional assays for MP analysis will be used. In collaborative studies, MPs will be analyzed in blood samples from patients with different types of cancer (e.g. head and neck cancer, hematologic malignancies) to investigate diagnostic and prognostic utility of MP analysis in cancer.

Regulatory Activity

Laboratory of Cellular Hematology regulates cellular transfusion products, including red blood cells, platelets, and platelet substitutes. We also regulate devices and solutions used for collection, processing, storage, and pathogen reduction of these products. In addition, bacterial detection assays and leukocyte counting assays for blood product testing are regulated in our laboratory.


Mate Tolnay, Ph.D.

Principal Investigator, Division of Monoclonal Antibodies, Office of Biotechnology Products, Center of Drug Evaluation and Research, Food and Drug Administration
mate.tolnay@fda.hhs.gov

301-594-6049

Project

The physiological role of Fc Receptor-Like proteins, implicated in tumors and autoimmune diseases

Project Summary

Fc-receptor like (FCRL) comprises a family of membrane proteins implicated in both B cell tumor development and autoimmunity. Due to their restricted expression on specific subpopulations of B cells, FCRL are potential new tumor markers and candidate targets of tumor immunotherapy. Our laboratory has been investigating the functional roles of FCRL5 protein and the regulation of its expression. We have established that FCRL5 promotes B cell proliferation and Ig isotype switch. In addition, we showed that FCRL5 expression is induced upon B cell activation and by Epstein-Barr virus.

Proposed Project for IOTF Fellow

The fellow will study the functional role of FCRL5 in human B lymphocyte activation and differentiation. One possible study area is the role of FCRL5 in the context of a normal immune response, specifically its role in the expansion and development of antigen-primed B cells. Another topic concerns the role of FCRL5 in promoting growth of malignant cells in FCRL5 expressing tumors such as hairy cell leukemia. B cells that develop upon FCRL5 stimulation simultaneously display various surface Ig isotypes, a phenotype that was described in hairy cell leukemia. Thus, FCRL5 may drive the development of B cells that co-express Ig isotypes, with currently unknown functional consequences.

Regulatory Activity

The Division of Monoclonal Antibodies regulates therapeutic and diagnostic monoclonal antibodies. The fellow will perform regulatory review of new oncology products as part of an inter-disciplinary team to assess the potential efficacy and safety of the drugs, and communicate directly with product Sponsors.


Wendy C. Weinberg, Ph.D.

Senior Investigator and Chief, Laboratory of Molecular Oncology, Division of Monoclonal Antibodies, Office of Biotechnology Products (OBP), Center for Drug Evaluation and Research (CDER), FDA
wendy.weinberg@fda.hhs.gov

(301)827-0709

Program

Molecular Mechanisms Involved in Regulating Epithelial Differentiation, Neoplasia and Therapeutic Efficacy

Project Summary

Despite major advances in identifying rational targets and early promising pre-clinical findings, the majority of cancer treatments proceeding through clinical trials fail. To maximize the predictive value of pre-clinical data supporting clinical trials, the models utilized must reflect as much as possible the disease etiology. Our laboratory applies a variety of in vitro and in vivo approaches to correlate in vitro assay endpoints with preclinical in vivo models. Our research focuses on the functional relationships between members of the p53 tumor suppressor gene family in epithelial growth regulation and cancer pathogenesis as well as their impact on therapeutic efficacy. The wildtype p53 gene product is known to mediate numerous biological processes critical to maintaining normal tissue homeostasis including apoptosis, cell cycle regulation and DNA repair. P53 homologues p63 and p73 each encode multiple variants capable of overlapping or opposing specific functions of p53, and independent activities of these proteins remain to be elucidated. Our efforts are focused on defining the biological impact and mechanism of action of p53 dysregulation, as has been described in human squamous cell cancers of the head and neck, lung, breast, cervix and ovaries. The overall goal of our research is to identify biomarkers of tumor progression and responsiveness for monitoring therapeutic efficacy.

Proposed Project for IOTF Fellow

A research position is available to evaluate the normal function and effects of dysregulation of specific p53 homologues on normal keratinocyte growth regulation, differentiation and neoplasia, and their interactions with p53 and oncogenic pathways in multistep carcinogenesis. The project will utilize a variety of cellular and molecular biology methodologies, in vivo and in vitro approaches, human cancer cell lines, and novel knockout mice and transgenic mice developed in out lab to clarify the molecular pathways contributing to epithelial cell transformation, and the role of p63 in the response to cancer therapeutics. The particular project to be undertaken will reflect the specific interests of the fellow. Candidates must have a Ph.D. and/or M.D. and experience in cell/molecular biology. Posiiton is located on the main NIH campus in Bethesda, MD. Fellow is invited to participate in journal clubs and data clubs held regularly in conjunction with the NCI and other NIH laboratories.

Regulatory Activity

The development of antibody-based therapies comprises one of the most active areas of clinical research in oncology today. Many targeted therapies based on our current molecular understranding of cancer pathogenesis are under development to optimize the treatment outcome of tumors with specific genetic alterations. The Division of Monoclonal Antibodies is responsible for product review of antibodies, antibody conjugates, Ig-linked fusion proteins, ScFv, Fab’s, and other antibody related proteins, including those currently under development for detection and treatment of solid cancers. Fellow will be mentored to participate in regulatory responsibilities which may range from pre-IND guidance through review of licensing applications and post-marketing manufacturing changes.


Steven Wood, Ph.D.

Biologist, Laboratory Leader, Laboratory of Biomolecular Mechanisms, Division of Biology, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health
wendy.weinberg@fda.hhs.gov

(301)827-0709

Program

Neo-Angiogenesis induced by Medical Devices

Project Summary

One important failure mode of medical devices is the development of pseudotumor which are a highly vascularized network that surrounds and implant. Pain, loss of mobility and device failure are manifest as the pseudotumor enlarges. Pseudotumor formation has been linked to wear particle release from medical devices and often intense inflammatory reactions precede pseudotumor formation. Size and surface chemistry of the particles does alter immune recognition and vascular response. Nano-materials, nano-drug delivery systems and nano-imaging agents may also alter angiogenesis. The focus of these studies is to identify inflammatory cytokines, growth factors, receptors as well as the micro-environmental factors that promote neo-angiogenesis in response to selected micro and nano-sized particles generated during device failure. This will provide scientific basis for safety evaluation, regulatory guidance and policy.

Proposed Project for IOTF Fellow

The fellow will use real time PCR, Luminex bead based assays, antibody blocking assays, confocal microscopy, flow cytometry and si RNA knock downs to identify pro-angiogenic factors released by immune cells and endothelial cells in response to micro/nano wear particles. Of interest are angiogenic cytokines, nitric oxide, coagulation factors, growth factors, receptors, cell adhesion molecules, proteases and their respective inhibitors as well as transcription factors. The ability of these cytokines to induce tube formation in endothelial cells and explanted aortas and other in vitro models will be examined. For the in vivo experiments, nude mice will be implanted with directed in vivo angiogenesis assay (DIVAA) chambers that contain the pro-angiogenic factors released by immune and endothelial cells in response to wear particles.

Regulatory Activity

For preclinical review training, the fellow will take a core curriculum on drug or device law, deficiency letter writing, the 510K workshop and how to lead an IDE/PMA review team. Elective courses such as preclinical toxicology are available. In addition, the fellow will participate in the bio-compatibility standards and in a selected special interest groups. The mentor will assist the fellow in reviewing pre-clinical applications. Finally, the fellow will also participate in the post market evaluation of device performance.


Wen Jin Wu, M.D., Ph.D.

Senior Investigator, Division of Monoclonal Antibodies (DMA) Office of Biotechnology Products (OBP), Office of Pharmaceutical Science (OPS), Center for Drug Evaluation and Research (CDER), FDA
wen.wu@fda.hhs.gov

301-827-0253

Program

Investigating the mechanisms of trastuzumab resistance and cardiotoxicity

Project Summary

Human Epidermal Growth Factor Receptor 2 (HER2) is overexpressed in approximately 20-25% of breast cancers, and overexpression of HER2 is associated with an aggressive tumor phenotype. Treatment with trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of HER2, significantly improves outcomes for women with HER2-positive breast cancer. However, tumor resistance to trastuzumab poses a significant hurdle in breast cancer therapy. Clinical data showed that approximately two thirds of HER2-positive metastatic breast cancer patients demonstrated primary resistance to single-agent trastuzumab and that the majority of patients with HER2-positive breast cancer who achieve an initial response to trastuzumab acquired resistance within one year. The research project in our laboratory involves studies of the molecular mechanisms contributing to trastuzumab resistance. Trastuzumab treatment was also linked to serious cardiotoxicity, and the mechanisms of which remain elusive. The second area of our research interest focuses on understanding the mechanisms of trastuzumab-induced cardiotoxicity and identifying safety biomarkers for trastuzumab-induced cardiotoxicity.

Proposed Project for IOTF Fellow

The fellow will carry out research programs concerning important current issues related to the therapeutic resistance of monoclonal antibodies and trastuzumab-induced cardiotoxicity. The research projects will be focused on understanding the mechanisms of trastuzumab resistance. The IOTF fellow may have the opportunity to work on a different research project that is currently conducted in our laboratory depending on fellow’s background and interest.

Regulatory Activity

The Division of Monoclonal Antibodies is responsible for the product quality review of monoclonal antibodies and monoclonal antibody-derived products, including antibody conjugates, Ig-linked fusion proteins, and other antibody related proteins. Our laboratory is involved in regulating novel monoclonal antibodies for the treatment of human cancers. The fellow will participate in regulatory review of investigational new drug (IND) applications. This provides the opportunity for the fellow to work as part of regulatory team to assess the product quality of therapeutic monoclonal antibodies.


Baolin Zhang, Ph.D.

Senior Investigator, Office of Biotechnology Products, Center for Drug Evaluation and Research (CDER), Food and Drug Evaluation and Research (FDA)
baolin.zhang@fda.hhs.gov

240-402-6740

Program

Understanding cell death to improve drug safety and efficacy

Project Summary

FDA regulates a large number of drug and biologic products that function through modulation of cell death or cell survival pathways in the target cells. These include products that induce cell death for treating cancer or viral infection as well as products that promote cell survival for wound healing or treating chronic heart failure. Among these products, therapeutic proteins and monoclonal antibodies are complex molecules with a high degree of heterogeneity and less defined structure-function relationships when compared to small molecule drugs.

Our research aims at advancing regulatory science for the development of safe and effective medicines. We follow three lines of investigation 1) in-depth analysis of cell death and cell survival pathways modulating therapeutic response and toxicity, 2) identifying predictive biomarkers to promote personalized or precision cancer medicines, and 3) analytical innovation for assessing critical product attributes such as potency, glycosylation and aggregation of therapeutic proteins.

Proposed Project for IOTF Fellow

The Fellow will join in a multi-disciplinary team of research scientists investigating cell death and cell survival pathways leading to cancer drug resistance and drug-induced cardiotoxicity.

Regulatory Activity

The Office of Biotechnology Products (OBP) regulates a broad range of biotechnology products, including recombinant proteins, monoclonal antibodies, biosimilars, and combination products. The PI has 15 years of FDA experience regulating drug product quality (CMC — chemistry, manufacturing, and control) for these products. The Fellow will participate in the quality review of biotechnology product applications submitted under Investigational Investigation New Drug Applications (INDs) and Biologics License Applications (BLAs).

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