The Toxicologist - Society of Toxicology

1 BIOLOGICAL PATHWAY ANALYSIS: AN
INTRODUCTION TO THE PATHWAY KNOWLEDGE
BASES FOR TOXICOLOGICAL RESEARCH.
M. E. Gillespie. Department of Pharmaceutical Sciences, St. John’s University,
Queens, NY.
Genomic and proteomic datasets are a complex but information rich resource.
Toxicology is expanding to new omics-based technologies to identify important
gene and protein expression changes. A critical step in such studies is the analysis of
the data set to derive reasonable mechanistic meaning and testable hypothesis.
Additionally, the use of genomic and proteomic approaches to identify new lead
molecules for biologically relevant targets is rapidly expanding. A challenge for scientists
is how to properly and effectively incorporate high-throughput omics technologies
into their research programs. This course will present practical cases
demonstrating how the Reactome pathway analysis tools can be used to identify relevant
biological pathways within large and immensely complex data sets derived
from multiple high-throughput technology platforms. The course will begin with
an overview of how genomic and proteomic data sets are generated including, but
not limited to, microarray gene expression data, mass-spectrometry data, protein
interaction data, and RNAi screening. All of these methods share a common endpoint,
the generation of large datasets that the toxicologist must analyze without
prior knowledge of a reasonable mechanistic basis or outcome. Often the analysis of
such data can be biased by focusing on known genes and pathways. The creation of
new knowledge bases, often called pathway databases, incorporates information on
protein, gene, and literature databases to facilitate the identification of relevant
schemes using combinations of data, resulting in predictions that more closely approximate
biological networks. The course will review how available knowledge
bases such as Reactome and PharmGKB can be used to interrogate large and complex
datasets to identify the contributions of specific pathways in a given biological
response to toxicant exposure.
2 BIOLOGICALS: INTRODUCTION TO DRUG
DEVELOPMENT.
J. D. Green 1 and L. Andrews 2 . 1 Biogen Idec, Inc., Cambridge, MA and 2 Genzyme
Corporation, Framingham, MA.
Toxicologists and other preclinical scientists have developed an extensive experience
base with a wide range of product classes of biologics over the last two decades.
These product classes include: proteins, monoclonal antibodies, vaccines, cell therapies,
gene therapy products, peptides, and oligonucleotides. These product classes
are diverse in origin and are manufactured by a variety of production methods. For
example, host cells (e.g., E coli, yeast, CHO cells) are used in the production of antibodies
and proteins; various solid and liquid state chemical syntheses have been
used for the production of peptides, siRNA’s and oligonucleotides, and a variety of
vectors (e.g., retrovirus, AAV) have been used to produce gene therapy products.
The historical information that has set the ground work for current practices will be
reviewed and important global regulatory requirements will be identified that
should be considered collectively when designing the battery of nonclinical safety
studies. Unique considerations for each of these product classes will be highlighted
as well as the timing of the considerations. Emphasis will be placed on two distinct
phases; in particular, those that occur prior to the conduct of human clinical trials
and those that occur during clinical development. The course will be an integrated
discussion of the scientific, risk/benefit, and regulatory considerations that should
be considered for the development and human testing of biotherapeutics. We intend
to address evolving regulatory requirements in each specific product area and,
as appropriate, discuss important differences from the development of small molecule
drugs. Students with little or no experience in this area, as well as toxicologists
working in pharmaceutical drug development will benefit from taking this course.
3 COMPARATIVE BIOLOGY OF THE LUNG.
R. Parent 1 and D. Costa 2 . 1 Consultox Ltd., Damariscotta, ME and 2 U.S. EPA,
Research Triangle Park, NC.
All mammals have evolved respiratory structures to ensure that the principal function
of the lung, gas exchange, is met under varying physiological conditions.
However, this essential function is achieved despite significant differences in the
structural organization, cellular composition, and related functions mediated
through the respiratory system and across mammalian species. Translational toxicology
requires that one understand these innate differences in fundamental respiratory
biology if one is to appropriately interpret and extrapolate findings in animal
models. On a gross level, the nasal passages, pleural thickness, vascularity, and connective
tissue structure vary between species. Quantitative evaluation of the tracheobronchial
airway tree demonstrates few consistent features between species.
The epithelial cell populations lining the lung differ in cell type, location, and
abundance. The metabolic enzymes, cytokines, chemokines, protease, and anti-oxidant
potential, although showing some similarities, also demonstrate vast differences.
Similarly, basic immunological functions in laboratory animals must be understood
and related to those in humans to enable appropriate species translation.
We will illustrate many of these fundamental differences, describe methods for
making measurements in different species, and most importantly, focus on the fundamentals
of appropriate interpretation of study data derived in animals for human
use. Attendees will gain a basic understanding of the value and pitfalls extending
from these species differences, which will enable improved study design and extrapolation
of research data for efficacy, safety pharmacology, and toxicology studies.
This course is intended to provide attendees with a basic understanding of lung
structure-function relationships and associated immunological and metabolic functions
in laboratory animals that will aid in the extrapolation of inhalation or respiratory
data to humans.
4 CYTOKINES: BALANCING THERAPEUTIC UTILITY
AND IMMUNE SYSTEM-MEDIATED.
L. A. LeSauteur 1 and R. A. Ponce 2 . 1 Preclinical Sciences, Immunology, Charles River,
Montréal, QC, Canada and 2 Preclinical Development, Amgen, Inc., Seattle, WA.
Direct and indirect modulation of cytokines via therapeutics, either increasing or
decreasing cytokines, is a central factor in the success of current therapies targeting
cancer, autoimmunity, inflammation, and infection. However, nonclinical and clinical
data demonstrate that these therapies can overwhelm compensatory mechanisms
designed to protect the host, resulting in toxicity. The therapeutic benefits
and potential toxicities can be best understood through an understanding of the
central role of cytokines in modulating cellular function. To address these specific
issues, we will define the central toxicities and syndromes that have been identified
as arising from cytokine-mediated immunomodulation; establish the immunological
basis for these toxicities using in-depth exploration where possible, including
useful biological markers that can inform clinicians and toxicologists; develop an
understanding of cytokine modulation in the treatment of cancer, autoimmunity,
inflammation, and infection; and identify deficiencies in current toxicological practice
for predicting certain immune system-mediated risks arising from cytokinemediated
immunomodulation in humans. Finally, we will explore specific case
studies where these principles have been applied to reinforce these central concepts.
5 NUCLEAR RECEPTORS: ROLE IN CHEMICAL MODE
OF ACTION AND TARGETS FOR TOXICITY TESTING.
C. Corton 1 and J. P. Vanden Heuvel 2 . 1 Environmental Carcinogenesis Division, U.S.
EPA, Research Triangle Park, NC and 2 Center for Molecular Toxicology and
Carcinogenesis, Pennsylvania State University, University Park, PA.
Nuclear receptors (NR) are one of the most abundant classes of transcriptional regulators
in animals and function as ligand-activated transcription factors. They provide
a direct link between signaling molecules and transcriptional responses that
impact diverse functions including development, metabolic homeostasis, and reproduction.
NR are not only promising pharmacological targets but can be activated
inappropriately by environmentally relevant chemicals leading to a broad
spectrum of adverse effects. The intent of this basic course is to provide an overview
of the biology of nuclear receptors, the pathways and modes of action of a subset of
nuclear receptors involved in chemical toxicity, and strategies for screening chemicals
for NR interactions as well as placement in mode-of-action categories. To begin
with, we will cover the structure, function and general mechanisms of activation as
well as basic biological roles of NR that are targets of xenobiotics in different tissues
and cell types. We will then explore the role of NR in both augmenting and suppressing
chemical carcinogenesis, which will include a summary of mode of action
and human relevance of those NR (CAR, PPAR, PXR, RXR) commonly associated
with liver cancer. Following this summary, the adverse effects of xenobiotics on the
endocrine system associated with activation or modulation of estrogen, androgen,
and thyroid hormone receptors will be addressed. Finally, both the primary and secondary
screening strategies to define effects of chemicals on NRs and the pathways
that mediate their adverse effects will conclude this course. The intended audience
for this course includes those who desire a basic knowledge of the state of the science
of nuclear receptors in chemical mode of action and strategies for accelerating
the placement of chemicals into mode-of-action pathways. The course will be of interest
to many who are engaged in wider aspects of carcinogenesis, reproductive biology
and risk assessment.
SOT 2010 ANNUAL MEETING 1