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Draft brief synopses of topics

Brief Synopses of Suggested Topics
Breakthroughs Subcommittee
Breakthroughs in Bioscience



Personalized Medicine:
“One size no longer fits all”- due to the promise of pharmacogenomics.
Discoveries in Personalized Medicine
have allowed physicians and scientists to provide diagnoses and treatments which are “tailor
made” for individual patients. This new approach minimizes risk of adverse drug events (a
leading cause of hospitalization and death), drug toxicity, and allows us to optimize therapy.
a)Warfarin: About 2 million people annually are treated with blood thinners
(anticoagulants). Warfarin, the most commonly used anticoagulant, is used to treat blood
clotting tendencies, cardiac conditions including post- myocardial infarction or heart valve
surgery, and atrial fibrillation. Warfarin is very difficult to properly dose, and improper
dosing can result in the adverse effects of bleeding or excess clotting. The marked variability
in response to Warfarin is due to multiple factors including genetic polymorphisms encoding
enzymes regulating pharmacodynamics and drug response. The new pharmacogenetic testing-
analysis of CYP2C9 and VKORC1 helps doctors to target the Warfarin dose appropriately,
minimize risks, optimize therapy, and decrease emergency room visits and hospitalizations
due to adverse drug
effects
b)Breast cancer therapy has been revolutionarized with new testing of multiple genes,
which identifies the early stage breast cancer patients who will benefit from chemotherapy.
This test allows oncologists to target chemotherapy to those patients who truly require it,
instead of using the past approach which provided chemotherapy to many women with breast
cancer. The new genetic testing changed treatment decisions in about 1/3 of cases, and is now
accepted as a pivotal step in customizing cancer treatment to the unique aspects of each
woman’s cancer.
c)Treatment of psychiatric conditions, including depression, is challenging due to limited
response or adverse effects due to medication. Pharmacogenetic testing, using genotyping for
CYP2D6 can help psychiatrists target pharmacotherapy for their patients, minimizing adverse
drug effects, and finding most efficiently the medication that will be most efficacious.
Prostate Cancer: Prostate cancer is the second leading health-related cause of death in American
men. About 1 man in 6 will be diagnosed with prostate cancer during his lifetime. More than 2
million men in the United States who have been diagnosed with prostate cancer at some point and
are still alive today. Prostate cancer is one of the most treatable forms of cancer, particularly if
caught early. This is largely due to a variety of treatment options ranging from surgical removal
of the prostate, to antiandrogen therapy and chemical castration, to recently developed drugs that
target testosterone synthesis. A Breakthroughs article on this topic might focus on the basic
research underlying hormone therapies and some of the new drugs that are emerging, such as
abiraterone, which has been found to reduce tumor size and PSA levels in 70% of patients in an early clinical trial. Diabetes*: Then and Now
*text refers to type 2 diabetes
Importance to Reader (introduction) (numbers quoted are CDC data)
• One in 10 US adults has diabetes now. • About 24 million Americans have diabetes, and one quarter of them do not know they • Prevalence increasing: one in 3 US adults estimated to have diabetes by 2050 due to aging • Diabetes is a leading cause of illness and death: It is the leading cause of blindness under age 75, kidney failure, non-accidental leg injury and foot amputations among adults • People with diabetes have more than double the healthcare costs of those without the disease (total costs: $174 billion, annually) • You can prevent diabetes, or if you have diabetes, you can minimize associated health • Diabetes should not be considered in isolation, as a single condition. It is associated with several other health conditions which are interconnected. History • Insulin was discovered in 1921 in Toronto, Canada o It was first used to treat a 14 year old boy in Toronto in 1922! o The Nobel Prize in Physiology or Medicine in 1923 for the discovery of insulin was • Type 2 diabetes is different from Type 1 diabetes (explain) • Evolution of treatments including oral hypoglycaemic agents • Understanding of Metabolic syndrome: o discovered by Stanford University Professor and researcher Gerald Reaven, MD in 1988: synergistic effects of insulin resistance, obesity, dyslipidemia, and hypertension markedly increase coronary artery disease (CAD) risk. • Evolution in our understanding of Metabolic syndrome o Mitochondrial etiology? o Environmental factors and Genetic Factors including Epigenetics o Biochemical basis: synergies of multiple metabolic derangements • Public health impact and preventative strategies
What is Diabetes Type 2?
Brief summary including complications: cardiac, renal, ocular, peripheral vascular
(macro- and micro- vascular disease)
What is the Breakthrough?
1. Understanding of cause: (facilitates treatment): Diabetes cannot be viewed in
isolation as one disease; It is associated with other complex diseases; synergies
contribute to adverse health impact (CAD, hypertension, dylipidemia, diabetes,
obesity)
-must synergize treatment of all these conditions to limit morbidity and mortality
Collaborative research (ie biomarkers, outcomes): Example:

2. Treatment
a. Oral hypoglycemics including new options: discuss traditional agents and newer including DPP-4 (dipepidyl peptidase-4) inhibitors b. Refinement of use of insulin (used when oral hypoglycemics have limited -new insulins (briefly describe) c. Environmental control: weight control (including diet, physical activity), treatment of comorbidities (dyslipidemia, hypertension) d. Anticipatory intervention/awareness: in those at increased risk (older age groups, positive family history, gestational diabetes, sedentary, race/ethnicity) 3. Optimizing Diabetic Control Optimizes Outcome…
-but control which is too “tight” can increase CAD risks (Accord study, etc)
4. The Powerful Impact of Environment: You can prevent this disease
*provide evidence- based (brief) information documenting positive impact *public health initiatives *if not treated: impact includes increased risk of CAD, stroke, renal disease, blindness, dementia, etc. 5. The Future
• Islet cell transplants • Stem cell therapy • New discoveries about pathophysiology Mar 28, 2012: In a paper being published online this week in the Proceedings of the National Academy of Sciences, researchers in the laboratory of Gladstone Investigator Katerina Akassoglou, PhD, describe an unexpected role of the p75 neurotrophin receptor p75NTR in controlling how the body processes sugar. (future target for pharmacotherapy) *There are numerous examples of NIH-funded research relevant to all of the above,
including public health efforts

Pharmacoepidemiology: Perhaps not a good title, but some aspect of this discipline might be of
interest as it could combine genomics, drug side effects that turn out to be beneficial for other use
("repurposing") along with fascinating findings from exploring large data bases.
Multiple Sclerosis: Highlight emerging treatments, disease modifiers and new insights.

Horizons in Bioscience
Pain:
Morphine and aspirin were introduced for the treatment of pain over 100 years ago and
they, or variations of them, remain the mainstay for many disorders in which pain is a prominent
component. The recognition that pain is not a singular pathophysiological condition, coupled to
the perspective that there are ‘plastic changes’ in the CNS involved in the transition from acute to
chronic pain have sparked initiatives to explore new targets and to incorporate new technologies
ranging from the introduction of alternative animal models to imaging of pain states associated
with different conditions. A large number of new targets are being explored both in academic
research centers and in the pharmaceutical industry that focus on small molecule therapeutics to
monoclonal antibodies. These new directions promise to yield greater insight into pain
mechanisms, leading to the hope that science will break the barrier in this relatively impervious
area of medicine to develop new therapeutics
GPCRs: GPCR’s are a superfamily of receptors that have broad physiological roles. There are
nearly 1000 known GPCRs and they are grouped into five subfamilies. Among members of this
family ligands are highly diverse and these receptors are activated by small biogenic amines such
as epinephrine (adrenaline), peptides such as glucagon and somatostatin, growth factors such as
parathyroid hormone and many tastants and odorants. Must pertinent to the Breakthroughs series
these receptors are drug targets and more than one third of all current therapeutics target GPCRs.
This has resulted in blockbuster drugs with tremendous economic significance such as COREG
(carvedilol) with sales of over 2 billion dollars and CLARITON (loratadine) with sales of close to
3 billion dollars. Recent success in the structural characterization of GPCRs has stimulated
structure-based drug designs efforts with some promising leads currently approaching the clinic.
The story of this family of receptors is a compelling adventure involving discovery of the G
proteins and the race for the first crystal structures. It features excellent basic science,
collaborations from disparate disciplines (medicine, molecular biology, X-ray crystallography,
pharmacology) many clinical successes and should be appropriate for the Breakthrough series.
microRNA: This is perhaps best stated first as a quote from Garzon et. Al., 2010: Targeting
microRNAs in cancer (Nature Reviews Drug Discovery): “
Uncovered from the forgotten
landscape of ‘dark genomic matter’, microRNAs (miRNAs) have become the rising stars in
cancer genetics.” miRNAs are small evolutionarily conserved non-coding RNAs of 18-25
nucleotides in length that act as expression regulators of genes involved in fundamental cell
processes such as development, differentiation, proliferation, survival and death.” Their potential
application goes far beyond cancer and into a wide variety of other diseases, including their utility as potential biomarkers for translational medicine.

Source: http://opa1.faseb.org/agendas/spc/PDF/2012/July/Breakthroughs%20-%20Draft%20Suggestions%202012.pdf

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