Exam 2 lectures 14 & 15 Flashcards
targeted therapies are treatments that
target specific characteristics of diseased cells
targeted therapies are generally less
harmful to normal, healthy cells
targeted therapies can be various forms:
small molecules, RNA/DNA-based oligonucleotides, antibodies, & peptides/proteins
key factors in the discovery & development of targeted therapy
- new technology
- new targets
- target validation in early development phase
- predictive models
molecular targeted drug may target at various levels:
molecular, cellular, tissue/organ, system, whole body, population
effects of targeted therapy can be
physiological
biochemical
functional
criteria for target validation
- causal relation between target & disease
- correlation with disease status
- specificity
- affinity
- mode of action (onset)
- regulation of effects
methods of target validation
- molecular/ genetic/ genomic
- biochemical/proteomic
- physiological/functional
- pharmacological/ tocicological
- population-based
testing system in target validation
- cell-free in vitro
- cell
- organ (in vitro & in vivo)
- small animals
- non-human primates
- humans
- computational biology/bioinformatics
evaluation of target validation
- qualitative (yes/no, withdrawal effect)
- quantitative ( dose-effect& dose-response relationships)
- biological effects vs. statistical signnificance
dose-effect
individual level
dose-response
group level
- most drugs are approved based on the population level
interpretation of target validation
- geno vs pheno
- in vitro vs in vivo
- animals vs humans
- healthy subjects vs patients
- other host factors (age,, sex, race)
- other limitations (dose-range)
- research tools vs drug class/entiiy
biomarkers for selection of cancer therapy: EGFR
- erlotinib (lung cancer)
- cetuximab (colon cancer)
biomarkers for selection of cancer therapy: HER2
- trastuzumab (breast cancer)
- lapatinib (breast cancer)
biomarkers for selection of cancer therapy: KRAS
cetuximab (colon cancer)
oncotype DX scoring
- for breast cancer therapy with tamoxifen
- recurrence score
- 31 high risk (benefit from chemo)
MammaPrint
- breast cancer therapy
- predict risk of metastasis
- aggressive therapy can be considered for those with poor prognosis
- for pts <61, early stage I & II
DPD (Dihydroprimidine dehydrogenase)
- drug disposition in cancer therapy
- DPD responsible for >85% 5-FU breakdown
thymidylate synthase (TS)
- drug disposition in cancer therapy
- molecular target for 5-FU
- over expression linked to drug resistance
PGX factors in targeted therapy
genetic variations in pathogens, targeted genes, in genes associated with drug metabolism/dispoition, & in signalling pathways involved in drug response & toxicity other factors (interactions & physiology/disease status)
purpose of PG testing
- provide evidence for PG variations
- improve healthcare outcome by enhancing selection & dosing of therapy
- provide rationale for stratification of subjects in clinical studies
- facilitate PG research & developing novel drugs
CYP2D6/PM
- poor response to tamoxifen
- for postmenpausal women with breast cancer can be treated with aromatoase inhibitor
- in pre-&perimenopausal women, no alternative therapy
- test can be used for monitoring response & prognosis
nocebo
negative response to treatment
- can be an effect of PG testing
selection of target patient population: conventional approaches
- age. sex, race, etc
- disease status, pathology, stage
- co-morbidity
- physiology/ pathology,: prego, liver & kidney function
PG approaches add on
PK characteristics (ADME: disease-independent)-differentiating people - PD characteristics (disease subtype)- differentiating disease
approval of race-targeted drug BiDil
- fixed dose of isosorbide dinitrate & hydralazine hcl
- indication: HF; adjunct to standard therapy; black people
- commercial failure; negative publicity; high cost compared to the 2 separate drugs alone
- no comparison to other racial groups
about — drugs prescribed to children were not tested in children; they are not labeled for pediatric use
2/3
policies developed to encourage testing drugs in children
- pediatric research equity act
- best pharmaceuticals for children act
- marking incentive: 6-month exclusivity
PG considerations in children
- developmental changes in gene expression in children
- metabolizing enzymes-age related
- pediatric diseases vs adult diseases
- clinical trials in children- minimal risk
- including children in clinical trials
- including children in PG testing
lawsuit of lyme vaccine
- LYMeric
- OspA triggers development of autoimmune arthritis in individuals with HLA-DR4 gene
- withdrawn from market
OBRA90
pharmacist has to inform patient of risk of ADE if known genetic variant in patient or it will be a breach of duty
if PGX testing is considered different for traditional genetic testing
a detailed consent form is probably NOT needed
formal consent form needed if:
familial implication
ancillary info needed
risk of discrimination
laws
under federal law & laws of many states
individuals DO NOT own their health data or stored specimens (at least in the sense of medical research)
HIPAA pricacy rule distinguishes
individually identifiable health info (IIHI) from de-identified health info
in general, disclosure or research use of IIHI needs
informed consent
de-identified health info can be used
without authorization
major goal of PG in clinical trials
stratify patients- improve response & reduce side effects
