Upload
theresa-shields
View
216
Download
0
Embed Size (px)
Citation preview
1
Bringing Proteomics to the Clinic:Bringing Proteomics to the Clinic:From Discovery to Validation From Discovery to Validation
November 4, 2007November 4, 2007
Support: NHLBI, NIDDK, NCRR, AHA, Cystic Fibrosis FoundationSupport: NHLBI, NIDDK, NCRR, AHA, Cystic Fibrosis Foundation
Frank J. Accurso, MDFrank J. Accurso, MDProfessor of Pediatrics Professor of Pediatrics University of ColoradoUniversity of Colorado
““Biomarkers of Pulmonary Arterial Hypertension”Biomarkers of Pulmonary Arterial Hypertension”
Acknowledgements – Dunbar Ivy, MD; Steve Abman, MDAcknowledgements – Dunbar Ivy, MD; Steve Abman, MD
DisclosuresDisclosures: None: None
2
Biomarkers of Pulmonary Arterial Biomarkers of Pulmonary Arterial Hypertension (PAH): OverviewHypertension (PAH): Overview
• PAH in adults and childrenPAH in adults and children
• PAH and biomarkersPAH and biomarkers
• Exploratory protein biomarker studies in PAH in Exploratory protein biomarker studies in PAH in children children
Take home messages:Take home messages:
1.1. Improved biomarkers are needed to quickly Improved biomarkers are needed to quickly “ “test” new treatment approaches.test” new treatment approaches.
2. Biomarker studies should be incorporated into2. Biomarker studies should be incorporated into clinical trials and investigations in PAH. clinical trials and investigations in PAH.
3
PAH - definitionPAH - definition
• Sustained elevation of mean pulmonary arterial Sustained elevation of mean pulmonary arterial pressure to > 25 mm Hg at rest or >30 mm Hg pressure to > 25 mm Hg at rest or >30 mm Hg with exercise, with a mean pulmonary capillary with exercise, with a mean pulmonary capillary and left atrial pressure < 15 mm Hg at rest.and left atrial pressure < 15 mm Hg at rest.
• “ “fixed” (structural) and “reactive” componentsfixed” (structural) and “reactive” components
• Better treatments are needed.Better treatments are needed.
Rubin, Chest supplement, 2004Rubin, Chest supplement, 2004
4Simonneau G, et al. Simonneau G, et al. J Am Coll CardiolJ Am Coll Cardiol , Supplement, 2004. , Supplement, 2004.
WHO Classification of PH (Venice, 2003)WHO Classification of PH (Venice, 2003)
Primary Pulmonary Hypertension (PPH) Primary Pulmonary Hypertension (PPH) – – idiopathic or unknown causeidiopathic or unknown cause
ORORSecondary Pulmonary Hypertension (SPH) Secondary Pulmonary Hypertension (SPH)
– – all other causesall other causes
1. Pulmonary arterial hypertension1. Pulmonary arterial hypertension2. Pulmonary hypertension with left heart failure2. Pulmonary hypertension with left heart failure3. PH with lung diseases and/or hypoxemia3. PH with lung diseases and/or hypoxemia4. PH due to chronic thrombotic and/or embolic diseases4. PH due to chronic thrombotic and/or embolic diseases5. Miscellaneous 5. Miscellaneous
FormerFormer
CurrentCurrent WHO (Venice, 2003)WHO (Venice, 2003)
5
PAH (WHO Group I)PAH (WHO Group I)
• Idiopathic (IPAH) Idiopathic (IPAH)
• Familial (FPAH)Familial (FPAH)
• Associated with (APAH)Associated with (APAH)
– Collagen vascular diseaseCollagen vascular disease
– Congenital systemic-to-pulmonary shuntsCongenital systemic-to-pulmonary shunts
– Portal hypertensionPortal hypertension
• Associated with significant venous or capillary Associated with significant venous or capillary involvementinvolvement
– Pulmonary veno-occlusive disease (PVOD)Pulmonary veno-occlusive disease (PVOD)
– Pulmonary capillary hemangiomatosis (PCH)Pulmonary capillary hemangiomatosis (PCH)
• Persistent pulmonary hypertension of the newbornPersistent pulmonary hypertension of the newborn
– HIV infectionHIV infection
– Drugs/toxins Drugs/toxins
– OtherOther
Simonneau G, et al. Simonneau G, et al. J Am Coll CardiolJ Am Coll Cardiol , Supplement, 2004. , Supplement, 2004.
6
PAH: Diagnostic EvaluationPAH: Diagnostic Evaluation
• History*History*
• PhysicalPhysical
• BloodBlood
• EKGEKG
• ECHOECHO
• Physiologic*Physiologic*- Lung function- Lung function- Exercise testing- Exercise testing
• ImagingImaging
• Sleep studySleep study
• Right Heart CatheterizationRight Heart Catheterization
* Difficult in young children* Difficult in young children
? Biochemical biomarkers of disease? Biochemical biomarkers of disease
7
Idiopathic PAH: SurvivalIdiopathic PAH: SurvivalUntreated - survival worse in childrenUntreated - survival worse in children
Adult median survival: 2.8 years (n=194)Adult median survival: 2.8 years (n=194)Pediatric median survival: 0.8 yearsPediatric median survival: 0.8 years (n=16)(n=16)
00
2020
4040
6060
8080
100100
00 0.50.5 11 1.51.5 22 2.52.5 33 3.53.5 44 4.54.5 55
Years of Follow-upYears of Follow-up
% S
urv
ival
% S
urv
ival
D’Alonzo, et al. D’Alonzo, et al. Ann Internal MedAnn Internal Med 1991 1991
(n=194)(n=194)
68%68%
48%48%
34%34%
8
PAH: Acute vasodilator responsePAH: Acute vasodilator responsedepends on agedepends on age
Barst et al.
9
PAH: Treatment Approaches PAH: Treatment Approaches
• PathophysiologyPathophysiology- “fixed” – structural, associated with proliferation- “fixed” – structural, associated with proliferation- “reactive” – amenable to vasodilator treatment- “reactive” – amenable to vasodilator treatment- treatments based on known pathways of vasoactivity- treatments based on known pathways of vasoactivity
• Calcium channel blockers – vasodilatorsCalcium channel blockers – vasodilators
• Prostacyclin – vasodilator, antiproliferativeProstacyclin – vasodilator, antiproliferative
• Nitric oxide – vasodilator, antiproliferativeNitric oxide – vasodilator, antiproliferative
• Endothelin – vasoconstrictor, proliferative – need antagonistEndothelin – vasoconstrictor, proliferative – need antagonist
• Vascular reactivity is a favorable prognostic signVascular reactivity is a favorable prognostic sign
10
Years after DiagnosisYears after Diagnosis
Ev
ent
Fre
e P
rop
ort
ion
Ev
ent
Fre
e P
rop
ort
ion
Idiopathic PAH in Children:Survival and Treatment Success with
Chronic Oral CCB in Acute Responders
Yung, et al. Yung, et al. CirculationCirculation 2004 2004
11
Complex, long-term PAH treatment Complex, long-term PAH treatment strategies have been developedstrategies have been developed
Trial of Trial of Calcium Channel Calcium Channel BlockerBlocker
Acute Vasodilator ResponseAcute Vasodilator ResponseYesYes
CHFCHF
EpoprostenolEpoprostenolTreprostinilTreprostinil
Trial of :Trial of :BosentanBosentanAmbrisentanAmbrisentanSildenafilSildenafilIloprostIloprostTreprostinilTreprostinilEpoprostenolEpoprostenol
Incomplete responseIncomplete response
IncompleteIncompleteresponseresponse
EpoprostenolEpoprostenolNitric OxideNitric Oxide
NoNo
YesYesNoNo
Adapted from Rashid A, Ivy D. 2006: Adapted from Rashid A, Ivy D. 2006: Current Paediatrics Current Paediatrics
Biomarkers would be helpful in adding treatments.Biomarkers would be helpful in adding treatments.
12
Biomarkers of Pulmonary Arterial Biomarkers of Pulmonary Arterial Hypertension (PAH)Hypertension (PAH)
• PAH in Adults and ChildrenPAH in Adults and Children
• Biomarkers and PAHBiomarkers and PAH
• Exploratory Biomarker Studies in PAH in Exploratory Biomarker Studies in PAH in Children Children
13
Outcome MeasuresOutcome Measures
Clinical efficacy measures: A characteristic or variable that A characteristic or variable that reflects how a patient feels, functions, or survives.reflects how a patient feels, functions, or survives.
Surrogate endpoint:Surrogate endpoint: A laboratory measurement or physical A laboratory measurement or physical sign that is used in therapeutic trials as a substitute for a sign that is used in therapeutic trials as a substitute for a clinically meaningful endpoint that is a direct measure of how clinically meaningful endpoint that is a direct measure of how a patient feels, functions, or survives and is expected to a patient feels, functions, or survives and is expected to predict the effect of therapy. predict the effect of therapy.
Biomarker: Biomarker: A characteristic that is objectively measured and A characteristic that is objectively measured and evaluated as an indicator of normal biologic process, evaluated as an indicator of normal biologic process, pathogenic process, or pharmacologic response to apathogenic process, or pharmacologic response to atherapeutic intervention.therapeutic intervention.
Pulmonary Hypertension Review : Snow and Kawut, 2007 ; Hamblett et al, 2007
14
Biomarker Need in PAHBiomarker Need in PAH NeedNeed Current biochemical Current biochemical
biomarkerbiomarker
DiagnosisDiagnosis
- Early identification- Early identification NoNo
- Staging- Staging NoNo
PrognosisPrognosis
- - Rapid progression of diseaseRapid progression of disease NoNo
- Ongoing structural Injury - Ongoing structural Injury NoNo
- Predict complications- Predict complications NoNo
TreatmentTreatment
- Select treatment- Select treatment NoNo
- Response to treatment- Response to treatment NoNo
- Toxicity with treatment - Toxicity with treatment NoNo
- Clinical Trials - Clinical Trials
a. Stratificationa. Stratification NoNo
b. Proof of conceptb. Proof of concept NoNo
c. Efficacyc. Efficacy NoNo
15
Value Added: Proof of ConceptValue Added: Proof of Concept
16
The specific goals of the Clinical Proteomics The specific goals of the Clinical Proteomics Program are to:Program are to:
(1) design panels of candidate proteins for disease (1) design panels of candidate proteins for disease areasareas
(2) develop high throughput analytic methods(2) develop high throughput analytic methods
(3) assess the predictive value of these proteomic (3) assess the predictive value of these proteomic measurements using biological specimens and measurements using biological specimens and clinical data from existing study populationsclinical data from existing study populations
(4) establish procedures and standards for quality (4) establish procedures and standards for quality control control http://www.mc.vanderbilt.edu/root/vumc.php?site=proteomicshttp://www.mc.vanderbilt.edu/root/vumc.php?site=proteomics
17
Approaches to Protein Biomarkers
ProteomicsProteomics(Discovery)(Discovery)
CandidateCandidate - Single - Single - Panel- Panel
ValidationValidation Value Value AddedAdded
Single/Few Single/Few Protein Protein Assay(s)Assay(s)(Hypothesis)(Hypothesis)
Multiplex Protein Multiplex Protein Assay(s)Assay(s)(Hypothesis/ (Hypothesis/ Discovery)Discovery)
18
Candidate Biomarker Pathways in PAHCandidate Biomarker Pathways in PAH
CandidateCandidate SourceSource
Natriuretic peptide (BNP)Natriuretic peptide (BNP) myocytes myocytes
Troponin T Troponin T myocytes myocytes
Uric acidUric acid ubiquitous ubiquitous
Endothelin-1 Endothelin-1 endothelium endothelium
Serotonin Serotonin platelets platelets Angiotensin systemAngiotensin system vascular wall vascular wall
NO related productsNO related products endotheliumendothelium
Cyclic nucleotidesCyclic nucleotides vascular wall,vascular wall,smooth muscle smooth muscle
Fibrinogen related productsFibrinogen related products fibrinfibrin
Cytokines, Growth factors Cytokines, Growth factors varietyvariety
Acute Phase ReactantsAcute Phase Reactants liverliverAubert, Swiss Med Weekly, 2007
19
Caveat: Different Reagent SourcesCaveat: Different Reagent Sources
Brand XBrand X
B
ran
d
Bra
nd
YY
Serum Il-Serum Il-66
• StandardsStandards AgreeAgree
• Controls Controls AgreeAgree
• Duplicate Duplicate Clinical samplesClinical samples do do notnot agree agree
• A second analyticalA second analytical method is neededmethod is needed for validation.for validation.
20
Biomarkers of Pulmonary Arterial Biomarkers of Pulmonary Arterial Hypertension (PAH): OverviewHypertension (PAH): Overview
• PAH in adults and childrenPAH in adults and children
• PAH and biomarkersPAH and biomarkers
• Exploratory protein biomarker studies in PAH in Exploratory protein biomarker studies in PAH in children children
Take home messages:Take home messages:
1.1. Improved biomarkers are needed to quickly Improved biomarkers are needed to quickly “ “test” new treatment approaches.test” new treatment approaches.
2. Biomarker studies should be incorporated into2. Biomarker studies should be incorporated into clinical trials and investigations in PAH. clinical trials and investigations in PAH.
21
Characteristics of biomarkersCharacteristics of biomarkers
• Is the outcome measure specific to a process occurring Is the outcome measure specific to a process occurring either early or late in the disease process?either early or late in the disease process?
• Is the biomarker in the causal pathway of the drug?Is the biomarker in the causal pathway of the drug?
• • How is the biomarker expected to change in response to How is the biomarker expected to change in response to the drug?the drug?
• • How long will it take to see an expected change in How long will it take to see an expected change in response to the drug? response to the drug?