biotechnology in fighting fatal disease – cancer national biotechnology symposium 2012 innovations...
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Biotechnology in Fighting Biotechnology in Fighting FatalFatal Disease – Disease – CancerCancer
National Biotechnology Symposium 2012National Biotechnology Symposium 2012Innovations in Biotechnology: From Education to IndustryInnovations in Biotechnology: From Education to Industry
Sep 1, 2012, AMA, AhmedabadSep 1, 2012, AMA, Ahmedabad
Dr. Chirag DesaiDr. Chirag Desai, , MD, DM (Oncology)MD, DM (Oncology)
Hemato-oncology Clinic, Vedanta, Hemato-oncology Clinic, Vedanta, AhmedabadAhmedabad
Metastatic colon cancer Metastatic colon cancer (unresectable)(unresectable)
1970s – Only 5-FU – survival of 6 mths
1980s – Leucovorin/5-FU – survival of 9 mths
1990s – Only 5-FU – Addition of oxaliplatin/Irinotecan/capecitabine - – survival of 18 mths
2000s – Avastin - – survival of 21 mths
Now – Erbitux – survival of 25 mths
Survival
Increased
4 folds
In
30 years
Breast Cancer – stage IIBreast Cancer – stage II
1960s – Only surgery - 40% cured
1970s – CMF - 50% cured
1980s – CMF and Tamoxifen - 60% cured
1990s – Anthracyclines and taxanes - 67% cured
2000s – Aromatase inhibitors - 73% cured
Now – Herceptin - 80% cured ??
Cure
Rate
Doubled
In
40
years
Biotechnology in Cancer:Biotechnology in Cancer:
Translational Research
Bench to bedside
The biological revolution of 20The biological revolution of 20thth century century totally reshaped all fields of biomedical totally reshaped all fields of biomedical study -- cancer research being only one study -- cancer research being only one of them.of them.
Biotechnology helps in elucidating the Biotechnology helps in elucidating the normal cellular functioningnormal cellular functioning
And the derangements thereof resulting in And the derangements thereof resulting in diseasedisease
Including cancer…….andIncluding cancer…….and
The ways to tackle these derangementsThe ways to tackle these derangements
Chronic Myeloid LeukemiaChronic Myeloid LeukemiaOne
cancer
One gene
One Treatment
One chromosome
Most CancersMost CancersEach
cancer
Multiplegenes
MultipleTreatments
Multiple chromosomes
InitiationNormal Cell
Pre-Cancerous Cell
Cancer Cell
Invasion
Angiogenesis
Metastases
Signal transduction
Migration
Seed/Soil
Immune Surveillance
Promotion
Prevention/early detection
Diagnosis/prognosis
Treatment
Biotechnology techniques and processes Biotechnology techniques and processes (Evans, P. R. Biotechnology and Biological Preparations in Encyclopaedia of (Evans, P. R. Biotechnology and Biological Preparations in Encyclopaedia of
PT vol. 1, 3PT vol. 1, 3rdrd edn.) edn.)
Growth Factor
Growth Factor receptor
Signal Transduction
Research and development Research and development networknetwork
Examples of Biologicals:Examples of Biologicals:
Growth Growth Factors:Factors:
EGFEGF
VEGFVEGF
FGFFGF
IGFIGF
PDGFPDGF
Receptors:Receptors:
EGFREGFR
Her-2Her-2
VEGFRVEGFR
PDGFRPDGFR
ER/PRER/PR
STIs:STIs:
TKIsTKIs
mTORImTORI
CDKICDKI
FTIsFTIs
OthersOthers
Mabs:Mabs:
RituximabRituximab
AvastinAvastin
HerceptinHerceptin
ErbituxErbitux
BiomabBiomab
clinicaloptions.com/oncologyProviding Personalized Care in an Era of Molecular Medicine
Evolution From Empiric to Personalized Therapy in NSCLC
Factors Agent Affected
Clinical
Asian, never-smoker, female Erlotinib, gefitinib
Untreated CNS metastases, no hemoptysis, uncontrolled hypertension
Bevacizumab
Histologic
Adenocarcinoma Erlotinib, gefitinib
Nonsquamous Bevacizumab, pemetrexed
Thymidylate synthase Pemetrexed
Molecular
EGFR mutation Erlotinib, gefitinib
ERCC1/RRM1 Platinum
RRM1 Gemcitabine
KRAS mutation Erlotinib, gefitinib
↑ EGFR by FISH Erlotinib? Gefitinib?
↑ EGFR by IHC Cetuximab?
EML4-ALK fusion Crizotinib
Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:148-150.
Patient Selection Patient Selection Improves Treatment Improves Treatment
Results in NSCLCResults in NSCLCM
edia
n su
rviv
al (
mo
nth
s)
1970s 1980s 1990–2005
BSC:2–4
months
Cisplatin-based
regimens:6–8 months
Platinum-based
doublets (3rd gen):
8–10 months
2005
Bevacizumab + platinum-
based doublet:>12 months
28
24
20
16
12
8
4
02008 2008
Pemetrexed+ platinum:>12 months
Bevacizumab + platinum:>14 months
Non-Non-squamoussquamous
Adeno-Adeno-onlyonly
Adeno-Adeno-onlyonly
Molecular selection….
EGFR-EGFR-mut+mut+
Erlotinib alone
>27 months
2009/10
No selection Clinical selection
VEGF in clinicVEGF in clinic
Antibody – Bevacezumab (Avastin)Antibody – Bevacezumab (Avastin) Lung Cancer, Colon Cancer, Ovarian Cancer, Renal Cell Lung Cancer, Colon Cancer, Ovarian Cancer, Renal Cell
Carcinoma, Brain Tumors, Carcinoma, Brain Tumors, Breast CancerBreast Cancer
Tyrosine kinase Inhibitors:Tyrosine kinase Inhibitors:Sunitinib, Sorafenib, Pazopinib, Axitinib, Dovitinib, Sunitinib, Sorafenib, Pazopinib, Axitinib, Dovitinib, othersothers
Renal Cell Cancer, Neuro-endocrine tumors, Liver Renal Cell Cancer, Neuro-endocrine tumors, Liver cancers, GIST, cancers, GIST, SarcomaSarcoma
Biologicals are effective in:Biologicals are effective in:
Lung cancerLung cancer
Colon cancerColon cancer
Breast cancerBreast cancer
Head and neck cancerHead and neck cancer
Leukemias/LymphomasLeukemias/Lymphomas
Renal/Liver cancersRenal/Liver cancers
OthersOthers
Biologicals help in the treatment of >80% of cancers either curatively or in advanced cancers
Challenges in the development of Challenges in the development of biologicalsbiologicals
RBF Symposium Feb 2011RBF Symposium Feb 2011
A Nobel Prize by ChanceA Nobel Prize by Chance
Start at the topStart at the top
1.1. Formulate testable hypothesisFormulate testable hypothesis
2.2. Make the plan / design the studyMake the plan / design the study
Generate Hypothesis
Design study
Collect information
Analyse and interprete finding
Develop new theory
clinicaloptions.com/oncologyProviding Personalized Care in an Era of Molecular Medicine
Phase I(~ 18 mos)
Phase II(~ 18 mos)
Phase III(~ 36 mos)
Preclinical(~ 18 mos)
Total Time~ 90 mosor 7.5 yrs
Biomarker Biomarker IntegrationIntegration
N = 30 N = 300 N = 1600 DrugApproval
Confirm target
Assay development
Integrate biomarker
Assay performance
Phases of Development of New Biomarker linked to New Drug
Biomarkerinformative?
Assayperformance
Clinical validation
Coprimaryendpoint
Clinicalapplication
ofbiomarker
Gandara D, et al. NCI CAPR Workshop. 2011. Printed with permission.
New Therapeutic Agent: Development Phases
A large number of biologically/molecularly A large number of biologically/molecularly acting drugs are under developmentacting drugs are under development
Traditional end points are less relevantTraditional end points are less relevant
New end points requiredNew end points requiredOS still is a gold standard end pointOS still is a gold standard end point
Surrogate end points need to be re-definedSurrogate end points need to be re-defined
Even though response rate is less important, exact Even though response rate is less important, exact definition of response is criticaldefinition of response is critical
Ongoing analysis of tissue/blood based biomarkers Ongoing analysis of tissue/blood based biomarkers is criticalis critical
Surrogate End points with Surrogate End points with targeted Therapies:targeted Therapies:
TraditionalTraditional PFSPFS QoLQoL OSOS PharmacoeconomicsPharmacoeconomics OthersOthers
ExploratoryExploratory Target inhibitionTarget inhibition
Tissue levelTissue level
Blood levelBlood level PharmacogeneticPharmacogenetic
Tissue basedTissue based
Blood basedBlood based
clinicaloptions.com/oncologyProviding Personalized Care in an Era of Molecular Medicine
Primary endpoint: 8-wk disease control rate; 30% assumedKim ES, et al. AACR 2010. Abstract LBA1. Reprinted with permission.
BATTLE: Phase II NSCLC Biomarker Study
Umbrella protocol
Core biopsy
EGFR KRAS/BRAFVEGF RXR/CyclinD1
Biomarkerprofile
Randomization:Equal Adaptive
ErlotinibEqual (n = 25)
Adaptive (n = 33)
VandetanibEqual (n = 23)
Adaptive (n = 29)
Erlotinib + BexaroteneEqual (n = 21)
Adaptive (n = 15)
SorafenibEqual (n = 26)
Adaptive (n = 72)
clinicaloptions.com/oncologyProviding Personalized Care in an Era of Molecular Medicine
Kim ES, et al. AACR 2010. Abstract LBA1. Reprinted with permission.
BATTLE: Phase II NSCLC Biomarker Study—Discovery Platform
Who should do this?Who should do this?
Generate Hypothesis
Design study
Collect information
Analyse and interprete finding
Develop new theory
•Academic institutions
•Corporate hospitals
•Individual practitioners
•Medical associations
•Collaborative effort
Who should do this?Who should do this?
Generate Hypothesis
Design study
Collect information
Analyse and interprete finding
Develop new theory
InnovationsInnovations
Future:Future:
Tests like Oncotype Dx21 in breast cancerTests like Oncotype Dx21 in breast cancer
Drugs like Imatinib in CMLDrugs like Imatinib in CML
Outcome like sequential use of chemo and Outcome like sequential use of chemo and targeted drugs in myelomatargeted drugs in myeloma
Making cancer a chronic Disease