a multi-pronged approach to treat cancer jonathan rios-doria, ph.d. bite of science towson...
TRANSCRIPT
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A multi-pronged approach to treat cancer
Jonathan Rios-Doria, Ph.D.
Bite of Science
Towson University, Baltimore, MD
September 10th, 2014
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Outline of my talk
1 My career path
3 MedImmune’s approach to cancer therapy
4 A day in the life at MedImmune and critical skills needed
2 Fundamentals of cancer biology and why cancer is hard to treat
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Education and Experience
Eisenhower H.S, Shelby Twp., MI
University of Michigan, B.S., Cellular and Molecular Biology
University of Michigan, Ph.D. Cellular and Molecular Biology
– Cancer Biology focus Postdoctoral fellowship at Moffitt
Cancer Center in Tampa, FL
Employed at startup biotech company in Tampa, FL
– Nanomedicines to treat cancer
Joined MedImmune in 2011
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Hallmarks of Cancer
4Hanahan and Weinberg, Cell. Volume 144, Issue 5, 2011, 646 - 674
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Cancer Statistics, 2014
Siegel R., et all. CA Cancer J Clin. 2014 Jan-Feb;64(1):9-29
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Why is cancer hard to treat?
Cancer is not one disease, it is a collection of diseases
Cancer is heterogeneous
– Identifying which patients will respond to a therapy is challenging
Cancer cells are good at avoiding death
Most cancers recur and are develop drug resistance
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MedImmune Headquarters, Gaithersburg
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Fast Facts: MedImmune and AstraZeneca
MedImmune: a world-leading biologics company
– Founded 25 years ago– Combines several former biotechs; merged with CAT in
2008– Biologics subsidiary of AstraZeneca
MedImmune “Firsts”
– First approved fully human MAb drug: Humira (world’s top selling drug)
– First FDA-approved MAb for infectious disease: Synagis
– First VLP technology for HPV vaccines
– First advance in flu technology in 60+ yrs: FluMist
AstraZeneca: world leading oncology company
– tamoxifen (Nolvadex), bicalutimide (Casodex), gefitinib (Iressa), fulvestrant (Faslodex), anastrozole (Arimidex)
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Tumor Targeted Therapies
Activating and shaping a potent and durable anti-tumor immune response
Directly and specifically attacking tumor cells with powerful biologics
Immune Mediated Therapies
Two major areas of focus
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Target Cell
Bi-SpecificAntibody Drug Conjugate
ADCC enhanced
TM(effector null)
YTE(half life
extension)LigandMimetic
NK
Th
e b
iolo
gic
s IM
ED
s
We Match the Target to the Best Therapeutic Technologies
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• MedImmune is a world leader in the development of antibody drugs
• Multiple sophisticated biologics platforms within our tool kit
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ADC Mechanism of Action
11Schrama et al 2006. Nat Rev. Drug Disc
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Target– High expression in tumors
– Very limited normal expression
Antibody– Target specific
– Internalized to lysosome
– Site-specific conjugation technology
Anatomy of ADCs
Linker– Non-cleavable, cleavable
– Stable to prevent release of the warhead
Cytotoxic warhead– Highly potent small molecule
– Chemically-modifiable to attach linker
– Payload = Linker + Warhead
http://www.biooncology.com/research-education/adc/about-adcs/index.html
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Cancer Stem Cells: A paradigm shift
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Targeting cancer stem cells may provide a durable clinical response
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Cancer Immunotherapy – 2013 Breakthrough of the year*
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*as chosen by the editors of SciencePardoll., et al. Nat Rev Cancer. 2012 Mar 22;12(4):252-64
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My primary role at MedImmune
In vivo pharmacology
– New model development
Evaluating in vivo efficacy of various anti-cancer drugs in the pipeline
Determining pharmacokinetics and mechanisms of action of drugs
Identifying which tumor models and types in which the drugs work
Identifying molecular markers of drug response
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Drug Development Timeline
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Approval
Clinical Trials (~10 years)Preclinical Research (~3-5 years)
TargetDiscovery
IND
Where most of my work is
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Example of evaluating efficacy of a candidate anti-cancer drug
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8 13 18 23 28 33 38 43 48 53 58 63 68 73 78 830
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
Antibody 1Antibody 2Antibody 1+2
last dose
Days Post Implant
Mea
n T
um
or
Vo
lum
e (m
m3 )
Control
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Patient-Derived Xenograft (PDX) models
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-Tumor is directly from patient-Never cultured in vitro
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Determining pharmacokinetics of antibodies in mice
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Days
Co
nce
ntr
atio
n (
ug
/mL
)
0.01
0.1
1
10
100
1000
0 4 7 10 13 16
3 mg/kg
0 4 7 10 13 16
10 mg/kg
0 4 7 10 13 16
0.01
0.1
1
10
100
100030 mg/kg
10.3 2C5
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Exploring mechanism of action of antibodies
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pAktAkt
3mg/kg 30
pSrc
Src
NonspecificIgG
10 30
Antibody X
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Fluorescent imaging of ovarian cancer
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Untreated Untreated
B07 B07
Antibody 1 Antibody 1
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Why I chose this career
Patient is the primary focus
Discovery is exciting
Opportunities for innovation and novel therapies
– New technologies
Variety and dynamic nature of work
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Example of typical day
7:30-9:00am – catch up on emails, prepare for meetings
9:00-10:00am – meeting with project team
10-11am – seminar from invited speaker or candidate interview
11-11:30am – chat in hallway around cool idea or recent piece of data
11:30-12:30pm – lunch
12:30-1:00pm – respond to emails received in the morning
1:00-2:00pm – meeting with another project team
2-3:30pm – individual or team meetings with members of staff
3:30-4:00pm – teleconference or video chats with colleagues or external partners
4-5:00pm – catch up on emails and start to prepare for next day’s activities
5:00pm- Leave
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What I look for in a job candidate
Creative thinker and intellectually sharp
Evidence of problem solving ability
Good educational background and record of accomplishment
The ability to work in a team environment
Good communication skills
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Any questions?
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