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
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
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
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)
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
ADC Mechanism of Action
11Schrama et al 2006. Nat Rev. Drug Disc
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
Cancer Stem Cells: A paradigm shift
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Targeting cancer stem cells may provide a durable clinical response
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
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
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
Patient-Derived Xenograft (PDX) models
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-Tumor is directly from patient-Never cultured in vitro
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
Exploring mechanism of action of antibodies
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pAktAkt
3mg/kg 30
pSrc
Src
NonspecificIgG
10 30
Antibody X
Fluorescent imaging of ovarian cancer
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Untreated Untreated
B07 B07
Antibody 1 Antibody 1
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
Any questions?
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