Transcript Bite of Science Center for Excellence in Education

A multi-pronged
approach to treat
cancer
Jonathan Rios-Doria, Ph.D.
Bite of Science
Towson University, Baltimore, MD
September 10th, 2014
Outline of my talk
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My career path
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Fundamentals of cancer biology and why cancer is hard to treat
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MedImmune’s approach to cancer therapy
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A day in the life at MedImmune and critical skills needed
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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
Hanahan 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
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)
Two major areas of focus
Tumor Targeted Therapies
Immune Mediated Therapies
Directly and specifically attacking
tumor cells with powerful biologics
Activating and shaping a potent and
durable anti-tumor immune response
We Match the Target to the Best Therapeutic
Technologies
• MedImmune is a world leader in the development of antibody drugs
• Multiple sophisticated biologics platforms within our tool kit
ADCC enhanced
The biologics IMEDs
NK
TM
(effector null)
Antibody Drug
Conjugate
YTE
(half life
extension)
Bi-Specific
Ligand
Mimetic
Target Cell
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ADC Mechanism of Action
Schrama et al 2006. Nat Rev. Drug Disc
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Anatomy of ADCs
http://www.biooncology.com/research-education/adc/about-adcs/index.html
Target
Linker
–
High expression in tumors
–
Non-cleavable, cleavable
–
Very limited normal expression
–
Stable to prevent release of the warhead
Antibody
Cytotoxic warhead
–
Target specific
–
Highly potent small molecule
–
Internalized to lysosome
–
Chemically-modifiable to attach linker
–
Site-specific conjugation technology
–
Payload = Linker + Warhead
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Cancer Stem Cells: A paradigm shift
Targeting cancer stem cells may
provide a durable clinical response
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Cancer Immunotherapy – 2013 Breakthrough of
the year*
*as chosen by the editors of Science
Pardoll., 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
Clinical Trials (~10 years)
Preclinical
Research (~3-5 years)
Target
Discovery
IND
Approval
Where most of my work is
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Example of evaluating efficacy of a candidate anticancer drug
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M e a n T u m o r V o lu m e ( m m )
1300
C o n tro l
1200
A n t ib o d y 1
1100
A n t ib o d y 2
1000
A n t ib o d y 1 + 2
900
800
700
600
500
400
300
200
100
0
8
13
18
23
28
33
38
43
48
53
58
63
68
73
78
83
D a y s P o s t Im p la n t
la s t d o s e
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Patient-Derived Xenograft (PDX) models
-Tumor is directly from patient
-Never cultured in vitro
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Determining pharmacokinetics of antibodies in
mice
10.3
2C5
Concentration (ug/mL)
0
3 mg/kg
1000
4
7 10 13 16
10 mg/kg
30 mg/kg
1000
100
100
10
10
1
1
0.1
0.1
0.01
0.01
0
4
7 10 13 16
0
4
7 10 13 16
Days
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Exploring mechanism of action of antibodies
Nonspecific
IgG
mg/kg
pAkt
Akt
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Antibody X
3
10
30
pSrc
Src
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Fluorescent imaging of ovarian cancer
Untreated
B07
Antibody 1
Untreated
B07
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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