A multi pronged approach to treat cancer
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A multi-pronged approach to treat cancer. Jonathan Rios-Doria, Ph.D. Bite of Science Towson University, Baltimore, MD September 10 th , 2014. Outline of my talk. 1. My career path. 2. Fundamentals of cancer biology and why cancer is hard to treat. 3.

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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


Outline of my talk

1

My career path

2

Fundamentals of cancer biology and why cancer is hard to treat

3

MedImmune’s approach to cancer therapy

4

A day in the life at MedImmune and critical skills needed


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


Hallmarks of Cancer

Hanahan and Weinberg, Cell. Volume 144, Issue 5, 2011, 646 - 674


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


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

YTE

(half life extension)

Antibody Drug Conjugate

Bi-Specific

NK

TM

(effector null)

The biologics IMEDs

Ligand

Mimetic

Target Cell

10


ADC Mechanism of Action

Schrama et al 2006. Nat Rev. Drug Disc


Anatomy of ADCs

  • http://www.biooncology.com/research-education/adc/about-adcs/index.html

Target

  • High expression in tumors

  • Very limited normal expression

    Antibody

  • Target specific

  • Internalized to lysosome

  • Site-specific conjugation technology

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

12


Cancer Stem Cells: A paradigm shift

Targeting cancer stem cells may provide a durable clinical response


Cancer Immunotherapy – 2013 Breakthrough of the year*

Pardoll., et al. Nat Rev Cancer. 2012 Mar 22;12(4):252-64

*as chosen by the editors of Science


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


Drug Development Timeline

Clinical Trials (~10 years)

Preclinical

Research (~3-5 years)

Target

Discovery

Approval

IND

Where most of my work is


Example of evaluating efficacy of a candidate anti-cancer drug


Patient-Derived Xenograft (PDX) models

-Tumor is directly from patient

-Never cultured in vitro


Determining pharmacokinetics of antibodies in mice


Exploring mechanism of action of antibodies

Nonspecific

IgG

Antibody X

mg/kg

30

10

3

30

pAkt

Akt

pSrc

Src


Untreated

Untreated

B07

B07

Antibody 1

Antibody 1

Fluorescent imaging of ovarian cancer


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


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


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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