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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 2 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 3 Hallmarks of Cancer Hanahan and Weinberg, Cell. Volume 144, Issue 5, 2011, 646 - 674 4 Cancer Statistics, 2014 Siegel R., et all. CA Cancer J Clin. 2014 Jan-Feb;64(1):9-29 5 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 6 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 10 ADC Mechanism of Action Schrama et al 2006. Nat Rev. Drug Disc 11 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 12 Cancer Stem Cells: A paradigm shift Targeting cancer stem cells may provide a durable clinical response 13 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 14 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 15 Drug Development Timeline Clinical Trials (~10 years) Preclinical Research (~3-5 years) Target Discovery IND Approval Where most of my work is 16 Example of evaluating efficacy of a candidate anticancer drug 3 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 17 Patient-Derived Xenograft (PDX) models -Tumor is directly from patient -Never cultured in vitro 18 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 19 Exploring mechanism of action of antibodies Nonspecific IgG mg/kg pAkt Akt 30 Antibody X 3 10 30 pSrc Src 20 Fluorescent imaging of ovarian cancer Untreated B07 Antibody 1 Untreated B07 Antibody 1 21 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 22 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 23 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 24 Any questions? 25