NIBR Postdoctoral Program - Stanford Medicine - Stanford University

NIBR Postdoctoral Program - Stanford Medicine - Stanford University

NIBR Postdoctoral Program Stanford University 21 September 2010 W. Ross Tracey, PhD Associate Director, Education Office A B Jefferson, PhD Investig...

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NIBR Postdoctoral Program Stanford University

21 September 2010

W. Ross Tracey, PhD Associate Director, Education Office A B Jefferson, PhD Investigator III, Cancer Biology, Oncology

Agenda  Novartis and NIBR background

 Emeryville: research and postdocs in Cancer Biology  Postdoctoral training program highlights

Novartis at a Glance  Unique portfolio to meet changing healthcare needs: • • • •

Leading innovative pharmaceuticals High-quality, low-cost generics Preventive vaccines Consumer health products

 World’s third largest pharmaceutical company by sales ($44.3 billion)

 One of 20 largest companies by market capitalization

 Ranked among most respected companies worldwide

 R & D investment of ~ $7.4 billion/year

Our mission at Novartis We want to discover, develop and market successfully, innovative products to prevent and cure diseases, to ease suffering, and to enhance quality of life. We also want to provide a shareholder return that reflects outstanding performance and to adequately reward those who invest ideas and work in our company.

Access to medicine programs – in 2009 we contributed 3.4% of net sales  Coartem® (malaria): 84 million treatments shipped in 2009 – cumulatively delivered 300 million treatments which helped save an estimated 750,000 lives

 Leprosy medication free of charge: >4.5 million patients cured since 2000

 TB donations (DOTS): 500,000 patients in five years

 Global patient assistance: Medicines free or at reduced cost to 143,000 patients, valued at $1.1 billion

2009:

 79.5 million patients supported

 Programs and research valued at USD $1.51 billion3

 NITD1 in Singapore: Focus on TB, dengue fever and malaria

 NVGH² in Siena, Italy: Vaccines Research Institute for neglected diseases 1

Novartis Institute for Tropical Diseases; 2 Novartis Vaccines Institute for Global Health; 3 Based on approximate market value

Novartis Institutes for BioMedical Research (NIBR)

 15 sites worldwide

 Approx. 7000 employees globally

 Approx. $1.8 billion budget ($1 billion pre-clinical)

 Specific centers focus on different disease areas and several platforms

NIBR Sites Horsham

Rueil/ Malmaison

East Hanover

Emeryville

Basel

Cambridge

Madhapur/ Hyderabad Beijing

Vienna

Shanghai Tokyo

NIBR Sites Translational Sciences Sites

NIBR Disease Areas

Autoimmunity, Transplantation & Inflammation (ATI)

Cardiovascular & Metabolism (CVM)

Neuroscience (NS)

Gastrointestinal (GI)

Oncology (ONC)

Infectious Diseases (ID)

Ophthalmology (OPH)

Musculoskeletal Disease (MSD)

Respiratory Diseases (RD)

NIBR Platforms Biologics Center

Global Discovery Chemistry

Metabolism and Pharmacokinetics (MAP & DMPK)

Center for Proteomic Chemistry

Developmental & Molecular Pathways

Biomarker Development Preclinical Safety Translational Medicine Scientific Operations

Research Focus at NIBR sites United States

United Kingdom

Cardiovascular & Metabolism

Gastrointestinal

China

Infectious Diseases

Respiratory

Infectious Diseases

Oncology

Global Discovery Chemistry

Oncology

Ophthalmology

Translational Sciences

Epigenetics Chemistry

Musculoskeletal

Translational Sciences

Center for Proteomic Chemistry Developmental and Molecular Pathways Global Discovery Chemistry Biologics Center

Japan

Translational Sciences

Switzerland

IT Automation & Support

Neuroscience

Translational Sciences

Oncology

~110 postdocs in Basel, Cambridge, East Hanover, Emeryville, Horsham, Shanghai

Autoimmunity, Transplantation & Immunology

Center for Proteomic Chemistry Global Discovery Chemistry Biologics Center

Specific centers focus on different disease areas and several platforms

Translational Sciences

India Translational Sciences

Extensive External Collaborations Enhance the Pipeline Joint ventures in research, technology and therapeutic products

Academia

Industry

 Almost 300 alliances with academic

 More than 150 alliances with major

centers

biotech companies

Drug Discovery & Development Takes a Long Time 10’000 compounds in the beginning 1’000 compounds in vitro testing 10 compounds in the clinic

1 new Medicine

Preclinical Research

Clinical

Clinical

Clinical

Phase I

Phase II

Phase III

~14 years

Registration

Unmet Medical Need

NIBR’s Research Strategy

Basic

Drug

Research

Discovery

Science-Driven

X

Business

Rationale

Knowledge of mechanism

Pathways thinking...

Translation of the Genome to Therapeutics Defining the key druggable nodes within the network

Genome

Human Disease

Pathways: Collections of Targets for Multiple Indications Tuberous sclerosis

Retinitis pigmentosa

Immune diseases, Tx rejection

Cancer (colon/breast)

Vascular proliferation (stent implant)

mTOR pathway

Postdoctoral Program at Emeryville A B Jefferson, PhD, Investigator III, Cancer Biology, Oncology

EMV NIBR Research Organization NIBR SITE HEAD Emma Lees Biochemical Lead Discovery

Analytical Chemistry

Protein Sciences

Cellular Assays

Pharmacology

Biological Therapeutics

ONC HEAD Emma Lees 125 FTE

Cancer Biology

Bioinformatics

Project Mgmt.

Medicinal Chemistry

Structural Chemistry

GDC HEAD Mike Dillon 75 FTE

Cheminformatics

MAP

Departments currently with post-doc 18 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Computatl. Chemistry

Medicinal Chemistry

Medicinal Chemistry

Emeryville is a Fully Integrated NIBR-Oncology Site  Target identification through early clinical trial

 Small molecule and antibody therapeutics  10-12 drug development programs in addition to early discovery Drug Discovery Innovation Chain

D0 – D2

Development

D3

Target Selection, 1 Quelle: Bain 2003 Lead Assay Development Optimization & HTS / Lead Selection

Lead Selection

D4 & PoC Candidate Selection Process

CSP Initiation

19 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Early Clinical Safety and Efficacy

sPoC

Full Dev Large Clinical Trials

Registrat ion PoC Outcome

Cancer Biology What we do Support the pipeline in three major area:

Target Identification & Validation

Mechanistic Biology

Cancer Drivers Amplicon Discovery

SNP 6.0 across cancer cell lines

20 | Cancer Biology Organization | Chuck Voliva | January 16, 2009 | Business Use Only

Translational Sciences

Identification of Oncogenes at Focal Amplified Chromosomal Region Found in Pancreatic cancer Novartis Cell Line Encyclopedia

Cancer Targets Identification

SNP 6.0 (CNV Analysis of Tumor Samples) Validation by TMA-FISH 3000+ Primary Tumor & Cell lines

CCNE1 Co-Amplified Region

Fine-mapping by qPCR

Identification of Amplicon dependent gene by pool shRNA screen

Gain of function studies Coding genes

 Mentor: Albert Lai, Cancer Biology, ONC  Post-doc: Bosun Min 21 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Understand the role for p90 S6 kinases in supporting an EMT  Which of the EMT characteristics is dependent on signaling via RSK?

 Does an active K-Ras-driven EMT = an active B-Raf-driven EMT?

 What happens to the dependency on RSK for this process in the face of additional pathway mutations as occur in tumors?

Thiery et al, CELL 2009

 Mentor: A B Jefferson, Cancer Biology, ONC  Post-doc: TBD 22 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Current Emeryville Post-docs Matthew Holderfield: Molecular Mechanisms of KRAS Oncogene Dependence Mentor: Tobi Nagel, Cancer Biology

Debbie Chang: Tumor-Associated Macrophages in Breast Cancer Mentor: Dylan Daniel, Pharmacology

Prasenjit Mukherjee: Protein Family Modeling Mentor: Eric Martin, Computational Chemistry

Jing Lu: Cancer dependency on survival signaling pathways Mentor: Pablo Garcia

Bosun Min: ID of Oncogenes at Focal Amplifications in Pancreatic Cancer Mentor: Alberta Lai, Cancer Biology

Meghna Das Thakur: Mechanisms of Resistance to Novel Kinase Inhibitors Mentor: Darrin Stuart, Pharmacology 23 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

NIBR Research Facility at EMV All research departments centralized in one building Highly interactive working environment State of the art facilities

24 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

NIBR Postdoctoral Program

Objectives  Support the postdocs’ scientific and career development  Inform next generation of scientists of NIBR’s approach to drug discovery

 Effectively partner with academic centers of excellence

2 application tracks:  NIBR Postdoctoral Fellowships  Presidential Postdoctoral Fellowships

NIBR Postdoctoral Fellowship

Proposal from

Candidate interviewed

Disease Area/Platform

and hired

reviewed and approved

NIBR Presidential Postdoctoral Fellowship

1st Interview CV Review

~2 weeks

2nd Interview

3rd Interview

EO

DA/Platform

DA/Platform

(phone)

(phone)

(on site)

~3 – 4 weeks

Variable

Proposal

Proposal

writing

review

8 - 12 weeks

<4 weeks

• Outline project • Identify academic mentor

EO: Education Office DA: Disease Area

NIBR Postdoctoral Training Program  3 years  Well-defined project proposal  Yearly progress reports  Scientific seminars: 2-3/week  Postdoctoral seminar series  Participation in scientific conferences  Annual Postdoctoral Retreat  Academic Mentor

Some Topics for Postdoctoral Research at NIBR  Autoimmunity: T cell activation, lymphocyte trafficking, Th17 cells

 Biologics: metabolic stability of siRNAs  Chemistry: computer-aided drug design  Dev & Mol Pathways: CNS lipid storage, vascular biology

 Gastrointestinal: gut epithelial function, sensory neurobiology  Infectious Diseases: pathogen-host interactions  Neuroscience: neurodegeneration; protein misfolding  Oncology: apoptosis, Raf/Ras/MAPK, bioinformatics tools

(Work) Life after a postdoc at NIBR 2007 - 2009 Alumni  Scientist - Novartis

~25%

 Scientist – other pharma/biotech

~25%

 Faculty – academic/research institute

~ 5%

 Non-research (including Novartis)

~20%

 Another postdoc position/transition to faculty ~10%  Other/unknown

~15%

What do we look for in postdoc candidates?  Solid scientific background in almost any area – molecular and cell biology, biochemistry, mouse models, etc.

 Strong critical abilities  Scientific vision  Passion for science

Apply Online

 NIBR Postdoctoral Fellowship http://nibr.com => Careers => Working at NIBR => Search for jobs, keyword “postdoc”

 Presidential Postdoctoral Fellowship http://nibr.com => Careers => Postdoctoral positions Please mention that you attended this presentation.

Thank you!

Back-ups

34 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Challenges facing the pharmaceutical industry Internal challenges

External challenges

 Organizational complexity

 Public perception

and mindset

 Advancing patent expiries  Identifying/understanding new targets

 Rising costs of research and development

 Increasing complexity and breadth of development programs

 Product safety concerns (FDA and public)

 Aging population  Declining industry productivity  Scientific and technological advances

 Rise of generics and biotechs  Price control pressure from payors

 Parallel imports

R&D investment has increased by 80% while NME output has remained stationary

 Data referenced to 2002 data

 R&D spend is predicted to grow more slowly over the next 6 years (~2% pa)

NME = New Molecular Entity (both small molecule and biologics) Evaluate Pharma World report 2016

What are the Molecular Mechanisms That Determine KRAS Oncogene Dependence? A Novartis Post-Doc Project in Cancer Biology Post-Doc: Matthew Holderfield Mentor: Tobi Nagel

KRAS

 KRAS mutations occur in ~20% of NSCLC.  KRAS mutant cancers are frequently refractory to MAPK or

RAF

PI3K inhibitors.

PI3K

 Use an shRNA screen to identify genes that determine sensitivity to KRAS suppression.

Sensitive

Proliferation and Survival

Insensitive

Pharmacology What we do

Mission: Support drug discovery with murine cancer models reflecting

 Subcutaneous, orthotopic and metastatic tumor models • ~100 tumor cell line models • Primary human tumor model collection

Mean Tumor Volume (mm 3)

target biology and addressing drug mechanism of action 900

Vehicle

600

300 RAF265 0 14

16

18 20 22 24 Days Post Implant

26

28

 Genetically engineered mouse models • MMTV-PyMT mammary; K14-HPV16 cervical squamous cell carcinoma models; BRAF mutant melanoma model  Nude rat tumor models to estimate therapeutic index • PK, PD, efficacy, and preclinical safety readouts

 Pharmacodynamic measurements in tumors and normal tissues • ELISA, Western blot, FACS, IHC (w/ Experimental Pathology)  Imaging • Bioluminescence, fluorescence and ultrasound imaging 38 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

pERK1/2 PE

Inhibition of p-ERK in rat PBMCs by MEK inhibitor BYQ738

Mechanisms of Resistance to Novel Kinase Inhibitors  Transgenic and xenograft mouse models of human cancer to predict mechanisms of drug resistance to kinase inhibitors in Novartis pipeline - In contrast to in vitro screens, selective pressure is applied at pharmacologically relevant drug concentrations

Selection

Validation

Molecular Characterization

80000

60000 40000 20000 0 0.0001 0.001

Resistant

Sensitive

0.01

0.1

1

10

Drug Concentration (mM)

 Mentor: Darrin Stuart, Pharmacology, ONC

 Post-doc: Meghna Das Thakur 39 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

100

Tumor-Associated Macrophages in Breast Cancer  Mentor: Dylan Daniel (Pharmacology)  Postdoc: Debbie Chang  Project Overview: • Rationale: Increased inflammation is correlated with decreased survival in breast cancer patients • Goal: To identify the molecular pathways regulating pro-tumorigenic macrophage differentiation

• Model: Transgenic mouse model for breast cancer (MMTV-PyMT) • Hypothesis: M-CSF/CSF1R pathway promotes pro-tumorigenic differentiation of tumor-associated macrophages (TAMs)

• Approach: Novartis has developed a highly selective CSF-1R inhibitor, BLZ945, that we are using to test how loss of CSF1R signaling affects the survival, recruitment and/or differentiation of TAMs [in collaboration with the Coussens Lab at UCSF] Pro-tumorigenic macrophages

Differentiation Recruitment Survival M-CSF/CSF1R

Angiogenesis Growth Metastasis EGF

BLZ945 Cancer cells

Current NIBR Post-docs Matthew Holderfield: Molecular Mechanisms of KRAS Oncogene Dependence Mentor: Tobi Nagel, Cancer Biology

Ting Gong: Computation Dissection of Tissue Samples with Applications to Complex Samples from Clinical Trials Mentor: Joseph Szustakowski, Biomarker Development, Translational Sciences Sonya Fonseca: Enhancement of β-cell Function through ER Stress Signaling Modulation

Mentor: Mark Burcin, Cardiovascular and Metabolism Zachary Newby: Structure and Function of Intramembrane Proteases: The Rhomboid and SPP/SPPL Families Mentor: Michael Romanowski, Center for Proteomic Chemistry Nicolas Guérard: Characterization of specific patterns for Torsade de Pointes in isolated rabbit heart using transmural unipolar electrograms Mentor: Berengere Dumotier, Preclinical Safety, Translational Sciences Ken-Ichi Umehara: In vitro transporter assays and their use to understand hepatic and renal disposition of new drug candidates in clinics using PBPK techniques Mentor: Gian Camenisch, DMPK, Translational Sciences 41 | Presentation Title | Presenter Name | Date | Subject | Business Use Only