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Pharm 202 “Digitally Enabled Genomic Medicine” and Its Role in Cancer Treatment. Phil Bourne [email protected] http://www.sdsc.edu/pb -> Courses -> Pharm 202. Take Home Message. We are undergoing a revolution in our approach to treating disease

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pharm 202 digitally enabled genomic medicine and its role in cancer treatment
Pharm 202“Digitally Enabled Genomic Medicine” and Its Role in Cancer Treatment

Phil Bourne

[email protected]

http://www.sdsc.edu/pb -> Courses -> Pharm 202

take home message
Take Home Message
  • We are undergoing a revolution in our approach to treating disease
  • This has been driven by the human genome project and the technologies that go with it
  • A key element is the integration of information derived from genotype to phenotype
  • Much of this information is now digital rather than analog
  • This is much more than faster ways to develop drugs – it has to do with diagnostic treatments, preventive medicine, personalized medicine
  • Remember the two applications associated with cancer treatment
today
Today -
  • Overview of the revolution
  • Drug discovery specifically
  • The much more part as it relates to cancer
    • Improve the outcomes of radiotherapy in treatment of breast and prostate cancer
    • Predictive gene signatures to define treatments for breast cancer
approach today
Approach Today
  • Rather than discuss specific papers of work completed we will take a broader perspective on proposed work on large scale projects that have the potential to impact people’s lives through digitally enabled genomic medicine
  • The grants we have studied are from Genome Canada and should be treated as confidential
slide5
SCIENTIFIC RESEARCH

& DISCOVERY

Anatomy

Migratory

Sensors

Organisms

Physiology

Ventricular

Modeling

Organs

Cell Biology

Electron

Microscopy

Cells

Macromolecules

Biopolymers

Proteomics

Genomics

X-ray

Crystallography

Infrastructure

Technologies

Medicinal

Chemistry

Protein

Docking

Atoms & Molecules

Training

EXAMPLE

UNITS

REPRESENTATIVE

DISCIPLINE

REPRESENTATIVE

TECHNOLOGY

MRI

Heart

Neuron

Structure

Sequence

Protease

Inhibitor

digital vs analog
Digital vs Analog
  • The lower levels of biological complexity have always been digital – the higher levels analog
  • This made it very hard to correlate across biological scales
  • Some good examples of digital phenotypic data exist and it is now being collected in earnest
lower levels digital sort of
Lower Levels – Digital (sort of)

This digital image of cAMP dependant

protein kinase (PKA) depicts years of collective knowledge.

We can only interpret it in this form and the computer is vital

higher levels the patient record
Higher Levels – The Patient Record
  • 8% of patient records are lost
  • They are mostly paper (analog)
  • They can only be interpreted by humans
  • Errors are rampant
  • There are exceptions – tumor registries, digitized x-rays, clinical trials, the Cockrane library
drug discovery as an example of this revolution
Drug Discovery as an Example of this Revolution
  • Requires a higher level of digital enablement
  • Has been accelerated by the genome(s) and associated technologies
discovery and development
Discovery and Development
  • Discovery includes: Concept, mechanism, assay, screening, hit identification, lead demonstration, lead optimization
  • Discovery also includes in vivo proof of concept in animals and concomitant demonstration of a therapeutic index
  • Development begins when the decision is made to put a molecule into phase I clinical trials
discovery and development11
Discovery and Development
  • The time from conception to approval of a new drug is typically 10-15 years
  • The vast majority of molecules fail along the way
  • The estimated cost to bring to market a successful drug is now $800 million!! (Dimasi, 2000)
drug discovery status today
Drug Discovery - Status Today
  • Somewhat digitally enabled (FDA still requires paper submission)
  • Will benefit from emergent technologies
  • Human targets are relatively well defined
  • Process for finding appropriate targets in other organisms is evolving
  • Process for finding leads is under revision (we will see an example of that)
drug discovery processes today
Drug Discovery Processes Today

Physiological

Hypothesis

Primary Assays

Biochemical

Cellular

Pharmacological

Physiological

Molecular

Biological

Hypothesis

(Genomics)

Initial Hit

Compounds

Screening

+

Sources of Molecules

Natural Products

Synthetic Chemicals

Combichem

Biologicals

Chemical

Hypothesis

drug discovery processes ii
Drug Discovery Processes - II

Hit to Lead

Chemistry

- physical

properties

-in vitro

metabolism

Secondary

Evaluation

- Mechanism

Of Action

- Dose Response

Initial Hit

Compounds

Initial Synthetic

Evaluation

- analytics

- first analogs

First In Vivo

Tests

- PK, efficacy,

toxicity

drug discovery processes iii
Drug Discovery Processes - III

Lead Optimization

Potency

Selectivity

Physical Properties

PK

Metabolism

Oral Bioavailability

Synthetic Ease

Scalability

Pharmacology

Multiple In Vivo Models

Chronic Dosing

Preliminary Tox

Development

Candidate

(and Backups)

remains serendipity
Remains Serendipity
  • Often molecules are discovered/synthesized for one indication and then turn out to be useful for others
    • Tamoxifen (birth control and cancer)
    • Viagra (hypertension and erectile dysfunction)
    • Salvarsan (Sleeping sickness and syphilis)
    • Interferon-a (hairy cell leukemia and Hepatitis C)
issues in drug discovery
Issues in Drug Discovery
  • Hits and Leads - Is it a “Druggable” target?
  • Resistance
  • Pharmacodynamics and kinetics
  • Delivery - oral and otherwise
  • Metabolism
  • Solubility, toxicity
  • Patentability
slide18
What has changed in identifying targets?In principle we know all the human targets - The “Druggable Genome”
slide19
human genomeProblems with toxicity, specificity, and difficulty in creating potent inhibitors eliminate the first 3 categories...

polysaccharides

nucleic acids

proteins

lipids

slide20
human genome“druggable genome” = subset of genes which express proteins capable of binding small drug-like molecules

polysaccharides

nucleic acids

proteins

lipids

proteins with binding site

relating druggable targets to disease
Relating druggable targets to disease...

Analysis of pharmindustry reveals:

  • Over 400 proteins used as drug targets
  • Sequence analysis of these proteins shows that most targets fall within a few major gene families (GPCRs, kinases, proteases and peptidases)

Fig. 3, Fauman et al.

remaining issues
Remaining issues
  • Characterization of human proteins is on-going (see each revision from Ensembl)
  • Our ability to locate coding regions is improving
  • Our ability to annotate putative proteins is improving
  • More targets will be identified
slide23
No?
  • Bioinformatics
  • Distant
  • homologs
  • Domain
  • recognition
  • Bioinformatics
  • Alignments
  • Protein-protein
  • interactions
  • Protein-ligand
  • interactions
  • Motif recognition

Automation

Better

sources

  • Automation
  • Bioinformatics
  • Empirical
  • rules

Software integration

Decision Support

MAD Phasing Automated

fitting

Anticipated Developments

The Structural Genomics Pipeline

(X-ray Crystallography)

Basic Steps

  • Crystallomics
  • Isolation,
  • Expression,
  • Purification,
  • Crystallization

Target

Selection

Data

Collection

Structure

Solution

Structure

Refinement

Functional

Annotation

Publish

from structural genomix
From Structural Genomix
  • FAST™ is a proprietary lead generation technology developed by SGX for identification of novel, potent and selective small molecule inhibitors of drug targets within a rapid six-month timeframe. The FAST™ process involves crystallographic screening of lead-like drug fragments followed by structure-guided elaboration of the fragments by parallel chemical synthesis, guided by proprietary computational tools. Iterative determination of crystal structures for multiple target/compound complexes in parallel with assays, computational design and synthesis results in optimized leads with high binding affinities and low molecular weights. The combinatorial nature of FAST™ provides access to expansive chemical diversity in the order of 160 million compounds, while requiring only a small number of compounds to be synthesized and screened. Thus the FAST™ approach generates novel and potent lead compounds within months and with efficient deployment of chemistry resources.
summary
Summary
  • Need information flow from genotype to phenotype and back
  • Digital enablement provides that
  • The human genome and the associated technologies has accelerated this process dramatically
  • Example – human genome provides more targets
  • Example – structural genomics leads to faster identification of leads
  • Lets consider two examples related to cancer that illustrate this more specifically….
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