David Parkinson, Nodality, "Single Cell-based signaling network functional characterization as a basis for biologically driven clinic decision-making and drug development in oncology"

Rational Efficient Treatment

• Biological understanding of malignancy
• Dev. of targeted therapeutics
• Biological characterization of individual patients

Anticancer drugs development timeline

• 1980s: 
• conventional chemotherapy
• cytotoxics: platinums, taxanes, topoisomerase in hibitors, alkylating agents, etc.
• 1990s:
• 1st generation targeted (ERBB, VEGF)
• herceptin, gleevec...
• 2000s
• 2nd generation targeted (kinases)
• 2010
• Novel Targets (cytotoxic, cytostatic)

Progression over past 20 years:

• Anatomical => Biological characterization of cancer
• Tumor (histological) => Target (Tumor subsets) => Biology (pathways/networks/processes)

Biological characterization

• Must reflect pathophysiology (pathway and network characterization)
• Need to be able to characterize single/rare cell populations
• Must follow patient over time as tumor evolves
• Response and resistance biological profiles

Example: Morphological to Biological Classification in AML

• Today:
• morphology (does not characterize cell type)
• immuno-phenotype
• cytogenetic characterization (closer)
• Tomorrow: pathophysiology-based characterization
• core signaling pathways
• Hypothesis:
• internal signaling networks are superior for patient stratification, rx selection, prediction of outcomes

Disease downstream activity:

• DNA -> RNA -> protein -> ... -> cell signaling

Characterizing pathways

• Transport
• Signaling
• Cell division
• DNA damage
• Apoptosis
• Differentiation
• Patient response

(Nice laundry list...)

SCNP: Flow cytometry

• Gary Nolan (Stanford)
1. obtain sample
2. evoke and fix cels
3. stain with antibodies
4. single cell analysis
• -> can compare basal to evoked cell signaling response

Recent accomplishments in AML

• ID of pathway signatures highly predictive of induction response
• Can monitor individual drug response.

Personalized Medicine: Hurdles:

• Technological
• Regulatoryt
• Reimbursment
• vested interests
• cultural
• Resistance to change

Summary

• Systems approach to characterizing complex biology
• Function rather than anatomical chacterization
• Single cell resolution
• Defining biology/therapeutic outcome at key clinical decision points
• Toward biologically driven clinical decisions and drug development