Resistance in cancer therapy
M.BEBAWY – A MEDICATED NATION – 13 SEPT 2011
Evidence Based
Approach based on extensive research and clinical precedent.
• Treatment goal - curative, prolong life, palliative• Tumor characteristics - cytokinetics, size, location,
markers (Her2+, EGFR+, KRAS). • Stage - local, regional, systemic• Mechanism of drug action - phase vs non-phase specific• Tumor responsiveness – reoccurrence?• Dose limiting toxicity - life time maximal dose
Cancer – Proliferation, Invasion & Metastasis
Schmidt CC. Magazine 2 (1), 2007
Resistance
Gong J, Jaiswal R, et al. Cancer Treatment Reviews 2011 (in press)
Increased drug efflux
Altered molecular
targets
Vesicular sequestration
Increased drug metabolism
Decreased drug influx
Increased DNA repair
Altered cellular death apparatus
Altered cell cycle checkpoints
Multiple Drug Resistance (MDR)
Unique Resistance – cross resistance
Cause of treatment failure in 90% patients with metastatic disease
Functionally redundant
Poor prognosis and outcome
Unique Resistance – cross resistance
Cause of treatment failure in 90% patients with metastatic disease
Functionally redundant
Poor prognosis and outcome
DRUG EFFLUX
Fu, et al. Int. J. Cancer 109, 174-181, 2004
MDR ACQUISITION
DRUG INDUCED MDR
Kota BP, et al. Pharmacological Research 62 (2010) 426–431
CELL COMMUNICATION
• 0.1-1 µm vesicles
• Released from all cell types
• Image of donor cell (membrane, cytoplasmic, nuclear constituents)
• Transfer bioactive molecules between cells
• Biomarkers: thrombosis and inflammation
• 0.1-1 µm vesicles
• Released from all cell types
• Image of donor cell (membrane, cytoplasmic, nuclear constituents)
• Transfer bioactive molecules between cells
• Biomarkers: thrombosis and inflammation
Pro-coagulant
Disease
Pro-inflammatory
Microparticles: Bind to Cancer Cells
CEM
+ VLBMP
MICROPARTICLES: Alternative Cancer MDR PathwayBebawy M et al., Leukemia (2009) 23, 1643–1649
MPs shed
MPs transfer nucleic acids to sensitive cells to reduce drug uptake
IMPLICATIONS
