ICHO 2004 St. Louis, 20-24 April 2004
1. Highlights in Biology (Stuart)
1.1 HSP and the immune response
Hypothesis: intracellular/extracellular HSP exit cells, bind target APC and cross-present antigenic peptides. Role of heat? how do HSP capture antigens?
- Miller: HSP70 induce induce an immune response in a CD40-dependent manner
- Nössner: HSP70-PC cross-present tumor-derived antigenic peptides and activate APC via TLR
- Subjeck: large HSP chaperone are a potentially very effective component of vaccination. Ongoing studies on the chaperone domains and ability to bind APC
- Repaski: WBH is adjuvant to boost an immune response. Studies on effects on T lymphocytes and APC. Goal is to prime the immune response and combine with chaperone-based vaccination
- Graner: multiple chaperone cell lysates are even better vaccines. The potency can be enhanced by adding antigenic peptides to the mixture
- Milani: susceptibility to immune effector cells is maintained after heat shock heat, so that heat can be combined with chaperone-based vaccines
- Facciponte/Therriault: role of scavenger receptor on HSP70, 110 and effects on APC
1.2 HSF in biological system (transcription factors)
Hypothesis: HSF1 is the regulator of the heat shock response. Does it play a role?- increase of HSF= increase in HSP and inhibition of apoptosis
- Induction of HSF activates genes that encode cytoprotective proteins: tumor progression?
- signalling HSF (downstream of HER2; ERK represses HSF1; HSF1 and NFkB : the conection between innate immunity and heat shock)
1.3 Targeting HSP in cancer treatment and resistance to thermal therapy
Hypothesis: HSP is overexpressed in tumor: can we target this?
- HSP is overexpressed in metastasis and in cancer; HSP is activated in breast cancer
- HSP27, HSP70 may be predictive for response to therapy
- HSP27 in chemoresistance and thermoresistance
- HSP70 protects against apoptosis
- Depletion of HSP72 sensitize cell to cisplatin and proteasome inhibitor and cell dye; Inhibition of total HSP synthesis and agents that reduce cellular HSP70
- Blocking HSP90 and HSP70 have proved to be effective
- HSP90 targeting (growth receptors and kinases) potential for significant cardiotoxicity
2. Highlights in Biology/Physiology (Leeper)
2.1 Physiology and Biological modifiers of thermal response
2.1.1 P53 Status:
- Increase of heat sensitivity by suppression of heat-induced anti-apoptosis
- P53 gene-therapy
2.1.2 Physiological changes
- Blood flow and tumor oxygenation
- mild HT (41,5°C) increases blood flow -> increases tumor oxygenation -> increases tumor radiosensitivity
- severe HT (>42°C) induce a vascular damage -> directly and indirectly induces cell deaths by increasing heat sensitivity by inducing hypoxia and tumor acidity.
- Vascular permeability and angiogenesis
- HT in combination with chemotherapy reduces angiogenesis by decreasing VEGF
- Bioenergetic and metabolic status:
- pH: acidity increases heat sensitivity
- hyperglycemia increases acidity
- purine catabolism
2.2 Thermal cytotoxicity and molecular chaperones
- Thermal damage (S-Phase Hypertoxicity)
- Direct protein damage: substantial denaturation of protein, aggregation in the cytoplasm, cytoplasmatic inclusion body, disruption of cellular process by aggregated proteins
- Indirect DNA damage: by depurination of DNA, DSB ? DNA damage does not plays a major role.
- In the nucleus heat shock during the S-phase compromises DNA replication process promoting the formation of potentially lethal lesions (overlap of Euchromatin and heterochromatin) by inhibition of DNA synthesis. Induction of genomic instability
- Lipid damage: is reversible and not directly causing cell killing
- Role of HSP70 and molecular chaperones in maintaining genomic stability
2.3 Hyperthermia dependent delivery of therapeutic agents
2.3.1 Liposomal drug delivery
- Studies on low temperature thermosensitive liposomes (40°C) encapsulating Doxorubicin
- Development of thermosensitive liposomes with prolonged circulation for drug-delivery and non-invasive thermometry
2.3.2 Stress activation and control of therapeutic genes (gene therapy)
- Correct defect genes
- Potentiate other cancer therapies
- Kill cancer genes (activation of suicide genes)
- Generate bystander effects
- Several different cellular stress induce exogenous genes for therapeutic use
- By enhancing tumor plasmid delivery
- By using HSF promoters
- By using adenoviral vectors (for IL-12 or p53); mild heat increases viral vector distribution in vivo
2.4 Mechanism of radiosensitivization and radioresistance
Heat as radiation dose modifier by augmenting the amounts of DNA that remain unrepaired (enhancement of radiation-induced chromosomal aberrations):
- inhibition of DNA repair mechanisms (reduced chromatin accessibility as mechanism for inhibition of DNA repair by heat)
- inhibition of repolymerization step in base excision repair (BER)
- Theory of DSB (double strand breaks) and heat toxicity (Onishi)
