Lectures included: signal transduction as target of therapy, radiation oncology, pediatric cancer therapy, surgery & prostate cancer, targeted therapy for NSCLC, antibody-based therapy, epigenetic therapy
Module 4: Innovative Tumor Therapy (Week 3)
LECTURE: TARGETING SIGNAL TRANSDUCTION (E. Giovannetti) Monday, 10/12/2018
Signal transduction: connect stimulus with response, example &
cascade see slide
Molecular process (interconnected):
A. Protein-protein interaction
B. Protein modification
C. Protein translocation
Several hallmarks are connected to alterations in signal transduction (see slide); genetic alterations determine cancer
phenotypes:
Gain of function Loss of function
Activation of oncogene d/t amplification Deletion/epigenetic signaling
Overexpression Interaction with microenvironment
Rationale of transduction modulation:
ONCOGENE ADDICTION Growth & survival
depend on altered pathways, targeting the
pathways may kill tumor
Benefit: less toxicity/SE; normal cell = well
established feedback mechanism for normal
function (many alternative pathways no
deleterious effect from signal inhibitors)
Targeting pathways have challenges:
Pathway redundancy
Substance resistance (acquired)
Complex network
Toxicity (e.g. off target effect)
Targeting protein interactions = difficult, targeting phosphorylation = more reasonable (e.g. TKI, phosphorylation
inhbition, etc)
, Module 4: Innovative Tumor Therapy (Week 3)
Example: targeting protein kinase
Phosphorylation guides signal to activate TF in
nucleus, EGFR pathway see slide, implicated in
cancer:
a. Overexpression of EGF
b. Mutated EGFR
c. Mutated RAS
d. Amplified cyclin D
Analysis:
A. Tissue microarray (IHC stain w anti EGFR
antibody)
B. FISH/CISH
C. PCR/sanger seq
Targeted Tx for EGFR inhibition:
a. TKI (small molecule)
b. MoAB (involve ADCC)
TKI (tyrosine kinase inhibitor): occupy ATP
binding site, different selectivity/activity
profiles across types
First gen TKI: combined with first
line Tx (see slide) - unsatisfactory
result
Second line TKI: little bit more
advantageous
Third gen TKI (addressing resistant
tumor d/t further EGFR mutation)
First gen: reversible binding to ATP binding
site of EGFR; Second gen: irreversible
binding
Possible cause of Tx failure: wrong targeting, wrong prey (e.g. not addressing type switch); example: successful response in
women Asian non-smoker less activating mutation in EGFR, different compound activity
Mutations that induce sensitivity to drug = deletions in exon 18/nucleotide binding loop (see slide) prevalent in Asian
population, probably d/t different genetic background
, Module 4: Innovative Tumor Therapy (Week 3)
Future strategies Overcoming resistance in the future:
Address additional mutation/clonogenic
switch leading to acquired resistance
Address EGFR target mutation
Address bypass tracks (see slide)
Resistance to third gen TKI = analyse with NGS &
KINASE ARRAY Result: NFKB signaling play a role
(coTx with NFKB inhibitor; see slide)
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