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Cancer Chemotherapy 3: Targeted Therapy and Biological Response Modifiers
&Treatment of ADRs
Dr. Syed Shariq NaeemAssistant Professor
Signal Transduction Pathway
EGF
TK
RAS
RAP
MEP
PI3K
Akt
mTOR
Gene Expression
1. Cell Proliferation2. Protein synthesis
Targeted Therapy
• Biological Response Modifiers: o Monoclonal antibodies
o Cytokines
o Gene Therapy
• Small Molecules: o Tyrosine Kinase Inhibitors
o Angiogenesis Inhibitors
o Proteosome Inhibitors
o Histone Deacetylase Inhibitors
EGF
TK
RAS
RAP
MEP
PI3K
Akt
mTOR
Gene Expression
1. Cell Proliferation2. Protein synthesis
Transtuzumab(HER2/neu/Erb B2)
Inhibit Dimerization
Ca Breast
Monoclonal antibodiesCetuximab(EGFR/HER1/ ErbB1)
BlocksReceptor + Cytotoxicity
Adv. Squamouscell Ca. of head and neck
Colorectal CaPanitumumab
Blocks Receptor
Types of Monoclonal Antibodies
TK TK TK
Naked Mab Poison Tagged Mab Radioactive Tagged Mab
CD 20
Rituximab B cell Lymphoma
CD 33 Gemtuzumab-Ozogamycin
AML
IL 2 + DiptheriaToxin (EF2)
DenileukinDifitox
CTCL
Mab internalized Cleaved in lysosome Toxin in Nucleus Double strand Breaks
Tositumomab- I131
(γ emmiter)
CD 20 Relapsing Lymphoma
Ibritumomab- Y90
(β emmiter)
CD 20 Relapsing Lymphoma
Tyrosine Kinase Inhibitors
TK
RAS
RAP
MEP
PI3K
Akt
mTOR
Gene Expression
1. Cell Proliferation2. Protein synthesis
I
TKI
TKITKI
TKI
EGF
Gefitinib(EGFR/HER1/ ErbB1)
Blocks ATP binding site
3rd line therapy for –Non small cell lung cancer
Erlotinib Blocks ATP binding site
Lapatinib(HER2/neu/Erb B2)
Tyrosinkinaseinhibitor
Ca Breast
EverolimusTemsirolimus
m TOR inhibitor
Renal / hepatic Ca
• Imatinib:
– Tyrosine kinase Inhibitor
– CML- 9:22 Bcr-Abl Oncoprotein expression
• Dasatinib, Nilotinib
– Bcr-Abl kinase mutation with resistant to imatinib
TK
1. Cell Proliferation2. Angiogenesis3. Metastasis
Signal Transduction
Cascade
VEGF- Vascular Endothelial Growth FactorFGF- Fibroblast Growth FactorTGF-β- Transforming Growth FactorPDGF- Platelet Derived Growth Factor
Bevacizumab
TKI
Tyrosine Kinase Inhibitor: Sorafinib, Sunitinib,
Pazopanib
Decoy Receptor: Aflibercept
Angiogenesis Inhibitors
Epigenetics
Histone Deacetylase
inhibitor: Vorinostat
Thalidomide
• Following the thalidomide disaster of 1961, when Dr. McBride of Australia reported increased frequency of birth defects (seal limbs) that left 10,000 babies disabled for life, monitoring centres were started the world over.
Thalidomide
Questions!!
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