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!!