Targeted Cancer Therapy Flashcards
Targeted Therapy for Cancer
- foundation of precision medicine
- cancer treatment that targets proteins that control how cancer cells grow, divide, and spread
Small molecule drugs
- small enough tot enter cells easily
- used for targets that are inside cells
Monoclonal Antibodies
- proteins designed to attach to specific targets found on cancer cells
- – can mark cancer cells so they are better seen and destroyed by the immune system
- – can directly stop cancer cells from growing or cause them to self-destruct
- – can carry toxins to cancer cells
Tamoxifen
- metabolized into compounds that also bind the estrogen receptor but do NOT activate it
- blocks binding to cancer cells in some breast cancers
Imaging Mesylate
Gleevec
- approved for chronic myelogenous leukemia, gastrointestinal stromatolites tumor, and some other types of cancer
Gefitnib and Erlotinib
- target epidermal growth factor receptor (EGFR) tyrosine kinase and is approved in the US for non small cell lung cancers which have activating mutations in EGFR
PARP inhibitors
- inhibit PARP whose activity is critical for survival of cells with defects in homologous recombination
- under clinical trials to treat breast/ovarian cancers with mutations in BRCA genes
BRAF inhibitors
- approximately half of melanomas harbor the V600E activating mutation in the BRAF gene
- majority of cancer cells rely on sustained hyper activation of the oncogene for growth
Chronic Myelogenous Leukemia
- kinase mutation allows over expression of Philadelphia chromosome -> cell growth
Gleevec
Imantinib
- tyrosine kinase inhibitor
- binds to catalytic cleft of ABL
- remarkable effective in treating CML as a single agent
- leads to high rate of long term cytogenic remission
BCR-ABL
- promotes cell growth, inhibits cell death
- inhibited by Imantinib
- CML (chronic myelogenous leukemia)
ERBB Family of Receptor Tyrosine Kinases
- when overexpressed becomes oncogene and is problematic
- mutations/amplifications of EGFR (ERBB) gene are common in non-small cell lung cancer and epithelial cancers
- found on Extracellular domain
— dimerization must occur to become active
Targeting ERBB family of receptor tyrosine kinases
- ** SMALL MOLECULES EFFECTIVE ***
- antibodies bind Extracellular domain & block dimerization (can’t activate)
- inhibit kinase activity => shut off transduction
- inhibit fold eyeing helpers
Tratuzmab
Targets the Her2 (ErB2) receptor expressed in some types of breast cancers
Cetuximab
- binds Extracellular domain of ERBB and blocks dimerization
- prevents activation
Lapatnib
- inhibits tyrosine kinase activity shutting off signal transduction (targeting ERBB)
17-AAG
- inhibits folding of helpers
- targeting ERBB family of receptor tyrosine kinases
HER2
- very over-expressed in breast cancer
Trastuzumab
- weaponized humanized portion of chimeric mouse-human antibody (which causes immune response)
- bind Extracellular domain and prevent activation of HER2 (which causes increased pathway proliferation)
- recruits immune cells to kill tumor cells
- Cardiac toxicity
BRCA proteins
- required for homologous recombination (DNA double strand break repair)
PARP-1
- acts as tag for DNA repair enzymes for single strand breaks
Original theory of PARP inhibition
- results in accumulation of SSBs, which lead to broken replication forks during the S phase that require HR and thus BRCA 1/2 for repair
PARP Inhibitors
SYNTHETIC LETHALITY
- lock PARP onto DNA
- very problematic ( increases PARP affinity for DNA)
— stalls replication fork, and blocks DNA replication (unless have healthy BRCA to repair issue)
- selectively kills tumor cells because healthy cells will still have BRCA and will be able to overcome the stall and continue replication; tumor cells lacking BRCA will die
Mechanism of Resistance to PARPi
- secondary “reversion” mutations in BRCA1, BRCA2, RAD51C/D
- restoration of HRR in BRCA1 mutant tumor cells via loss of 53BP1, REV7
- loss of PARP1 expression
- pharmacological resistance
