Cancer Biology - Targeting Pathways (Breast Cancer Mostly) Flashcards
what is precision medicine?
a form of medicine that uses info about a person’s genes and proteins to prevent, diagnose and treat disease
- anti-raf
- anti-EGFR
- anti-VEGFR
- dual-inhibitors
- anti-Her2
- anti-PDGFR
- anti-mTOR
- sorafenib
- cetuximab, gefitinib, erlotinib
- sunitinib, semaxinib
- lapatinib, afatinib
- trastuzumab, pertuzumab
- imatinib
- everolimus
how do targeted therapies work (general classifications)?
cause cell death (apoptosis), carry other drugs to a tumor, target defects in the cancer cells, cut off blood flow to tumor, prevent/block/interrupt cell growth, make the cancer cells more receptive to the immune system
how are targeted cancer therapies identified? give examples as well
- block growth and spread of cancer by interfering with specific molecules that are involved in the growth, progression and spread of cancer
- potential targets should include proteins that are present/more abundant in cancer cells compared to normal cells…ex: HER2/herceptin
- determine whether cancer cells produce mutant (altered) proteins that drive cancer progress…ex: BRAF mutation/Zelboraf in melanomas
- abnormalities in chromosomes that are present in cancer cells but not normal cells (produce proteins that can be targeted)…ex: BCR-ABL protein/Gleevec/imatinib in lukemia
what drives cell proliferation in breast cancer (that has been targeted) and what does this result in?
estradiol and other steroid hormones; facilitates fixation of genetic errors
what is the mechanism of action of estrogen/estrogen receptors?
estrogen will bind to estrogen receptors which can then either bind to ERE on DNA directly, bind to other TF on DNA or can signal other TF to go to to DNA
will increase transcription of estrogen responsive genes to increase cell proliferation, such as c-MYC, Cyclin D1 and Cyclin E
what are the two main strategies to block the action of estrogen?
- block production
2. limit ability to reach the tumor cells by blocking the estrogen receptor: ER-alpha
describe the estrogen receptor alpha protein
- nuclear receptor superfamily
- 6 functional domains
A/B: DNA…N-terminal domain
C: DNA binding domain (DBD)
D: hinge region
E: ligand binding domain (LDB) - where estrogen binds
F: c-terminal domain
what are the hormonal therapies? what are the antibody therapies? when would you use each type?
- hormonal: use when ER+ tumors (70% of all tumors)
aromatase inhibitors: exemestane, anastrozole and letrozole; use only in post-menopausal women
antiestrogens: tamoxifen, fulvestrant - antibody: use when ERB-B2/Her2 + tumors (20%)
herceptin (Trastuzumab) and pertuzumab
how do tamoxifen and fulvestrant work?
both antiestrogens used when the tumor is ER+; have bulky side chains that cannot be contained within the binding pocket of ER and this causes H12’s orientation to be sterically hindered from aligning in the proper agonist conformation
tamoxifen: competitively inhibits estradiol on ER-alpha - stops transcription of estrogen regulated genes; has a dimethylaminoethoxy side chain with a trans configuration that is crucial for its antiestrogenic activity….is considered a cytostatic drug because blocks cell in G1 phase; metabolized by CYP2D6 to form active metabolites: 4-hydroxytamoxifen (4OHT) and endoxifen (ENDOX)
fulvestrant (faslodex): competitive binding to ER-alpha that marks the ER for degradation (completely inhibits ER signaling); is a second line therapy (especially in tamoxifen-resistant breast cancer) because a major concern is resistance; is a pure anti-estrogen, not a SERM (acts the same in all tissues)
how do aromatase inhibitors work?
they block the conversion of androgens to estrogen in postmenopausal women
bind to aromatase enzyme and blocks the enzymes function
what types of aromatase inhibitors are there? name examples and explain how they work/when you should use them
- steroidal inhibitor: exemestane
- nonsteroidal inhibitor: anastrozole and letrozole
these enzymes selectively block the heme moiety of the enzyme; active sites of other steroidogenic enzymes remain free; are 3 times more potent than aminoglutethemide
if a patient is given non-steroidal AI and cancer returns, can give steroidal AI
if a patient is given steroidal AI and cancer returns, must stick with steroidal AI
Ok, so tamoxifen is a super important drug to remember because it is used a lot, but it is also a AAA (she said “write this down because it is an important term to remember”…). what does this mean.
is a Selective estrogen receptor model: SERM…selective in that it depends on which proteins it recruits in the specific tissues
this means it has both antagonist and agonist effects:
antagonist: tumor inhibition and hot flashes
agonist: lowers cholesterol, preserves bone density, stimulates uterine cell proliferation
how do you treat different types of breast tumors and the ages?
ER, PR and Her2 negative: no endocrine therapy; chemo
premenopausal and ER/Her2 positive: tamoxifen, ablation of ovarian function
postmenopausal and ER/Her2 positive: tamoxifen, AI
how to treat Her2+ tumors
use trastuzumab/herceptin; binds to Her2 and prevents Her2 from forming an auto-homodimer (this is because there is amplification and overexpression of Her2 on the cell membrane)….inhibition of ligand independent signaling
certified for treatment of metastatic (stage 4) and early stage Her2+ breast cancer
trastuzumab combined with chemo increases overall survival and reduces the probability of relapse compared to chemo alone
other drugs and how they work:
- pertuzumab: inhibition of ligand-dependent signaling
- lapatinib: inhibition of ligand-dependent and ligand-independent signaling
- tykerb: tyrosine kinase inhibitor
