Oestrogen + Androgenic Cancers Flashcards
Describe the endocrine pathways
Androstenedione —> oestrone (E1)
Testosterone —> oestradiol (E2)
BOTH converted via aromatase
Describe the hormone synthesis pathway
17alpha-hydroxyprogesterone
Androstenedione then can go straight to estrone
Testosterone
Estradiol ⇋ Estrone
Describe oestrogen + progesterone receptors
Oestrogen signalling to cell
HSP90 (chaperone) = builds ER
Oestrogen binds + HSP90 releases
Oestrogen + ER dimerises around DNA
Kinase phosphorylates protein = signalling
This means lots of targets in cancer
What is the MoA of endocrine therapies?
All target oestrogen receptor
What are examples Selective Estrogen Receptor Modulators (SERM)?
Tamoxifen
Torimefene
What are examples Aromatase inhibitors?
Block aromatase = stop hormone conversion
Letrozole
Anastrozole
Exemestane
What are examples Progestins?
Megestrol acetate
Medroxyprogesterone acetate
What are examples LHRH agonists?
Leuprolide
Goserelin
Describe how SERMs work
Tertiary structure allows them to bind to oestrogen
Change oestrogen-receptor expression
Structural change of oestrogen-receptor
Change expression + binding to oestrogen-receptor of coregulator proteins = weaken binding to DNA
Describe Tamoxifen MoA
Competitive binding to oestrogen receptor = reduction in transcription of oestrogen regulated genes
Block G1 phase = slow cell proliferation
Cytostatic drug
Describe 3rd generation of Aromatase inhibitors MoA
Prevent peripheral conversion of androgens to oestrogen
Block the heme moiety of the enzyme
Describe treatment of symptomatic metastatic prostate cancer
Orchiectomy = removal
LHRH analogues (+/- anti-androgens)
Removal of androgens kills majority of prostate cancer cells = prostate cells + cancer cells dependent upon androgens for survival + growth
What is the adjuvant hormone therapy for advanced + metastatic prostate cancer?
Androgen ablation performed prior to prostatectomy or radiation
Describe how to remove androgens
Orchiectomy (castration) = surgical removal
LHRH agonists = same effect as castration = block testosterone production
Anti-androgens = block the effects of testosterone = block binding of DHT to androgen receptors
5-alpha-reductase inhibitor = enhances intracellular androgen blockade
Combination therapies
Describe the hormonal impact of Abiraterone
Block androgen precursor inside + outside of the cell
Describe LHRH agonists
Goserelin (Zoladex) = most common
Castrate levels of testosterone attainable in a few weeks
Describe anti-androgens
Flutamide
Bicalutamide
NOT superior to LHRH agonists alone
Higher cost + more SEs than LHRH
Describe Enzalutamide (novel anti-androgens)
Has potential of multiple targets + effective early on in cascade
Inhibits binding of androgens to AR = NO longer enters nucleus
Inhibits nuclear translocation of AR = NO longer bind to DNA
Inhibit association of AR with DNA = tumour can NO longer grow
Describe hormone-refractory prostate cancer (HRPC)
Despite initial response rates nearly all men with advanced prostate cancer develop hormone-resistant prostate cancer
These hormone-refractory prostate cancer cells can grow in absence of androgens
