PMCOL 344 - Hormones and molecularly targeted therapies

hormonal therapy of cancer

- directed at specific cancers
- treatment that adds, blocks, removes hormones

what hormones have been implicated in the development of breast cancer, prostate cancer, and endometrial cancer

androgens and estrogens

hormonal agonists and antagonists are

NON-cytotoxic drugs (do not kill cells --> just slow down proliferation)

effects of endocrine therapy are mediated through

estrogen receptors and progesterone receptors

what is likely to influence the outcome of therapy

the level of receptor expression

70% of pts with primary breast cancer have

ER+ tumors (ER- tumors are not regulated by hormones, therefore they are harder to treat)

what molecules target estrogen receptor (ER) action in breast cancer

1. aromatase inhibitors
2. antiestrogens, SERMS
3. peptides and small molecules
4. small molecule inhibitors

aromatase

converts testosterone to estrogen (E synthesis)

TAMOXIFEN

- competitive inhibitor of estradiol binding to the ER in breast tissue
- treatment of choice in women with ER+ and PR+ breast cancer
- decreases disease recurrence and mortality rates by as much as 50% and 30% respectively
- prophylactic treatment for those at high risk of developing breast cancer

tamoxifen is a prodrug, it is metab by

CYP2D6 in the liver (there is high interindividual variability in expression of this P450 enzyme)

side effects of tamoxifen

- hot flashes (can lead to non-compliance)
- increased risk of endometrial cancer (partial agonist on ER)
- increased risk for thromboembolic events as well as clinical depression

what drugs can be used to treat hot flashes and depression, but what is the negative side effect

SSRIs can be used but they have anti-CYP2D6 activity which could lead to a decrease in tamoxifen efficacy

RALOXIFEN

- SERM
- antiestrogenic (antagonist) actions on the uterus and breast (only ER+ breast cancer is reduced)
- estrogenic (agonist) effects on bone (treatment of osteoporosis in post-menopausal women)

ANASTROZOLE

- 2nd line hormonal therapy for breast cancer
- selective aromatase inhibitor
- blocks the production of estradiol, estrone from androstenedione

what hormone modulates prostate growth

dihydrotesterone (DHT)

DHT binds to

cytoplasmic androgen receptors (the steroid receptor complex undergoes activation and transport to the nucleus where they bind to HRE in the promoters of hormone regulated genes)

prostate cancer depends on

DHT

"androgen sensitive" prostate cancer occurs in

80% of pts

androgen withdrawal therapies

- decrease androgen production
- androgen receptor antagonism

what are ways to decrease androgen production

- bilateral orchidectomy (castration)
- medical castration using GnRH (LHRH) agonist (LUEPROLIDE)
- GnRH antagonists (DEGARELIX)
- androgen synthesis inhibitors (Abiraterone)

LUEPROLIDE

This synthetic GnRH can be used to decrease androgen production

how does LUEPROLIDE work

block the secretion of LH by the pituitary gland and thereby inhibit the synthesis of testosterone by the testis (due to receptor desensitization)

DEGARELIX

GnRH antagonist

ABIRATERONE

inhibits CYP17A1 and is used to treat castration resistant prostate cancer

where is CYP17A1 expressed

testicular, adrenal, prostatic tumor tissues

CYP17 catalyzes what two sequential rxns

1. conversion of pregnenolone and progesterone to their 17-alpha-hydroxy derivatives by its 17-alpha hydroxylase activity
2. subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione

FLUTAMIDE

- non steroidal antiandrogen
- 2OH flutamide blocks binding of androgens at the AR

adverse effects of FLUTAMIDE

- diarrhea, nausea, vomiting
- liver fxn abnormalities

flutamide is usually coadministered with

leuprolide (attenuates initial testosterone "flare" with leuprolide)

ENZALUTAMIDE (MDV3100)

- treats castration-resistant prostate cancer
- androgen receptor antagonist
- prevents binding of AR to DNA and AR to coactivator proteins

molecularly targeted therapeutics

new generation of cancer drugs designed to interfere with a specific molecular target, typically a protein, believed to have a critical roe in tumor growth or progression (targets a specific protein unique to the cancer)

receptor tyrosine kinases (RTK)

molecules activated by ligands and phosphates to activate a response --> there are specific upregulated proteins related to certain types of cancers

EGF receptor activation

enhances proliferative capabilities of cancer cells

how do EGF receptor activation enhance proliferative capabilities of cancer cells

- self sufficiency in growth signals
- insensitivity to anti growth signals
- evasion from apoptosis
- limitless replication potential (influences telomeres)
- sustained angiogenesis
- tissue invasion and metastasis

RTK inhibition

1. block ligand binding to receptor
2. block dimerization of receptor
3. induce receptor endocytosis and degradation (via ubiquitination)
4. block tyrosine kinase activity

ErbB2/HER2 receptors in cancer

- amplification of the gene encoding HER2 was the first consistent genetic alteration detected in human breast tumors
- HER2 belongs to the epidermal growth factor (EGFR) family of receptor tyrosine kinases
- elevated HER2 = poor prognoisis

HER2 receptor a target for anticancer therapeutics via

-MCAB against extracellular domain
- tyrosine kinase inhibitors that inhibit the intracellular enzymatic activity of the receptor

HERCEPTIN

- binds to extracellular domain of the HER2 receptor
- disruption of receptor dimerization and downstream signaling
- arrest cells in GI phase
- suppresses angiogenesis
- most effective when used in combination with chemotherapy

CETUXIMAB

stimulates EGFR internalization (downregulates whole system)

PANITUMUMAB

fully human monoclonal antibody to EGFR (newer generation of antibody)

problems with antibody approach

- dose limiting systemic toxicities
- skin rashes, diarrhea
- high MW --> distribute slowly and incompletely
- require IV
- elicit immune response

a problem that arises when using mAb is that targeting one specific receptor species may not block heterogenous receptor combinations, what is a solution to this

use tyrosine kinase inhibitors

IMATINIB

- template for rational drug design
- targets BCR-ABL tyrosine kinase (competitively binds to site and inhibits protein)
- clinical use in CML

CML is characterized by

chromosomal translocation called the Philadelphia chromosome

the BCR-ABL tyrosine kinase activates

mediators of the cell cycle regulation (constitutively active)

what are the factors contributing to imatinib resistance

- BCR-ABL overexpression
- BCR-ABL kinase mutation
- BCR_ABL indepedent mechanisms

NILOTINIB

second gen tyrosine kinase inhibitor active against a wide range of imatinib-resistant or intolerant pts

GEFITINIB (IRESSA)

- ATP site competitive inhibitor of EGFR tyrosine kinase activity
- IC50 = 0.033uM (EGFR/HER2) and inhibits HER1-HER2 heterodimers
- used for non small cell lung cancer (NSCLC)
- 10% response
- withdrawn due to lack of response, only used in pts who had a response to it

ERLOTINIB (TARCEVA)

- EGFR inhibitor
- used for non small cell lung cancer (NSCLC)

LAPATINIB

- dual EGFR/ErbB inhibitor

TK inhibitors (TKI) vs mAb

- TKI = oral, mAb = IV
- TKI = low MW
- TKI cross react with other kinases, mAb are specific
- TKI lack immune response
- acneic skin rashes (folliculitis) and diarrhea
- TKI do not downregulate receptors, mAb do
- TKI and mAb exhibit diff clinical response profiles

angiogenesis inhibitors

- mAb against vascular endothelial growth factor-A (VEGF-A) and its receptor
- inhibits angiogenesis
- starves the tumor cell of oxygen and nutrients

Avastin (bevacizumab)

- used to treat metastatic colorectal cancer
- not a chemotherapeutic agent
- administered with standard chemotherapy treatment (5-FU)

proteosome inhibitors

- drugs that block the action of proteosomes
- proteosomes degrade unneeded or damaged proteins
- prior to degradation protein are first tagged by linkage to ubiquitin
- proteasomal degradation of certain proteins are critical for cell cycle regulation

BORTEZOMIB

- chemical proteosome inhibitor
- reversible
- B atom binds to the catalytic site of the proteosome (high affinity and selectivity)
- proteosome inhibition may prevent degradation of pro-apoptotic factors (cell cycle arrest and apoptosis)
- used in the treatment of relapsed multiple myeloma
- myelosuppression
- peripheral neuropathies

MARIZOMIB

- currently in clinical trials
- irreversible proteosome inhibitor
- less myelosuppression and peripheral neuropathy