Lecture 5: Hormones and molecularly-targeted therapies

Question 1

Hormonal Therapy of Cancer

Answer 1

Treatment that adds, blocks or remove hormones
Androgens and estrogens have been implicated in the development of breast cancer, prostate cancer and endometrial cancer
Hormonal agonists and antag are NON-cytotoxic=no kill, decrease growth
Effects of endocrine therapy are mediated through estrogen receptors and progesterone receptors
Level of receptor expression is likely to influence the outcome of therapy
Ex. 70% of breast cancer have ER+ tumours

Question 2

Tamoxifen

Answer 2

Competitive inhibitor or estradiol binding to the ER in breast tissue
Prodrug: metabolized by CYP2D6, hi levels CYP2D6=more effective
Treatment of choice in women with ER+ and PR+ breast cancer
Decrease disease recurrence and mortality rates as much as 50% and 30%
Used as prophylactic treatment for those at high risk

Question 3

Tamoxifen SFX

Answer 3

Hot flashes
Increase risk of endometrial cancer(partial agonist on estrogen receptor in this tissue)
Increase risk for thromboembolic events as well as depression
SSRIs are commonly used to treat both hot flashes and depression
Many SSRI have anti CYP2D6 activity which could lead to decrease tamoxifen efficacy

Question 4

Raloxifen

Answer 4

Non-steroidal selective receptor modifier(SERM)
anti-estrogenic(ANTAGONIST) action on uterus and breast
Only ER+ breast disease is reduced
Estrogenic(AGONIST) action on bone
Treatment and prevention of osteoporosis in post-menopausal women

Question 5

Anastrozole

Answer 5

Second line hormonal therapy for breast cancer

Selective aromatase inhibitor=decrease estrone and estradiol synthesis

Question 6

Hormonal Therapy of Prostate Cancer

Answer 6

Dihydrotesterone(DHT) modulates prostate growth
DHT binds to cytoplasmic androgen receptors
Receptors activated and transported to nucleus where they bind to HRE and promoters of hormone regulated genes
Prostate cancer depends on DHT
Androgen-sensitive prostate cancer occurs in 80% of patients

Question 7

Androgen Withdrawal Therapies

Answer 7

Decrease androgen production
Bilateral orchiectomy(castration-physically remove)
Medical castration using GnRH(LHRH) agonist-leuprolide
Blocks recreation of LH by the pit gland and thereby inhibits synthesis of testosterone by testis
GnrH antagonist(Degarelix)
Androgen synthesis inhibitors(abiraterone)
Androgen receptor antagonism

Question 8

Abiraterone

Answer 8

Inhibits CYP17A1 which is expressed in testicular, adrenal, and prostatic tumor tissue
CYP17 catalyzes two sequential reactions:
Conversion of pregnenolone and progesterone to their 17-alpha-hydroxy derivatives by its 17 alpha-hydroxylase activity
The subsequent formation of dehydroepiandrosterone(DHEA) and androstenedione respectively
Used in castration-resistant prostate cancer

Question 9

Flutamide

Answer 9

Non-steroidal antiandrogen
2-OH flutamide blocks binding of androgens at the AR
Adverse effect
Diarrhea, nausea and vomiting
Liver function abnormalities
Flutamide usually administered with Leuprolide-attenuates initial testosterone flare with leuprolide

Question 10

Enzaluntamide(MDV3100)

Answer 10

Approved in 2012 for treatment resistant prostate cancer(US)
Androgen receptor antagonist
Prevents binding of AR to DNA and AR to coactivator proteins

Question 11

Molecularly-Targeted Therapeutics

Answer 11

A new gen of cancer drug designed to interfere with a specific molecular target, typically a protein believed to have a critical role in tumour growth or progression
A receptor tyrosine kinase inhibitor
Glycolysis inhibitor
Proteosome inhibitors
Angiogenesis inhibitor
Apoptosis modulators

Question 12

Receptor tyrosine kinase(RTK)

Answer 12

Often upreg in cancer, activation of this by GF receptors

Question 13

EGF receptor activation enhances acquired capabilities of cancer cells

Answer 13

Self-sufficiency in growth signals
Insensitivity to anti-growth signals
Evasion from apoptosis limitless replicative potential
Sustained angiogenesis
Tissue invasion and metastasis

Question 14

RTK inhibition

Answer 14

Block ligand binding to receptor
Blocks receptor dimerization
induce receptor endocytosis and degradation(via ubiquitination)
Block tyrosine kinase activity

Question 15

ErbB2/HER2 Receptors in Cancer

Answer 15

Amplification of the gene encoding HER2 was the first consistent genetic alteration detected in human breast cancer
HER2 belongs to the epidermal growth factor(EGFR) family of receptor tyrosine kinases
Patients with elevated HER2 have poor prognosis
HER2 receptor a target for anti-cancer therapeutics
MCAB against extracellular domain
Tyrosine kinase inhibitors that inhibit the intracellular enzymatic activity of the receptor

Question 16

Herceptin

Answer 16

Binds to the extracellular domain of the HER2 receptor
Mechanism: Disruption of receptor dimerization and downstream signaling
Arrest cells in G1 phase
Herceptin suppresses angiogenesis
Most effective when used in combination with chemotherapy
Ex. Cetuximab: stimulated EGFR internalization
Panitumumab: fully human monoclonal Ab to EGFR

Question 17

Problem with Ab approach

Answer 17

Dose-limiting systemic toxicities
Mice lacking EGFR usually die the first postnatal week due to respiratory problems. They also show GIT phenotype, think skin and hair follicle defects
Some skin rashes and diarrhea
High molec weight, distributed slowly and incompletely
Required I.V.
Elicit immune response
TARGETING ONE SPECIFIC RECEPTOR SPECIES MAY NOT BLOCK HETEROGENEOUS RECEPTOR COMBINATIONS-Can dimerize btwn diff types of receptors

Question 18

Imatinib template for rational drug design

Answer 18

Target: BCR-ABL tyrosine kinase
Clinical use: chronic myeloid leukemia(CML)
CML is characterized by a chromosomal translocation called Philadelphia chromosome( translocation btwn #9 and #22)
Bcl-abl tyrosine kinase activates mediators of the cell cycle regulation
Constitutively active-bcl not normally continuously active

Question 19

Imatinib

Answer 19

Mechanism: binds to kinase domain on bcl-abl kinase competitively and inhibit proteins from binding=no growth signal
Resistance is multifactorial
Bcl-abl overexpression
BCR-ABL kinase mutation-decrease affinity for imatinib
BCL-ABL independent mechanism
Nilotinib: second-generation tyrosine kinase inhibitor active against a wide range of imatinib-resistant or intolerant patients

Question 20

Gefitinib(Iressa)

Answer 20

ATP site competitive inhibitor of EGFR tyrosine kinase activity
Shown to also effectively inhibit HER1-HER2 heterodimers
Approved for patients with non-small cell lung cancer(NSCLC)
Response rate was 10%
Due to lack of evidence, only admin to patients who responded to Getfitinib in past

Question 21

Erlotinib(tarceva)

Answer 21

EGFR inhibitor

Approved for patients with NSCLC

Question 22

Lapatinib

Answer 22

Dual EGFR/ErbB inhibitor

Question 23

Tyrosine Kinase inhibitor(TKI) compared to mABs

Answer 23

TKI are orally administered, mAb required IV
TKI have low moleculaar weights and distributed more rapidly and possibly more completely than mAbs
Cross react with other kinases(dual EGFR/ErbB2 inhibitors), mAb are specific
TKI lack immune responses
Severe acneic skin rashes and diarrhea
TKI do NOT downregulate receptors, while mAB do
TKI and mAbs exhibit different clinical response profiles

Question 24

Angiogenesis Inhibitors

Answer 24

Monoclonal Ab against vascular endothelial growth factor-A (VEGF-A) and its receptor
Inhibits angiogenesis and starves the tumour of oxygen

Question 25

Avastin(bevacizumab)-

Answer 25

used to treat metastatic colorectal cancer
First clinically available angiogenesis inhibitor in the US
Not a chemotherapeutic agent
Administered with standard chemotherapy treatment
See diagram for sorafenib

mAb against VEGF-A

Question 26

Proteosome inhibitors

Answer 26

Drug that blocks the action of proteasomes
Proteasomes degrade unneeded or damaged proteins
Prior to degradation, first tagged with ubiquitin
Proteasomal degradation of certain proteins are critical for cell cycle regulation

Question 27

Bortezomib

Answer 27

First line therapeutic proteasome inghibtor to be tested in humans
B atom binds to CATALYTIC SITE of proteasome(hi affinity and selective)
Proteasome inhibition may prevent degradation of pro-apoptotoic factors
Cell cycle arrest and apoptosis
Used to treate relapse multiple myeloma
Marizomib-currently in clinical trial=irreversible proteasome inhibitor
Derived from marine actinomycete and is less myelosuppression and peripheral neuropathy

Question 28

Using viruses to treat cancer

Answer 28

ONYX-015
Genetically-engineered Adenovirus
E1B 55kDa gene deleted
Can only replicate in human cells lackin p53(often cancer)
50% of all cancer contain p53 mutations
Lyses cancer cells, but is dormant in healthy cells
Controversy over ability to selectively kill p53-deficient cells
Clinical trials show ONYX-015 was not very effective monotherapy, however it showed good synergism with 5-FU and cisplatin