Targeted Drugs for Cancer

Question 1

What are the categories of anticancer drugs?

Answer 1

Action on existing DNA -> alkylating or free radical damage
Inhibit the synthesis or function of DNA -> interruption of function of topoisomerase
Interrupt cell division -> block activity of mitotic spindle
TARGETED DRUGS

Question 2

What are “TARGETED DRUGS”

Answer 2

interact with surface receptors or their associated tyrosine kinases, or by blocking downstream effect molecule for cell growth like mTOR or proteasomal activity

Question 3

Name the monoclonals and their targets

Answer 3

Bevacizumab (VEGF)
Cetuximab (EGFR)
Panitumumab (EGFR)
Rituximab (CD20)
Trastuzumab (HER-2)
Ipilimumab (CTLA-4)
Ofatumumab (CD20)

Question 4

Name the other inhibitors

Answer 4

Bortezomib (26-S Proteasome Inhibitor)

Visodegib (Hedgehog Pathway Inhibitor)

Question 5

Name the tyrosine kinase inhibitors

Answer 5

Crizotinib
Dasatinib
Erlotinib
Gefitinib
Imatinib
Lapatinib
Nilotinib
Pazopanib
Sorafenib
Sunitinib
Vemurafenib

Question 6

Name the general characteristics of MAB

Answer 6

large molecular weight, administered IV
current drugs based on IgG molecules
2 covalently linked antibodies are now approved, modified with cytotoxic microtubule antagonists

Question 7

Name the general characteristics of Tyrosine Kinase Inhibitors

Answer 7

small molecular drugs; given orally
bioavailability may vary with food and CYP (some are both substrates and inhibitors of CYP3A4)
MD should remain alert for the potential of drug-drug interactions

Question 8

What are the most commonly targeted cell surface receptors

Answer 8

HER-2 and EGFR

Question 9

Trastuzumab MOA and Toxicity

Answer 9

Immediate inhibition of stimulatory signal and downregulation of HER-2 receptor. Cyclin-dependent kinase inhibitor p27 accumulates and cell cycle arrest occurs

Cardiomyopathy, infusion reaction

Question 10

Pertuzumab MOA

Answer 10

Block heterodimerization of HER-2 and HER-3; HER-2 kinase usually phosphorylates the HER-3 cytoplasmic domain, activating it as a scaffold to promote the PI3-kinase cascade

Question 11

Ipilimumab MOA

Answer 11

Functions as an immunostimulant; by binding to CTLA-4 receptor on T cells, it prevents binding of CD80/CD86 and in doing so positively regulates T-cell activation and proliferation.

Question 12

Rituximab MOA and Toxicity

Answer 12

Bind to the surface of CD20 on B cells and produces a rapid and sustained depletion of B cells

Infusion reaction, B cell depletion, Lymphopenia

Question 13

VEGF Pathway

Answer 13

Pathway is activated mostly in large solid tumors that are beginning ot outgrow their vascular supply. Provides for angiogenesis and promotes metastatic tumor proliferation and survival.

Under conditions of low oxygen tension, hypoxia inducible factor (HIF-1) is no longer processed and degraded by the 26S proteasome complex, but rather it translocates to the nucleus to promote upregulation and expression of VEGF

Question 14

Tyrosine Kinase Inhibitors

Answer 14

bind to highly conserved ATP binding site, which makes specificity difficult.

Resistance follows initial responsiveness via kinase over-expression, binding site mutation, and others

Question 15

Describe the binding site mutations in TKIs

Answer 15

several mutations in the ATP binding domain have been identified:
BCR-ABL (T3151) - prevents appropriate binding of first generation drugs
Other include - KIT (T670I) and EGFR (T790M)

Question 16

What happens when there are binding site mutations in TKIs

Answer 16

mutations impact drug binding but do not inactivate kinase function –> alter the potency of effect and shift the crucial dose-response curves to the right. This has the effect of changing or diminishing the therapeutic window for the drug and may make it impossible to achieve adequate clinical effect in the absence of significant adverse effects caused by “off target” actions

Question 17

What are other mechanisms of resistance to oral TKIs?

Answer 17

decreased intracellular drug levels
increased plasma protein binding
MDR1 (p-gp) mediated efflux
genomic amplification of kinase
clonal evolution of kinase-independent mechanism
mutations of ATP-binding site affected drug binding or kinase activity

Question 18

Ubiquitin-Proteasome Function

Answer 18

intracellular target

26S proteasome functions to degrade proteins which have been targeted by ubiquitination

Question 19

What is one of the targets of the Ubiquitin-Proteasome Pathway

Answer 19

ikB-alpha, which is the inhibitory (regulatory) partner of the transcription factor NFkB

Question 20

Describe the normal circumstances (using the main example) of the Ubiquitin-Proteasome Pathway

Answer 20

under normal circumstances, ikB-alpha is broken down by the 26S proteasome, leaving NFkB free to translocate to the nucleus to instigate proliferative signaling

Question 21

Bortezomib

Answer 21

Proteasome Inhibitor
Unlike the receptor TKIs, this drug is administered IV bolus or SC.
Prevents NFkB from conducting proliferative action –> apoptosis, growth inhibition, reduced angiogenesis

Question 22

What are some of the adverse effects associated with Bortezomib

Answer 22

Hypotension, including postural and orthostatic

• additive with antihypertensives
• hydration; mineralocorticoid; vasopressors

Cardiotoxicity, including acute onset CHF, decreased LVEF and QT prolongation
Severe sensory and motor peripheral neruopathy
Hematologic and Hepato- toxicity reported
Pregnancy risk category D

Question 23

What is the most unusual adverse effect associated with Bortezomib

Answer 23

Peripheral neuropathic effects

unusual for “targeted” drugs, being more commonly associated with cytotoxic agents impacting microtubule function

Question 24

mTOR function

Answer 24

regulates cell proliferation, angiogenesis, and cell metabolism by activating or inhibiting protein synthesis upon receipt of appropriate biochemical signals

Question 25

mTOR inhibition

Answer 25

may be inhibited by small molecular weight drugs that form a three-way complex involving inhibitor, FKBP-12 and mTOR

Question 26

Name the drugs acting on mTOR and their primary indication

Answer 26

Temsirolimus and Everolimus are approved for the treatment of advanced renal cell cancer

Question 27

What is one of the main issues with “targeted drugs”

Answer 27

the target, while it may be over-expressed in tumor cells, is also expressed and has an essential role in normal non-tumorous tissue

Question 28

What is the main “off-target” effect

Answer 28

cardiovascular problems such as CHF are seen with both MABs and TKIs

Question 29

Name the adverse effects of MABs

Answer 29

Infusion related reactions: anaphylaxis, angioedema, and pulmonary toxicity (especially with intrinsic lung disease) –> pre-medicate with antihistamines and/or corticosteroids before resumption of infusions

Development of LV dysfunction and CHF; HTN

Depletion of cell populations in the blood where target is expressed in component of this tissue (e.g. B-cell depletion, pancytopenia, etc.)

Question 30

Approval for clinical use of some EGFR MABs in the individual patients is sometimes contingent on what?

Answer 30

Genetic testing for downstream protein markers like KRAS and BRAF

Patients with mutations in KRAS and BRAF oncogenes are less likely to respond to anti-EGFR therapies because the proliferative pathway downstream of the EGFR remains constitutively active, regardless of the presence of absence of endogenous ligand or MAB

Question 31

Name the adverse effect of TKIs

Answer 31

Ability to disrupt endocrine function

Common adverse effects include rash, fatigue, N/V, dyspnea, stomatitis, anorexia

Many produce various degrees of blood dyscrasias (e.g. neutropenia, thrombocytopenia, lymphocytopenia)

Many produce QT prolongation

Some produce “hand-foot” syndrome
- Sunitinib, Sorafenib, Pazopanib, Vemurafenib

Question 32

What should patients taking TKIs have monitored

Answer 32

Thyroid function, bone density, PTH, and 25-OH Vitamin D
Monitor child growth and pubertal development
Women of childbearing age need to be counseled about the known adverse effects of TKIs on fetal development
Montior diabetics for blood glucose levels

Question 33

What are TKIs associated with cardiovascular dysfunction

Answer 33

Lapatinib and Nilotinib

Question 34

What are the TKIs associated with thyroid dysfunction

Answer 34

Common: Sorafenib, Sunitinib, Imatinib
Moderate: Dasatinib, Erlotinib, Nilotinib, Pazopanib

Question 35

Explain how the multi-redundancy in cell signaling has an impact upon the design of cancer treatment regimens

Answer 35

RTK mediated signaling pathways share multiple elements and inhibiting the dominant kinase often results in compensatory downstream recruitment of secondary TKs
Dominant RTKs: EGFR or ErbB2
Secondary RTKs: c-Met, PDGFR, IGF-1R

The RTK coactivation events converge on a number of fragile points in the network, such as AKT. Appropriate medical management would be to target multiple TKs or fragile points.

Question 36

Magic Bullet or Shotgun Approach?

Answer 36

Shotgun method: multiple drugs target multiple pathways and critical fragile points concurrently

Question 37

What is foremost among the continuing issues with targeted drugs?

Answer 37

absence of prolonged clinical response because of the emergence of resistant clones. most effective outcomes will be derived from a multi-drug regimen of targeted therapy (i.e. shotgun approach).

Resistance may arise through activation of alternative TKs or other network elements.

Question 38

Amongst the drugs that might be employed are…

Answer 38

NSAIDs to inhibit actions of prostanoids that have been found to be elevated in many solid tumors