Targeted Drugs for Cancer Flashcards
What are the categories of anticancer drugs?
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
What are “TARGETED DRUGS”
interact with surface receptors or their associated tyrosine kinases, or by blocking downstream effect molecule for cell growth like mTOR or proteasomal activity
Name the monoclonals and their targets
Bevacizumab (VEGF) Cetuximab (EGFR) Panitumumab (EGFR) Rituximab (CD20) Trastuzumab (HER-2) Ipilimumab (CTLA-4) Ofatumumab (CD20)
Name the other inhibitors
Bortezomib (26-S Proteasome Inhibitor)
Visodegib (Hedgehog Pathway Inhibitor)
Name the tyrosine kinase inhibitors
Crizotinib Dasatinib Erlotinib Gefitinib Imatinib Lapatinib Nilotinib Pazopanib Sorafenib Sunitinib Vemurafenib
Name the general characteristics of MAB
large molecular weight, administered IV
current drugs based on IgG molecules
2 covalently linked antibodies are now approved, modified with cytotoxic microtubule antagonists
Name the general characteristics of Tyrosine Kinase Inhibitors
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
What are the most commonly targeted cell surface receptors
HER-2 and EGFR
Trastuzumab MOA and Toxicity
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
Pertuzumab MOA
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
Ipilimumab MOA
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.
Rituximab MOA and Toxicity
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
VEGF Pathway
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
Tyrosine Kinase Inhibitors
bind to highly conserved ATP binding site, which makes specificity difficult.
Resistance follows initial responsiveness via kinase over-expression, binding site mutation, and others
Describe the binding site mutations in TKIs
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)
What happens when there are binding site mutations in TKIs
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
What are other mechanisms of resistance to oral TKIs?
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
Ubiquitin-Proteasome Function
intracellular target
26S proteasome functions to degrade proteins which have been targeted by ubiquitination
What is one of the targets of the Ubiquitin-Proteasome Pathway
ikB-alpha, which is the inhibitory (regulatory) partner of the transcription factor NFkB
Describe the normal circumstances (using the main example) of the Ubiquitin-Proteasome Pathway
under normal circumstances, ikB-alpha is broken down by the 26S proteasome, leaving NFkB free to translocate to the nucleus to instigate proliferative signaling
Bortezomib
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
What are some of the adverse effects associated with Bortezomib
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
What is the most unusual adverse effect associated with Bortezomib
Peripheral neuropathic effects
unusual for “targeted” drugs, being more commonly associated with cytotoxic agents impacting microtubule function
mTOR function
regulates cell proliferation, angiogenesis, and cell metabolism by activating or inhibiting protein synthesis upon receipt of appropriate biochemical signals
mTOR inhibition
may be inhibited by small molecular weight drugs that form a three-way complex involving inhibitor, FKBP-12 and mTOR
Name the drugs acting on mTOR and their primary indication
Temsirolimus and Everolimus are approved for the treatment of advanced renal cell cancer
What is one of the main issues with “targeted drugs”
the target, while it may be over-expressed in tumor cells, is also expressed and has an essential role in normal non-tumorous tissue
What is the main “off-target” effect
cardiovascular problems such as CHF are seen with both MABs and TKIs
Name the adverse effects of MABs
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.)
Approval for clinical use of some EGFR MABs in the individual patients is sometimes contingent on what?
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
Name the adverse effect of TKIs
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
What should patients taking TKIs have monitored
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
What are TKIs associated with cardiovascular dysfunction
Lapatinib and Nilotinib
What are the TKIs associated with thyroid dysfunction
Common: Sorafenib, Sunitinib, Imatinib
Moderate: Dasatinib, Erlotinib, Nilotinib, Pazopanib
Explain how the multi-redundancy in cell signaling has an impact upon the design of cancer treatment regimens
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.
Magic Bullet or Shotgun Approach?
Shotgun method: multiple drugs target multiple pathways and critical fragile points concurrently
What is foremost among the continuing issues with targeted drugs?
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.
Amongst the drugs that might be employed are…
NSAIDs to inhibit actions of prostanoids that have been found to be elevated in many solid tumors
