Targeted Therapy Flashcards
What does “MAB” mean in the spelling of a medication?
Monoclonal antibody; target will be a cell surface receptor that activates a signaling cascade leading to proliferation
Drug names that end in “ib” indicate what?
The drug is an inhibitor agent of tyrosine kinase receptors
Trastuzumab
A monoclonal antibody drug
Target: Binds to and down-regulates HER-2 receptor
Effect: Cell cycle arrest
Cancer: Breast cancer
Which drug binds to and down-regulates the HER-2 receptor?
Trastuzumab
Which drug prevents dimerization of the HER-2 and HER-3 receptors, thereby preventing HER-2 from phosphorylation HER-3? What cascade does it prevent?
Pertuzumab
PI3K
Pertuzumab
Monoclonal antibody drug
Target: HER-2 and HER-3
Effect: Recall that HER-2 dimerizes with and phosphorylates HER-3, and they then promote the PI3K cascade. Pertuzumab prevents formation of the heterodimer.
Cancer: Breast cancer
T-DM1
These drug types contain in their structure both an antibody and a cytotoxic agent. In Sweatman’s example, they are binding the EGFR.
1) Antibody action finds the receptor
2) Delivery of a cytotoxic agent to the tumor target, thus minimizing distribution of the native drug throughout the body.
Ipilimumab
A monoclonal antibody drug
Target: Binds CTLA-4 so that the tumor cell cannot send its B7 to bind. Normally, if B7 binds CTLA-4, the T-cell gets the message that it need to activate and proliferate. Because this antibody drug takes up the CTLA-4 binding site, the only other one open for B7 is CD28, which activates the T-cell, perhaps giving it a chance to attack tumor cells.
Cancer: Melanoma
Interesting note: This drug was the first to utilize active immunotherapy, as opposed to the suppression tactic.
Which drug binds the CTLA-4 receptor on T-cells to prevent B7 (CD80/86) from binding?
Ipilimumab
Rituximab
A monoclonal antibody drug
Target: Binds to the surface of the transmembrane protein CD20, which is found on precursor and mature B-cells. Recall that CD20 regulates early steps in the activation process for cell cycle initiation and differentiation.
Effect: Binding of the antibody drug produces rapid and sustained depletion of B-cells, lasting for several months. ADCC, apoptosis, and CDC
Cancer: Chronic lymphocytic leukemia and non-Hodgkin’s lymphoma
VEGFR pathway normally activated with whom and when?
This pathway is activated in large, solid tumors that are beginning to outgrow their vascular supply. Because the cancer needs increased blood supply to spread, the VEGFR is a great target for monoclonal antibody drugs.
Hypoxia inducible factor-1 (HIF-1) in times of oxygen deprivation
In times of oxygen deprivation, VHL (Von Hippel Lindau) allows this molecule to translocate to the nucleus to promote up-regulation and expression of VEGF and PDGF, which then promotes angiogenesis.
The ultimate result is metastatic tumor spread, proliferation, and survival.
HIF-1 in times of plentiful oxygen
When oxygen levels are sufficient, any HIF-1 produced is sent by VHL (Von Hippel Lindau) to the 26s proteasome complex for degradation.
General Characteristics of MABs
Route of admin, immunoglobulin on which they’re based, general target
Administered by injection
Large protein structures
Based on IgG
Traditionally target classical proliferative cell surface targets
Ipilimumab, which you’ll recall targets CTLA-4, is the first drug to take the approach of immune system activation.
Adverse effects of monoclonal antibodies
Recall that we’re targeting mammalian targets, and that these targets, while OVERexpressed in tumor cells, are regularly expressed in non-tumor cells; thus, we see things like:
1) Cardiovascular problems, including CHF and HTN
2) Depletion of cell populations in blood where target is expressed in component of this tissue
3) Infusion related reactions, like anaphylaxis, angioedema, and pulmonary toxicity. To mitigate this issue, give antihistamines and/or corticosteroids.
Cetuximab
A monoclonal antibody drug
Target: EGFR-1, HER-1
Effect: Apoptosis, ADCC of cell
Panitumumab
A monoclonal antibody drug
Target: EGFR-1, HER-1
Effect: Apoptosis, ADCC
Which two drugs target EGFR-1 , HER-1? Their killing mechanisms?
Cetuximab and Panitumumab
ADCC and apoptosis
Bevacizumab
Target: VEGF
Effect: Prevents angiogenesis and neovascularization
Which drug targets VEGF to prevent angiogenesis by tumor cells?
Bevacizumab
Ofatumumab
Target: CD20
Effect: Apoptosis, ADCC, CDC
Cancer: chronic lymphocytic leukemia
Which drugs target CD20?
Rituximab and Ofatumumab
The ATP-binding site of tyrosine kinases is highly ___________.
Conserved
T3151 of the ATP binding site
When a tyrosine kinase inhibitor drug is given to a patient, response is initially great…but then we see resistant clones emerge. This is largely due to a mutation in T3151, which prevents binding of first-generation drugs.
Solution drug for the problems that a mutation in T3151 causes?
Ponatinib, a later generation of tyrosine kinase inhibitor.
Whisper in my ear the sweet nothings about tyrosine kinase inhibitors. The good, the bad, the ugly. I want to know it all.
Target binding site?
Resistance?
What do they look like?
How are they taken and metabolized?
They bind in the ol’ highly conserved ATP binding domain of the tyrosine kinase receptor
Resistance follows an initial successful response to the drugs; accomplished by kinase over-expression and binding site mutations.
Mutations impact drug binding but do not inactivate kinase function
Small, orally active drugs
Bioavailability can vary depending on food and CYP3A4
The potential for drug-drug interaction is very real.
What do mutations in the ATP binding site of the tyrosine kinase receptor do to the therapeutic window and the dose-response curve?
They change or diminish the therapeutic window, possibly making it impossible to achieve adequate clinical effect without initiating significant adverse effects caused by “off target” actions.
They shift the dose response curve to the right
Are there certain body parts that are especially affected by TKR inhibitors?
Yeah. Make sure to check your patient’s thyroid function, bone density, PTH, and vitamin D
If he’s a diabetic, monitor blood glucose
If it’s a she, warn her about fetal development
If it’s a kid, make sure it’s growing right, complete with puberty
List some adverse effects of tyrosine kinase inhibitors
Usual uncomfortable effects like N/V, fatigue, and rash
QT prolongation
Blood dyscrasia (this means dat blood fucked)
hand-foot syndrome
Basically anybody who takes these meds is going to look super hawt.
Crizotinib
ALK, HGFR
non-small-cell lung carcinoma
Erlotinib
EGFR
pancreatic cancer
Imatinib
BCR-ABL, c-KIT, and PDGFR
CML
Sunitinib
VEGFR, PDGFR, c-KIT
pancreatic tumor, GIST
Vemurafenib
BRAF
metastatic melanoma
Are down-stream mutations important to consider when preparing to administer a TKR inhibitor?
If so, provide an example
Bet your sweet bippy!
If a patient is to receive an EGFR monoclonal antibody, you must check for KRAS and BRAF first, as these are downstream of EGFR. A patient with KRAS and/or BRAF mutations are less likely to respond to anti-EGFR therapies because those mutations keep KRAS and BRAF constitutively active, regardless of what’s happening at the receptor.
Mechanisms of resistance to oral TKR inhibitors
Amplification of kinase
Mutating the ATP binding site
Evolution of kinase-independent mechanism
Decreased intracellular drug levels
P-gp mediated efflux
Explain the redundant nature of TKRs
There are dominant receptors, as well as secondary receptors that can kick in if the dominant goes out. These all converge on a “fragile point” in the pathway, such as AKT. Medical management should include inhibition of dominant and back-up receptors, as well as fragile points. Regardless, the TKs can still manage to find third, or even fourth string TKs to get shit done.
Is mTOR important in cancer? If so, why?
Yes. De-regulation of mTOR is associated with many types of human cancer.
Are there drugs that target mTOR?
Yes. Temsirolimus, sirolimus, and everolimus
In addition, small molecular weight drugs can form a three-way complex involving the inhibiting drug, FKBP-12, and mTOR, leading to mTOR’s inhibition.
The relationship among NfKB, IkB-alpha, and bortezomib
Nf-kB is a transcription factor that is inhibited by IkB-alpha. Inhibition is ended when Ikb-alpha is broken down by the 26S proteasome, allowing Nf-kB to get to the nucleus and instigate proliferative signaling. Bortezomib inhibits 26S so that IkB-alpha stays bound to Nf-kB, inhibiting it from causing proliferation.
So we have this drug called bortezomib that can inhibit the 26S proteasome. What are some of the other molecules affected by this inhibition?
P53 (leads to BAX over-expression)
BAX (overcomes Bcl-2 over-expression)
IkB-alpha of course (growth inhibition and reduced angiogenesis)
Who bortezomib?
Why an inhibitor of IkB-alpha of course!
Administered by INJECTION
Cardiotoxicity with our old friend prolonged QT.
Severe sensory and motor peripheral neuropathy (most unusual)
Put on your chastity belt! Or your accidental baby is gunna have a bumpy ride. (Teratogen)
Dag yo. It’s like…every time I think we’re getting somewhere, I end up nowhere! I guess that magic bullet just doesn’t exist…or does it?
NO.
For monoclonal antibodies: after these guys bind a target, what is the means of death for the cell?
For most of the drugs, it is apoptosis and ADCC. For drugs that target CD20 on B-cells (rituximab and ofatumumab), add CDC.
Finally, VGFR is the exception - only anti-angiogenesis occurs with this kid.
Dasatinib
Targets BCR-ABL
Cancer: CML, ALL
Gefitinib
Targets EGFR-1/HER-1
Cancer: non-small cell lung carcinoma and pancreatic cancer
Lapatinib
Targets EGFR and HER-2
Cancer: Breast cancer
Nilotinib
Targets BCR-ABL
Cancer: CML
Pazopanib
Targets: VEGF
Cancer: soft tissue carcinoma and RCC
Sorafenib
Target: VEGF and BRAF
Cancer: RCC and hepatocellular carcinoma
Which tyrosine kinase receptor inhibitors cause thyroid dysfunction?
In simple terms: the VEGF inhibitors, the BCR-ABL inhibitors, and erlotinib of EGFR
List: sorafenib sunitinib pazopanib imatinib dasatinib nilotinib
