Target Drugs for Cancer 2

Question 1

T or F. Unlike the monoclonal antibodies with their large protein structure, tyrosine kinases inhibitors are small orally active drugs with all of the caveats that this route of administration carries.

Answer 1

T. E.g. There is considerable variability amongst the drugs in terms of bioavailability. Most of these kinase inhibitors are substrates for CYP3A4 and a few are inhibitors of other isoforms. In view of the involvement of CYP, the potential for drug-drug interaction cannot be overstated.

These are PO

Question 2

How do protein kinases work in the body? Where are they found?

Answer 2

found everywhere

function dependent upon the binding of ATP to a highly conserved ATP-binding site located between the alpha and beta protein sheets.

Question 3

What is the “Achilles Heel” of the TKIs?

Answer 3

The fact that they rely upon successful binding within the conserved ATP-binding site. Therefore, tumor cells that express mutations in the binding site are inherently more resistant to the effect of the drugs.

Whereas the tumor may initially respond, successful eradication of the sensitive cell population will permit outgrowth of the less sensitive (“resistant”) clonal populations.

Question 4

What is another common mechanism of resistance to TKIs?

Answer 4

Through proliferative signals arising from events downstream of the EGFR/tyrosine kinase complex. Here we see that KRAS or indeed BRAF mutations can lead to independent proliferative signals continuing, despite TKI drug treatment.

For this reason, the ability to employ some drugs is contingent not only upon the presence of the constitutively active tyrosine kinase, as determined by appropriate genetic tests, but also to the absence of mutated KRAS.

Question 5

Why are side effects so common in TKIs?

Answer 5

There are over 500 protein kinases, so inhibiting them without specificity will undoubtedly cause concurrent dysfunction (especially endocrine/thyroid).

In addition the potential for fetal damage should always be a consideration.

Question 6

What are the side effects of TKIs?

Answer 6

• “uncomfortable” effects, such as N/V, fatigue, etc., many of the TKIs produce blood dyscrasias. Routine blood tests should be conducted in patients receiving TKIs.
• Adverse effects upon cardiac conduction in the form of QT prolongation.
• stocking-glove syndrome.

Question 7

Which TKIs produce the most intense cardiomyopic effects?

Answer 7

Trametimib and Dabrafenib (BRAF)

Question 8

Which TKIs produce stocking-glove syndrome?

Answer 8

Sunitinib, Sorafenib, Pazopanib, and Vemurafenib

Question 9

EGRF TKIs are associated with what other side effect?

Answer 9

a rash and increase UV sensitivity. These can be either the monoclonal antibodies or the TKIs.

Mabs- cetuximab and panitumumab
TKIs- erlotinib, gefitinib, and lapatinib

Question 10

Vismodegib is a hedgehog inhibitor used to treat what?

Answer 10

basal cell carcinoma

Question 11

Temsiroliums and everolimus are both motor inhibitors used to treat what?

Answer 11

advanced renal cell cancer. Still not widely used but approved

Question 12

What is Bortezomib? Used to treat?

Answer 12

a 26-S proteosome inhibitor used to treat MM

Question 13

Describe hedgehog signaling.

Answer 13

Hedgehog signaling is important in embryogenesis and organ maturation by regulating body patterning and organ development but is quiescent by adulthood, except for a small role in tissue maintenance

Question 14

Activation of the hedgehog pathway n adulthood leads to what?

Answer 14

Activation of this pathway leads to upregulation of pro-proliferative signals/pathways and compounds, such as Bcl-2 and VEGF

pathway is ligand independent

Question 15

How does Vismodegib target the HH pathway specifically?

Answer 15

Signaling for HH travels by way of a transmembrane protein known as smoothened (SMO), which Vismodegib targets

Question: naturally ligand binding to protein patched homolog 1 (PTCH1) cell surface complex for sonic hedgehog would down regulate SMO (which is ligand independent)- could it be treated that way?

Question 16

What are the BBW of Vismodegib?

Answer 16

Intrauterine fetal death, male-mediated teratogenicity, risk of pregnancy arising (need to use contraception)

Women should be on a highly effective form of birth control prior to starting vismodegib and for 7 months after the last dose

Question 17

How can vismodegib be spread?

Answer 17

through sex particularly- through semen to male partners of cancer patients. They can feel the effects.

Question 18

Other vismodegib side effects?

Answer 18

alopecia, GI pain, weight loss, fatigue

Question 19

How do mtor inhibitors work speficially?

Answer 19

they form 3-way complexes with mtor and FK BP-12

Question 20

How does Bortezomib work?

Answer 20

Amongst the targets is the inhibitory (regulatory) partner of the transcriptional factor NfKB. The inhibitor is called IkB-alpha. Under normal circumstances IkB-alpha is broken down by the 26S proteasome, leaving NfKB free to translocate to the nucleus to instigate proliferative signaling. By inhibiting proteasomal activity with Bortezomib, NfKB is prevented from conducting this proliferative action.

Question 21

What are some of the main consequences of NFkB inhibition?

Answer 21

elevated p53, Bax, cyclins, CDKs, and damaged cellular proteins all lead to apoptosis of tumor cells

Question 22

How is Bortezomib given?

Answer 22

IV or SC

Question 23

Side effects of Bortezomib?

Answer 23

cardiotoxicity and liver dysfunction, peripheral neuropathic effects, pregnancy risk category D

Question 24

RTK mediated signaling pathways share multiple elements and inhibiting the dominant kinase often results in compensatory downstream recruitment of secondary TKs. Examples of dominant RTKs include EGFR, or ErbB2, whereas secondary TKs such as c-Met, PDGFR, and IGF-1R have been reported. These 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. Nevertheless, resistance may arise through activation of alternative TKs or other network elements. Far from supporting the concept of a “magic bullet” treatment for cancer, the now recognized complexity of intracellular signaling would indicate that better outcome data might be enjoyed if one used a shotgun instead. That is to say, multiple drugs targeting multiple pathways and critical fragile points, concurrently.

Answer 24

RTK mediated signaling pathways share multiple elements and inhibiting the dominant kinase often results in compensatory downstream recruitment of secondary TKs. Examples of dominant RTKs include EGFR, or ErbB2, whereas secondary TKs such as c-Met, PDGFR, and IGF-1R have been reported. These 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. Nevertheless, resistance may arise through activation of alternative TKs or other network elements. Far from supporting the concept of a “magic bullet” treatment for cancer, the now recognized complexity of intracellular signaling would indicate that better outcome data might be enjoyed if one used a shotgun instead. That is to say, multiple drugs targeting multiple pathways and critical fragile points, concurrently.