Chapter 14: Technology and drugs and diagnostics development (Lecture, main) Flashcards
What are the different stages of drug development?
Molecular target -> screen for inhibitors/activators or design a specific inhibitor/activator -> optimization and formation -> pre-clinical studies -> clinical trials -> regulatory approval
What is the first targeted therapy that was made?
Imatinib
For what disease is imatinib used?
Chronic Myeloid Leukemia (CML)
What causes CML?
A translocation (of chromosome 9 and 22) that form the ‘Philadelphia chromosome’. The protein which is then formed (called Bcr-Abl) causes an increase of leukemic cells (CML)
How can CML be targeted?
By a tyrosine kinase inhibitor
What does the screening for compounds look like?
Potential compounds are tested on an assay, and through analysis a compound is identified
After a compound is identified (imatinib in this example), the compound is optimized. How is this done?
By adding molecules to the compound to:
- improve cell activity
- improve inhibition of BCR-ABL
- decrease specificity for protein kinase C
- to increase solubility for oral bioavailability (see the figure)
How does imatinib (and Gleevec, glivec) work?
By inhibiting tyrosine phosphorylation. It binds to the ATP-activation site and thereby prevents downstream activation (in the left figure you see how the substrate is not phosphorylated and therefore cannot bind to the effector)
After animal models, the targeted drugs enter several (oncology) trials. What are they and also explain what occurs
- Phase 0: testing drugs short period (<7 days, metabolism, targeting, farmocokinetics)
-
Phase I: dose escalation, new combinations.
- Primary endpoint: safety, tolerability (=find the maximum tolerated dose) (n= 3-60)
- Phase II: one dose in a specific cancer type. Primary endpoint: efficacy (n=20-60)
-
Phase III: randomized study in specific cancer type
- Endpoint: Superiority or non-inferiority to standard treatment. Registration study (n=600-5000)
-
Phase IV: one dose in specific cancer type.
- Endpoint: safety in larger group of patients (n=1000-10000)
In this table the results are shown of imatinib (phase I). What would you predict to be the maximum tolerated dose?
350-500 mg. You can see this by the amount of side effects, in the 600-1000mg you see that most patients have many side effects
The primary goal of a phase I study is
a) Safety of a drug
b) Efficacy of a drug
c) To determine the right dose of a drug
d) To investigate the farmacokinetics of a drug
c) To determine the right dose of a drug
In phase II of the trials of imatinib the efficacy was investigated (shown in figure). Keeping in mind that the maximum tolerated dose was 350-500, what dose would you agree upon to continue to the next phase?
400mg
In the last phase (IV) imatinib was investigated, comparing to the standard combination therapy. What were the results?
Very good! As you can see the response was very high and it was also then approved as a treatment for CML (and is still used today)
Imatinib was also tested in Gastro-Intestinal Stromacell Tumor (GIST), explain how this could work
GIST-cells (over)produce a ‘c-KIT’ receptor that induces cell division, metastases, angiogenesis and immunosuppression. This is often due to a mutation in the receptor. Imatinib can block the tyrosine kinase and thereby prevent the signaling effects of the receptor.
Did GIST have a positive response to imatinib?
Yes, as can be seen here, and this is also used in clinical practice today
Why is molecular diagnostics (with an example of GIST) so important?
Because, as you can see in the figure, the placing of a mutation is very important in the response rate of c-KIT: a mutation of exon 11 has a much higher response rate than the other mutations
What is a nevus?
A displastic nevus is a mole (=moedervlek) and is considered a precursor of sporadic melanoma
Which mutation is found in ~50% of the patients with melanoma?
A BRAF-V600E mutation (BRAF is a proto-oncogene involved in cell growth and cell proliferation)
Which drug is developed that inhibits the BRAF-V600E kinase (and downstream regulation)?
Vemurafenib.
For the standard design of phase I studies, a so-called ‘3+3’ design is used. How does this design work?
3 patients are treated with a certain dose. The DLT stands for dose-limiting toxicity. The amount of patients that get DLT determines the next step, as indicated by the three arrows: (1) increase the dose, (2) enter 3 more at the same dose and (3) decrease the dose. The maximum tolerated dose is considered highest dose at which > 1/6 patients experience DLT
Did Vemurafenib also show to be an effective drug in the Phase III trials?
Yes, as you can see it had a much better effect than the (chemo) treatment that was used before this invention
What did the phase IV study of Vemurafenib show?
This time it was studied in a very diverse population, older patients, patients with brain metastasis etc., and both the efficacy and the safety did not differ from the study with the Phase III melanoma patients
Unfortunately, tumor resistance occurred because the tumor found other pathways to increase cell proliferation. This is illustrated in the figure. Therefore, they developed MEK-inhibitors. What are some examples of these MEK-inhibitors?
Trametinib, Cobimetinib and binimetinib
What did the combined treatment with BRAF- and MEK-inhibitors show?
Combined treatment with BRAF- + MEK-inhibitors is superior to BRAF-inhibitors alone
Thus far we discussed targeted therapy treatments, but we will now focus on specific immunotherapy antibodies. What are the two immunotherapy antibodies that we are going to discuss/have to know?
Trastuzumab (Herceptin) and panitumumab (Vectibix)
The name of the drug is Herceptin, but the active ingredient is Trastuzumab! Similarly, the name of the drug is Vectibix, but the active ingredient is panitumumab (don’t get confused by the two names, since they mean the same)
To which type of cancer is Trastuzumab administered to?
Breast cancer
Where does trastuzumab bind to, and how does it work (name 3 mechanisms)?
It is an antibody that is anti-HER2/neu, which is an antibody that is expressed by tumor cells.
- The antibody binds to, and thereby inhibits HER-2/neu mediated signaling.
- The antibody activates antibody dependent cellular toxicity (ADCC)
- It inhibits tumor cell proliferation
HER-2 stands for: Human Epidermal growth factor Receptor 2
True/false: All patients respond good to the trastuzumab treatment
False, they noticed that patients with a higher HER-2-neu expression respond better than those with little expression
In the phase II trial of trastuzumab, only metastatic breast cancer patients with HER2-overexpressing were selected. What % of the patients responded well to the treatment?
21%
In the Phase III study of trastuzumab, combination therapy of chemotherapy and trastuzumab were studied. What were the results?
There was a much higher response rate (61% vs 36%), and most importantly the survival rate increased from 18.3 to 27.7 months
Tumor cells over-express the EGFR receptor, what does this activation lead to?
Cell adhesion, invasiveness, proliferation, differentiation, and angiogenesis effects (e.g. blood vessel recruitment, invasion, metastases)
What does Panitumumab do?
It is an (monoclonal) antibody that binds to, and inhibits EGFR (thus preventing angiogenic factors, cell growth and metazoic potential)
For what type of cancer is Panitumumab administered?
Metastatic Colorectal Cancer (mCRC)
In a study, Panitumumab was compared to chemotherapy (BSC), but the median is roughly the same (8 weeks vs 7.3 weeks). There were however some patients that responded good to the treatment. What caused this difference?
They found that the patients that were insensitive to the treatment had a RAS-mutation (which, when mutated causes cell proliferation, metastases, angiogenesis and immuno-suppression). RAS is a downstream process of the EGFR receptor, so you can imagine that although the receptor is inhibited, this has no effects on the downstream pathway of RAS.
What does this table show?
There is a correlation between the KRAS and BRAF mutations, you will see no response (0/11) when there is both a mutant in KRAS and BRAF
What are the final remarks of this lecture? (don’t learn please, we obv discussed this)
- The process of drug development through the 4 phases are important for the determination of their optimal dose/schedule, safety profile, efficacy and for patient selection
- Every year more and more molecularly targeted drugs are found to have activity in subsets of solid tumors
- Patient selection (pharmacogenomics) improves the impact of those treatments
