Pharmacology Iii - Biological Targeted Therapy - Hematological Cancer Targets

Front 1

The objectives for this lecture include 1) Describing the rationale for targeting BCR-ABL for CML 2) Describe the basic principle for BCR-ABL pathway 3) Describe the MOA for BCR-ABL targeted therapy

Back 1

4) Describe second generation for TKI for CML 5) Describe recent clinical data 6) Describe other biological targeted therapy for hematologic cancer (CD20, CD52)

Front 2

What is CML?

What is the cause?

Back 2

Chronic Myelogenous Leukemia

90% of patients with CML are positive for the Philadelphia Chromosome, which is caused by a reciprocal translocation and fusion of abelson (ABL) tyrosine kinase gene and break point cluster gene (BCR)

Front 3

What is the best phase to treat CML?

Back 3

Chronic phase, which lasts about 3-5 years

Front 4

Read notes taken

Back 4

on BCR-ABL pathway. Then continue cards.

Front 5

What was the first BCR-ABL tyrosine kinase inhibitor for CML?

How does it work?

Back 5

Imatinib mesylate

It works by inhibiting multiple tyrosine kinases such as platelet derived growth factor receptor and c-kit but NOT Scr.

It binds to the ATP-binding pocket of the BCR-ABL protein inhibiting the phosphorylation process. ATP-Mimetic

Front 6

Who should be treated with Imatinib? (4)

Back 6

1) Newly diagnosed Ph (+) patients with CML
2) Previously treated Ph (+) patients with CML
3) Refractory Ph (+) ALL patients
4) c-KIT gastrointestinal stromal tumors

Front 7

In terms of evaluating CML, what these mains areas are there to look at?
Describe each.

Back 7

Hematologic - Looks at WBC, Platelets and immature blood cell counts and splenomegaly

Cytogenetic - Looks at Ph (+) metaphase cells. Complete remission is evident with no Ph (+) metaphase cells.

Molecular - Looks at BRC-ABL messenger RNA

Molecular level testing is the most accurate and stringent data!

Front 8

Describe the clinical trial comparing imatinib vs. older therapy with Interferon-alpha + Cytarabine.

Back 8

-95% of patients saw complete hematologic remission with Imatinib vs 55% in the control arm.
-Complete cytogenetic remission was seen in 73% of patients with Imatinib vs 8% in the control arm.

Front 9

Continued answer.

Back 9

- Patients started on Imatinib and switched to the control arm so 0% remission where patients started on control arm and switched to Imatinib saw remission stats in between control arm and Imatinib alone showing that the drug can be given to previous treated patients.

Front 10

What are the most common side effects of Imatinib?

Back 10

Hematologic effects - anemia, thrombocytopenia, neutropenia etc.
Severity of toxicity seems to reduce over time
This is considered very mild compared to chemo.

Front 11

Why is Imatinib used for GI stromal tumors?

Back 11

These tumors are caused by a c-KIT over expression, and Imatinib inhibits c-KIT.

Front 12

What enzymes primarily metabolized Imatinib?

What is its metabolite?

Back 12

CYP3A4 (as well as many other CYPs) - Do not take with drugs/food that inhibit this enzyme

N-demethylated piperidine derivative - of similar potency to Imatinib

Front 13

Besides the major hematologic side effects, what other side effects does Imatinib show?

Back 13

Edema
Congestive Heart Failure
GI Bleeding
Skin Reactions
Hypothyroidism
Long term use --> Hepato, renal, cardio toxicity
Teratogenicity in rats - Do not take if breast feeding/pregnancy. Men should be ok

Front 14

What is the major obstacle in Imatinib treatment?

Back 14

Imatinib resistance - failure to achieve complete hematologic response at 3 months or cytogenetic response at 6 months. As you progress from chronic to blast crisis, the percentage of resistance increases substantially.

Front 15

There are 3 BCR-ABL dependent mechanisms for Imatinib resistance. Name them

Back 15

1) Point mutations that interfere with binding
2) Overexpression/Amplification of BCR-ABL gene

Front 16

There are 3 independent mechanisms of resistance. Name them.

Back 16

Alterations of Imatinib intracellular concentration (influx/efflux)
Activation of BCR-ABL independent pathways such as members of the Scr kinase family.
2nd generation agents have been developed such as dasatinib and nilotinib

Front 17

There are 33 point mutations that occur to give resistance to Imatinib. What are the two main mutations that occur in Imatinib resistance?

Back 17

T315I mutation
Loop mutations

Front 18

Describe the T315I mutation

Back 18

T315I mutation --> threonine --> isoleucine --> decreased hydrogen bonding between imatinib and BCR-ABL/steric hindrance of imatinib binding

Front 19

Describe loop mutations

Back 19

BCR-ABL contains two loops, the ATP-binding loop and the activation loop - Mutations of the p loop are the most common and this reduces imatinib effectiveness 70-100 fold. The frequency of p-loop mutations increases from AP to BC.

Front 20

How does Nilotinib work?

Back 20

Similar to Imatinib, by binding to the ATP-binding pocket. It is a multi-kinase inhibitor that inhibits the activity of BCR-ABL, ARG, c-KIT and PDGFR but NOT Src-family kinases.

Front 21

Nilotinib is effective against 32/33 imatinib-resistant point mutations. Which point mutation is it not effective against?

Back 21

T315I

Front 22

There are 33 point mutations that occur to give resistance to Imatinib. What are the two main mutations that occur in Imatinib resistance?

Back 22

T315I mutation
Loop mutations

Front 23

Describe the T315I mutation

Back 23

T315I mutation --> threonine --> isoleucine --> decreased hydrogen bonding between imatinib and BCR-ABL/steric hindrance of imatinib binding

Front 24

Describe loop mutations

Back 24

BCR-ABL contains two loops, the ATP-binding loop and the activation loop - Mutations of the p loop are the most common and this reduces imatinib effectiveness 70-100 fold. The frequency of p-loop mutations increases from AP to BC.

Front 25

How does Nilotinib work?

Back 25

Similar to Imatinib, by binding to the ATP-binding pocket. It is a multi-kinase inhibitor that inhibits the activity of BCR-ABL, ARG, c-KIT and PDGFR but NOT Src-family kinases.

Front 26

Nilotinib is effective against 32/33 imatinib-resistant point mutations. Which point mutation is it not effective against?

Back 26

T315I

Front 27

Myelosuppression is similar in both Imatinib and nilotinib. What adverse effects were found to be worse in Nilotinib?

Back 27

Rash
LFT's
Hyperglycemia
Hypercholesterolemia
Increased Serum Lipase
Headache

Front 28

What was found in the phase II trial on Nilotinib?

Back 28

More complete cytogenetic remission was found with Nilotinib.
The affect of Nilotinib was found to be 2 times effective as Imatinib

Front 29

Desatinib is similar to Nilotinib except for what important aspect?

Back 29

Desatinib also inhibits Scr but still has no activity against T315I

2nd generation TKI's (Nilo,Desa) do not take care of T315I

Front 30

Describe the 3 types of independent BCR-ABL resistance.

Back 30

ATP-binding Cassette transporters - drug efflux pumps that are overexpressed in resistance to TKI's in CML

Organic Cation Transporter 1 - Imatinib influx is dependent on OCT-1 expression. If OCT-1 is not expressed, then intracellular levels of Imatinib are low. Uptake of Dasatinib and Nilotinib do not depend on OCT-1

Non-adherence to the therapeutic regimen - ADAGIO study - Only 14% of patients were adherent to the prescribed dose of imatinib.