3.7 Cancer specific targeting.

Question 1

What is the hallmark of Chronic Myeloid Leukaemia?

Answer 1

BCR ABL fusion gene

Question 2

Myeloid (WBC)

What is chronic myeloid leukaemia?

Answer 2

A haematological malignancy characterised by abnormal growth and proliferation of myeloid white blood cells, caused by the BCR-ABL oncogene.

Question 3

What is the BCR-ABL fusion gene?

Answer 3

The BCR-ABL fusion gene is an abnormal gene which is formed when the:

• Breakpoint cluster (BCR) gene on chromosome 22 and the…
• Abelson (ABL) tyrosine kinase gene on chromosome 9

Join together to form a chimeric oncogene called BCR-ABL

In chronic myeloid leukaemia, BCR-ABL oncogene causes uncontrolled cell growth and proliferation of myeloid white blood cells.

Question 4

6

Chronic Myeloid Leukaemia symptoms?

Answer 4

**Fatigue: **
*Unexplained loss of appetite and weight Loss:

**Abdominal Discomfort: **
*Enlargement of the spleen (splenomegaly) and liver (hepatomegaly) is common in CML due to the accumulation of abnormal myeloid cells.

**Fevers and Night Sweats: **
* fevers and night sweats, often associated with an increased white blood cell count.

**Bone Pain: **
* May occur due to the expansion of bone marrow with abnormal cells, often in long bones of arms and legs

**Easy Bruising and Bleeding: **
* Abnormalities in blood cell production in CML can lead to a decrease in platelets, which are responsible for blood clotting. This can result in easy bruising, bleeding gums, and frequent nosebleeds.

**Infections: **
* CML can weaken the immune system, making individuals more susceptible to infections. Recurrent or severe infections may be a sign of advanced disease.

Question 5

Which treatment is often prescribed for chronic myeloid leukaemia?

Answer 5

Imatinib/Gleevec

Question 6

What is the mode of action of Imatinib/Gleevec?

Answer 6

Gleevec is a TKI - It binds to the ATP-binding site of the BCR-ABL1 protein.

By doing so, Gleevec inhibits the activity of the BCR-ABL1 tyrosine kinase, this:

• Prevents the BCR-ABL1 tyrosine kinase from phosphorylating downstream signaling molecules and initiating pathways that promote cell growth and survival.
• Disrupts the signaling pathways that promote the survival of leukemic cells resulting in apoptosis
• Inhibits uncontrolled growth and proliferation

Gleevec may also target leukaemia stem cells which help achieve a deeper and longer term response.

Question 7

Name two other TKIs which might be used in CML?

Answer 7

• Desatanib
• Nilotinib

Question 8

What is Anaplastic lymphoma kinase (ALK)?

Answer 8

A tyrosine kinase that can be overexpressed in several tumour types.

This overexpression is caused by the formation of an ALK oncogene

This activates several intracellular signalling pathways including the PI3K/AKT/mTOR pathway and the MAPK pathway

Which promotes uncontrolled cellular signaling, proliferation and survival.

Question 9

What is the mode of action of anaplastic kinase inhibitors?

Answer 9

ALK inhibitors bind to the ALK Oncogenes and block their activation, resulting in cancer cell death and restoration of normal cell growth signaling

Question 10

What is Brutons tyrosine kinase?

Answer 10

A non-receptor tyrosine kinase that plays a role in B-cell development and signalling

Question 11

What type of haematological malignancy is Brutons Tyrosine kinase associated with?

Answer 11

B-cell malignancies (such as chronic lymphocytic leukaemia and mantle cell lymphoma)

Where inhibition of BTK reduces cell migration, proliferation, survival and induces apoptosis

Question 12

What type of drugs are used to treat hematological malignancies associated with Brutons Tyrosine Kinase

Answer 12

Tyrosine kinase inhibitors e.g.

• Ibrutinib
• acalabrutinib.

Question 13

What is the mode of action if ibrutinib?

Answer 13

ibrutinib’s mode of action in cancer involves specifically targeting BTK, a key enzyme in B-cell signaling pathways, to inhibit the survival, proliferation, and migration of malignant B cells.

This targeted approach has demonstrated efficacy in the treatment of various B-cell malignancies, leading to improved patient outcomes and survival.

Question 14

What is myelofibrosis?

Answer 14

A myeloproliferative neoplasm characterized by the abnormal proliferation of blood cells within the bone marrow, leading to the replacement of normal marrow tissue with fibrous scar tissue (fibrosis).

This fibrosis disrupts the normal production of blood cells, causing a range of symptoms and complications.

Question 15

What is a specific cancer target for myelofibrosis

Answer 15

Janus kinase

Question 16

Which drugs have been developed to treat myelofibrosis?

Answer 16

Jak 2 inhibitors e.g. ruxolitinib

Question 17

Its all about DNA repair

What is PARP

Answer 17

PARP stands for Poly (ADP-ribose) polymerase

A family of enzymes involved in DNA repair, genomic stability, and cell death.

PARP plays a crucial role in repairing single-strand DNA breaks (SSBs) through a process called base excision repair (BER).

When DNA damage occurs, PARP is recruited to the site of damage, where it catalyzes the addition of poly (ADP-ribose) chains to itself and other target proteins, facilitating the recruitment of DNA repair factors.

Question 18

Why is PARP a specific cancer target?

Answer 18

In cancer, PARP has emerged as an important target for therapy, particularly in cancers with defects in DNA repair pathways, such as those with mutations in BRCA1 or BRCA2 genes.

These mutations impair the cells’ ability to repair double-strand DNA breaks (DSBs) through homologous recombination (HR), leading to genomic instability and susceptibility to further DNA damage.

By inhibiting PARP activity, these drugs prevent the repair of SSBs, leading to the accumulation of DNA damage and the formation of DSBs.

In cancer cells with intact HR pathways, these DSBs can be repaired; however, in cancer cells with defects in HR, such as those with BRCA mutations, the inability to repair DSBs leads to cell death.

Question 19

Name a PARP inhibitor

Answer 19

Olaparib