3.7. Cancer therapy I, II and III

Question 1

name the three types of cancer therapy available

Answer 1

1. non-specific
2. Targeted to specific pathways but generally applicable
3. targeted therapy specific to certain cancers

Question 2

list the non-specific cancer therapies available

Answer 2

1. Surgery
2. Radiotherapy
3. Conventional (non-specific) cytotoxic chemotherapy
4. Epigenetic modification
5. Some immunotherapy

Question 3

list the cancer therapies targeted to specific pathways but generally applicable

Answer 3

1. Anti-angiogenictherapy
2. Proteasome inhibition
3. PARP inhibitors
4. CDK inhibitors
5. PI3K inhibitors
6. BCL2 inhibitors

Question 4

list the targeted therapy specific to certain cancers

Answer 4

1. Hormone therapy
2. Specific inhibitors of signalling pathways
3. Immunotherapy
4. Viral therapy

Question 5

what are the benefits of surgery as cancer therapy

Answer 5

• Removes all cells whether sensitive to chemotherapy or not

* Removes cancer stem cells

Question 6

what are some of the results of radiotherapy

Answer 6

• Cell death from extreme damage
• Induction of apoptosis
• Induction of senescence
• Damage which can be repaired
• RESIDUAL or UNREPAIRED DNA damage

Question 7

what is radiotherapy?

Answer 7

• Induction of apoptosis and death of cancer cellsN.B. The role of P53 (and Rb) as well as apoptotic pathways
  •Effects of radiation on tumours may also depend on disruption of the blood supply by damage to endothelial cells
  •It also results in increased presentation of tumour antigens to the immune system

Question 8

describe Conventional cancer chemotherapy and some of its side effects

Answer 8

• Conventional agents are directed at actively dividing cells. Normal/differentiated tissue is not proliferating to same extent
• Side effects:
  1. Bone marrow suppression
  2. Hair loss
  3. GIT mucosal damage
• Problems: not all cancer cells are actively dividing –concept of “Cancer Stem Cell”

Question 9

list three ways in which dividing cells can be targeted

Answer 9

1. induce DNA damage
2. prevent replication of DNA
3. Disrupt mitosis

Question 10

name two manners in which DNA damage can be induced to target dividing cells

Answer 10

1. alkylating agents: Attach an alkyl group to guanine base of DNA causing cross-linking
2. Platinum–containing compounds: –> intra-strand links

Question 11

name the manner in which DNA replication can be prevented to target dividing cells

Answer 11

through topo-isomerase inhibitors interfering with DNA unwinding

Question 12

name the manners in which DNA replication can be prevented to target dividing cells

Answer 12

antimetabolites:

1. folate antagonists: prevent thymidine synthesis
2. Purine/pyrimidine analogues: become incorporated in DNA and prevent further synthesis

Question 13

name the manners in which mitosis can be disrupted to target dividing cells

Answer 13

1. Prevent microtubule assembly (e.g. vincristine)

2. Prevent microtubule breakdown at the end of mitosis (e.g. taxanes)

Question 14

what is the purpose of a bone marrow stem cell transplantation

Answer 14

• To allow very high doses of chemotherapy for a solid tumour which would otherwise destroy the bone marrow and kill the patient
• To replace cancerous bone marrow

Question 15

name two sources of bone marrow

Answer 15

1. Autologous–from the same person who is going to receive the cells. This would be used to rescue the patient from chemotherapy
2. Allogeneic–from a living donor who could be related or not. This would be used to replace a diseased marrow.

Question 16

name a major problem of allogeneic transplant

Answer 16

Graft versus host disease

- The donor marrow reconstitutes the host immune system.

Question 17

name and describe two methods of epigenetic cancer therapy

Answer 17

1. DNA methylation
   - Cytosine analogues lead to DNA hypomethylation by not accepting methyl groups and by depleting DNMTs
2. Histone modification Histone Deacetylase Inhibitors (HDACi).

Question 18

what is the problem with epigenetic cancer therapy

Answer 18

Lack of specificity –cannot be sufficiently targeted and so have very broad effects

Question 19

name Mechanisms to enhance endogenous immune defences in non-specific immunotherapy

Answer 19

1. William Coley’s Toxins
2. Use of infectious agents such as BCG
3. Interferon therapy

Question 20

name the immune checkpoint inhibitors in non-specific immunotherapy

Answer 20

1. Anti-CTLA-4

2. PD1 pathway inhibitors

Question 21

explain the process of Anti CTLA-4 therapy in non-specific immunotherapy

Answer 21

1. CTLA-4 is transiently expressed following T cell activation.
2. The signal delivered via CTLA-4 down-regulates T cell function and inhibits excessive expansion of activated T cells.
3. It is constitutively expressed in Tregcells and enhances their function

Question 22

explain the process of Anti PD-1 therapy in non-specific immunotherapy

Answer 22

PD-1 is expressed on T cells in the tissues.Binding to PD-L1 initiates apoptosis in cytotoxic T cells but inhibits apoptosis of Tregs

Question 23

describe the function of anti-angiogenic therapy and its cons

Answer 23

• Cannot be used on its own
• May also be useful to “normalise” tumour vasculature and make it easier to deliver other forms of chemotherapy
• Tumours usually become resistant –remember the other growth factors which can also stimulate angiogenesis

Question 24

describe inhibition of the proteosome

Answer 24

Bortezomib is used as an anti-cancer drug.
It blocks the proteasome and appears to cause increased apoptosis and decreased proliferation of some types of cancer cells

Question 25

what is the function of CDK inhibitors and give two examples

Answer 25

1. Keep cells in G1.
2. May be used in future to synchronise cells for chemo (this results in a higher hit rate)
   e. g. Palbociclib, Ribociclib

Question 26

what is the main use of Parp inhibitors

Answer 26

Main use is in BRCA deficient individuals or tumours.

Question 27

when are BCL2 inhibitors used and give an example of the inhibitor

Answer 27

These are becoming valuable in cancers which are very resistant to apoptosis e.g. Chronic lymphocytic leukaemia and follicular lymphoma.The latter has a translocation t(14;18) where BCL2 is the gene on chromosome 18.
*e.g. venetoclax

Question 28

what are the functions of hormonal therapy?

Answer 28

1. block the receptor

2. eliminate the hormone

Question 29

describe breast cancer hormonal therapy treatment methods

Answer 29

1. Ovarian suppression –surgery, radiotherapy or chemical
2. Oestrogen receptor blockade
3. Aromatase inhibitors to block conversion of androgens to oestrogen

Question 30

what is required to use specific pathway inhibitors?

Answer 30

knowledge of the specificmolecules and pathways relevant to a particular tumour

Question 31

list specific pathway inhibitors used in cancer therapy

Answer 31

1. imatinib
2. CML
3. monoclonal antibodies
4. CAR-T cells (chimeric antigen receptor)
5. Oncolytic viruses

Question 32

describe the use of Rituximab in B cell non Hodgkin lymphomas

Answer 32

• Anti CD20 monoclonal antibody
• CD20 is found on B lymphocytes
• Rituximab leads to immune destruction of B cells
• Has completely changed the prognosis of many lymphomas

Question 33

what are oncolytic viruses?

Answer 33

replication-competent viruses engineered to have killing activity which is selective for tumour cells

Question 34

describe how oncolytic viruses work

Answer 34

• Tumour selectivity may be on the basis of selective entry into tumour cells OR how well the cancer cell deals with the virus, including how well the cancer cell can support virus replication e.g. Oncorine(adenovirus)which selectively grows in p53 deficient cells.
• 3 OVs currently available commercially but many more are in the clinical trial stage.
• Viruses being used or tried include adenovirus, measles, ECHO virus, herpes simplex etc.

Question 35

how are oncolytic viruses used to treat glioblastoma?

Answer 35

• The virus PVSRIPO (recombinant nonpathogenicpolio–rhinovirus chimera) infects tumour cells, gaining entry via CD155 on the tumour-cell surface.
• The virus causes tumour-cell lysis and the release of tumour antigens and molecules recognized by cells of the natural immune response Macrophages, monocytes, and dendritic cells (i.e., antigen-presenting cells [APCs]) are recruited into the tumour mass to clean up cellular debris, and those cells can present tumour antigens to effector T cells to kill more tumour cells.