3.7. Cancer therapy I, II and III Flashcards
name the three types of cancer therapy available
- non-specific
- Targeted to specific pathways but generally applicable
- targeted therapy specific to certain cancers
list the non-specific cancer therapies available
- Surgery
- Radiotherapy
- Conventional (non-specific) cytotoxic chemotherapy
- Epigenetic modification
- Some immunotherapy
list the cancer therapies targeted to specific pathways but generally applicable
- Anti-angiogenictherapy
- Proteasome inhibition
- PARP inhibitors
- CDK inhibitors
- PI3K inhibitors
- BCL2 inhibitors
list the targeted therapy specific to certain cancers
- Hormone therapy
- Specific inhibitors of signalling pathways
- Immunotherapy
- Viral therapy
what are the benefits of surgery as cancer therapy
- Removes all cells whether sensitive to chemotherapy or not
* Removes cancer stem cells
what are some of the results of radiotherapy
- Cell death from extreme damage
- Induction of apoptosis
- Induction of senescence
- Damage which can be repaired
- RESIDUAL or UNREPAIRED DNA damage
what is radiotherapy?
- 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
describe Conventional cancer chemotherapy and some of its side effects
- 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”
list three ways in which dividing cells can be targeted
- induce DNA damage
- prevent replication of DNA
- Disrupt mitosis
name two manners in which DNA damage can be induced to target dividing cells
- alkylating agents: Attach an alkyl group to guanine base of DNA causing cross-linking
- Platinum–containing compounds: –> intra-strand links
name the manner in which DNA replication can be prevented to target dividing cells
through topo-isomerase inhibitors interfering with DNA unwinding
name the manners in which DNA replication can be prevented to target dividing cells
antimetabolites:
- folate antagonists: prevent thymidine synthesis
- Purine/pyrimidine analogues: become incorporated in DNA and prevent further synthesis
name the manners in which mitosis can be disrupted to target dividing cells
- Prevent microtubule assembly (e.g. vincristine)
2. Prevent microtubule breakdown at the end of mitosis (e.g. taxanes)
what is the purpose of a bone marrow stem cell transplantation
- 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
name two sources of bone marrow
- Autologous–from the same person who is going to receive the cells. This would be used to rescue the patient from chemotherapy
- Allogeneic–from a living donor who could be related or not. This would be used to replace a diseased marrow.
name a major problem of allogeneic transplant
Graft versus host disease
- The donor marrow reconstitutes the host immune system.
name and describe two methods of epigenetic cancer therapy
- DNA methylation
- Cytosine analogues lead to DNA hypomethylation by not accepting methyl groups and by depleting DNMTs - Histone modification Histone Deacetylase Inhibitors (HDACi).
what is the problem with epigenetic cancer therapy
Lack of specificity –cannot be sufficiently targeted and so have very broad effects
name Mechanisms to enhance endogenous immune defences in non-specific immunotherapy
- William Coley’s Toxins
- Use of infectious agents such as BCG
- Interferon therapy
name the immune checkpoint inhibitors in non-specific immunotherapy
- Anti-CTLA-4
2. PD1 pathway inhibitors
explain the process of Anti CTLA-4 therapy in non-specific immunotherapy
- CTLA-4 is transiently expressed following T cell activation.
- The signal delivered via CTLA-4 down-regulates T cell function and inhibits excessive expansion of activated T cells.
- It is constitutively expressed in Tregcells and enhances their function
explain the process of Anti PD-1 therapy in non-specific immunotherapy
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
describe the function of anti-angiogenic therapy and its cons
- 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
describe inhibition of the proteosome
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
what is the function of CDK inhibitors and give two examples
- Keep cells in G1.
- May be used in future to synchronise cells for chemo (this results in a higher hit rate)
e. g. Palbociclib, Ribociclib
what is the main use of Parp inhibitors
Main use is in BRCA deficient individuals or tumours.
when are BCL2 inhibitors used and give an example of the inhibitor
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
what are the functions of hormonal therapy?
- block the receptor
2. eliminate the hormone
describe breast cancer hormonal therapy treatment methods
- Ovarian suppression –surgery, radiotherapy or chemical
- Oestrogen receptor blockade
- Aromatase inhibitors to block conversion of androgens to oestrogen
what is required to use specific pathway inhibitors?
knowledge of the specificmolecules and pathways relevant to a particular tumour
list specific pathway inhibitors used in cancer therapy
- imatinib
- CML
- monoclonal antibodies
- CAR-T cells (chimeric antigen receptor)
- Oncolytic viruses
describe the use of Rituximab in B cell non Hodgkin lymphomas
- 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
what are oncolytic viruses?
replication-competent viruses engineered to have killing activity which is selective for tumour cells
describe how oncolytic viruses work
- 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.
how are oncolytic viruses used to treat glioblastoma?
- 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.
