CBIO8: Cancer Therapy Flashcards
(92 cards)
1
Q
What are the main pillars o cancer therapy?
A
- Surgery
- Radiotherapy
- Chemotherapy
- Immunotherapy
- Targeted therapy
2
Q
What does how a cancer patient is treated depend on?
A
tumour type, location, grade and stage of the disease as well as the general health of the patient: A single treatment modality can be used alone to treat a patient or different treatments types may be used in combination.
3
Q
What is the purpose of cancer treatment?
A
- Prolonged survival time
- Improved quality of life
4
Q
What are the goals of cancer treatment?
A
Cure
Control
Palliative care
5
Q
What is the most common treatment type in the UK?
A
Surgery
6
Q
If the breast mass in benign what do doctors do?
A
A regular physical exam is performed
7
Q
If the breast cancer is malignant and is a local disease, what do doctors do?
A
Surgery
Adjuvant (in addition): Chemotherapy, radiotherapy, hormone therapy
8
Q
If the breast cancer is a) malignant b) metastatic c) HR- what do doctors do?
A
Chemotherapy
Adjuvant (in addition):
Monoclonal antibodies
9
Q
If the breast cancer is a) malignant b) metastatic c) HR+ what do doctors do?
A
Hormone therapy and watch disease progression before chemotherapy (adjuvant: immunotherapy - monoclonal antibodies) and watch disease progression. Then Targeted therapy (mTOR inhibition)
10
Q
Describe: adjuvant therapy
A
treatment given in addition to the primary treatment
11
Q
Describe: neoadjuvant therapy
A
treatment given to shrink the tumour before the primary treatment
12
Q
Describe: cancer grade
A
describes the size of tumour and how far it has spread from the original site
13
Q
Describe: cancer stage
A
describes the appearance of tumour compared to original normal cells
14
Q
Describe: complete remission
A
treatment has eliminated cancer as measured by medical tests. Does not mean a cure
15
Q
What are the stages of surgery in cancer treatment?
A
Cancer prevention Diagnosis Staging Primary treatment Debulking Relieving symptoms or side effects
16
Q
When is surgery not suitable?
A
If the cancer is systemic such as in leukaemia (haematological cancer) or lymphatic cancer. It is also not suitable for metastasised cancer and if the tumour is near a risky or delicate area such as a major blood vessel.
17
Q
In order to reduce risk of recurrence in surgery what takes place?
A
A margin of healthy tissue is also removed sometimes including the surrounding lymphatic system
18
Q
What neo-adjuvant treatment is used alongside surgery?
A
Radiation can be given to reduce the tumour size and then surgery can be performed to remove it
19
Q
When could surgery be used to control symptoms or extend life/improve quality of life?
A
to remove the tumour even though it is not a cure
20
Q
Give examples of adjuvant surgery treatment
A
Surgery can be performed before chemotherapy or radiotherapy as an adjuvant treatment
21
Q
What are the different types of cancer surgery?
A
- Debulking
- Laparoscopic surgery
- Radical surgery
- Preventative (prophylatic) surgery
22
Q
Describe debulking
A
surgery that removes as much of the tumour as possible but not all of it. This improves the chances of successful chemo or radiotherapy, for example in the case of advanced cancer of the ovary.
23
Q
Describe laparoscopic surgery
A
Type of surgery is less invasive as it is carried out through smaller incisions. Also referred to as ‘keyhole’ surgery, laparoscopic surgery uses specialised instrument called a laparoscope.
A laparoscope is a small tube with a light source and a camera, which relays images of the inside of the abdomen or pelvis to a television screen for the surgeons to monitor their progress. (image courtesy of the Colorectal Cancer Alliance)
24
Q
What is radical surgery?
A
To lower the chance of recurrence, radical surgery will remove all nearby tissue including lymph nodes, muscles and nerves, for example radical mastectomy which is the removal of the breast and surrounding tissue.
25
What is Preventative (prophylatic) surgery?
Surgery to remove non-cancerous areas of tissue in patients who are genetically at a high risk of developing particular cancers.
Two examples are patients with a family history of breast cancer (BRCA1 and BRCA2) and familial adenomatous polyposis (a condition where large numbers of polyps form, mainly in the epithelium of the large intestine).
26
Name the risks in surgery
The risks of surgery include bleeding, blood clots, damage to nerves and nearby tissues, adverse reactions to drugs used in surgery, damage to other organs, pain, infections and slow recovery.
27
Radiotherapy
Uses ionising radiation delivered by a linear accelerator to cause DNA damage and kill malignant cells. It is useful in patients with localised tumours and in individuals who are too weak to undergo surgery. It is administered to match the 3D shape of the tumour to minimise radiation exposure to the surrounding tissue. Metastatic cancers and radio-resistant cancers (e.g. renal carcinoma) cannot be treated using radiation.
28
What is the treatment for radiotherapy like?
Radiotherapy is given in doses over several days to allow time in between doses for normal cells to repair and recover in order to reduce side effects. It is often used as an adjuvant or neoadjuvant with other therapies
29
List the names of the different types of radiotherapy
```
3DCRT
IMRT
IGRT
SBRT
Brachytherapy
```
30
Describe 3DCRT radiotherapy
3D conformal radiotherapy uses computer programs to analyse and design radiation beams to match the tumour shape and is the most common radiotherapy.
31
Describe IMRT radiotherapy
Intensity modulated radiation therapy divides the 3D tumour shape into several segments and varying intensities of radiation are delivered to each segment in order to deliver precise radiation doses.
32
Describe IGRT radiotherapy
Image guided radiotherapy treats tumours in moving areas (e.g. lungs) and uses frequent imaging to assist precise delivery of irradiation to the tumour.
33
Describe SBRT radiotherapy
Stereotactic body radiation therapy uses computer programs and imaging to deliver higher radiotherapy doses as a single treatment or a small number of treatments. Delivery is very accurate and it is used as an alternative to open surgery in small or moderately sized cancers.
34
Describe Brachytherapy radiotherapy
uses a radioisotope in a sealed container placed in or near the tumour.
35
What does ionising radiation consists of?
Particles with sufficient energy to cause ionisation by removing tightly bound electrons from the orbits of atoms. Using photons, protons and particle radiation DNA can be directly damaged by ionising radiation. Water molecules also become free radicals which also cause DNA damage. DNA repair mechanisms tend to be disrupted in cancer cells, making damage more likely to trigger apoptosis.
36
What can IR cause to cancer cells?
ssDNA and dsDNA breaks
37
What death mechanisms can IR induce?
```
apoptosis
mitotic catastrophe (two main mechanisms^)
necrosis
senescence
autophagy
(direct or indirect)
```
38
What is mitotic catastrophy?
Cell death that results from inappropriate entry into mitosis due to chemical or physical stress
39
How does IR kill cancer cells? (detailed mechanism)
Damaged DNA is detected by sensor proteins such as PARP, MRN, Ku and ATRIP which recruit transducer kinases such as DNA-PK, ATR, ATM, CHK1 and CHK2. ATM and ATR can amplify the signal by phosphorylating H2AX and recruiting mediator proteins such as BRCA1 and 53BP1. A positive feedback loop between transducers and mediators is created which maintains and amplifies H2AX phosphorylation. Effector proteins can be recruited and phosphorylated by CHK2 in order to cause cell cycle arrest, senescence and in response to radiotherapy – apoptosis.
40
What do the side-effects of radiotherapy include?
Sore skin, lethargy due to low red blood cells and energy depletion due to tissue repair, hair loss, feeling sick, appetite loss, sore mouth, diarrhoea and lymphedema.
41
When is chemotherapy used?
It is used as a curative or palliative treatment and uses cytotoxic drugs to kill cancer cells.
42
What genetic mutations cause cancer ?
Chromosome translocation, gene amplification, point mutations, deletions, insertions, epigenetic alterations and germline mutations.
43
How is chemotherapy administered?
Chemotherapy is a systemic treatment which travels in the bloodstream and can be administered orally or intravenously over a number of months and targets rapidly dividing cells.
44
Which normal cells are damaged by chemotherapy?
Those in the mouth, GI tract, reproductive system, haematopoietic cells and hair follicles
45
How is chemotherapy administered?
It's an adjuvant or neoadjuvant and is usually given as a combination of several drugs
46
What is MIC treatment?
It is a combination chemotherapy to treat non-small cell lung cancer and oesophageal cancer. It contains Mitomycin, Ifosfamide and Cisplatin.
47
What is CHOP treatment for and what does it contain?
```
C = cyclophosphamide
H = doxorubicin
O = vincristine (Oncovin)
P = prednisolone, a steroid
used for Non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukaemia (CLL)
```
48
How do alkylating agents function?
They add CnH2n+1 groups to guanine which results in the cross-linking of DNA strands which prevents DNA uncoiling for replication to occur. Pseudo-alkylating agents add platinum to guanine residues to activate the checkpoint and trigger apoptosis. Alkylating agents are also carcinogenic as they promote mis-pairing during DNA repair and they are toxic to rapidly dividing cells.
49
What are the common side effects of alkylating agents
```
hair loss (not carboplatin)
nephrotoxicity (toxicity in the kidneys)
neurotoxicity
ototoxicity (platinums) (toxic to the ear)
nausea
vomiting
diarrhoea
immunosuppression
tiredness
```
50
How do Antimetabolites function?
They interfere with enzymes involved in DNA synthesis by masquerading as purine or pyrimidine residues and inhibit DNA replication and transcription. They can also be folate antagonists which inhibits dihydrofolate reductase to prevent nucleic acid synthesis. Antimetabolites induce cell death during the S phase of the cell cycle.
51
What are the common side effects of Antimetabolites?
Fatigue, hair loss, anaemia, leukocytopaenia, neutropaenic sepsis, nausea, mucositis and palmar-plantar erthrodysesthesia.
52
How do Anti-microtubule agents function?
They inhibit cell proliferation by suppressing microtubule dynamics during mitosis which activates apoptosis. There are two main groups of anti-microtubules, Vinca alkaloids and taxanes. Vinca alkaloids inhibit assembly of microtubules whilst Taxanes inhibit their disassembly. Anti-microtubules are also antiangiogenic which prevents tumour vasculature forming.
53
What are the common side effects of Anti-microtubule agents?
Nerve damage, hair loss, nausea, vomiting, bone marrow suppression, arthralgia and allergy.
54
How do topoisomerase inhibitors work?
They bind to topoisomerase enzymes to prevent the re-ligation of cut DNA and cause the induction of apoptosis. An example is etoposide.
55
What are the common side effects of topoisomerase inhibitors?
hair loss, nausea, acute cholinergic type syndrome, fatigue and bone marrow suppression
56
How do Cytotoxic antibiotics work?
They interrupt cell division and fall into two main groups: Anthracyclins and Bleomycins. They mainly intercalate DNA to prevent DNA synthesis and transcription, inhibiting topoisomerase II, producing free radicals and damaging cell membranes.
57
What are the common side effects of Cytotoxic antibiotics?
cardiac toxicity, alopecia, nausea, neutropaenia, fatigue, skin changes and red urine.
58
What does resistance to chemotherapy involve?
Increased clearing/detoxification of the drug
Inhibition/loss of apoptosis
Increased DNA repair of damage caused by chemo
59
What does targeted therapy seek to reduce?
the damage done to normal cells and reduce side effects by rationally targeting cancer signalling.
60
Give an example of targeted therapy
Small molecule kinase inhibitors
61
What are the four main types of targeted therapy?
Cancer growth blockers
Monoclonal antibodies
Anti-angiogenics
PARP inhibitors
62
What are tyrosine kinase inhibitors?
They allow proliferation and survival signals to be blocked which stops cell growth and division
63
Give an example of a tyrosine kinase inhibitor
Gleevec/Glivec/Imatinib
64
What was Gleevec targeted to treat?
Philadelphia chromosome in seen in chronic myeloid leukaemia
65
What is the Philadelphia chromosome?
a 9,22 translocation which results in a Bcr-abl fusion protein which has “always on” tyrosine kinase activity, leading to an increase in the number of cancerous cells.
66
How does Gleevec function?
It binds close to the ATP binding site of Bcr-abl to prevent ATP binding and its enzymatic activity.
67
What do proteasome inhibitors do?
to block the degradation of unwanted proteins which allows pro-apoptotic proteins to remain and activate programmed cell death.
68
What do mTOR inhibitors do?
prevent cytoskeletal rearrangements and the production of new proteins involved in increasing cell size and proliferation.
69
What do PI3K inhibitors do?
Block signalling pathways which lead to proliferation, differentiation, growth, motility and survival.
70
What do histone deacetylase inhibitors do?
Prevent the regulation of DNA coiling and uncoiling and therefore gene expression and transcription. This induces cell cycle arrest or apoptosis.
71
What do Hedgehog pathway blockers do?
Prevent the embryonic signalling pathway used for Cell differentiation that is activated in brain and skin cancer.
72
What can monoclonal antibodies be directed against?
TSAs and TAAs on the surface of tumour cells.
73
Name the different types of monoclonal antibodies
Naked mAbs
Conjugated mAbs
Bispecific mAbs
74
Explain what naked mAbs are
Most common type used which is not conjugated to any therapeutic agents. They can block cancer-associated growth factor receptors and induce antibody-dependent cell-mediated cytotoxicity (ADCC)
75
Explain what conjugated mAbs are
Homing devices’ which take therapeutic agents (chemotherapy or radiotherapy) directly to cancer cells.
76
Explain what bispecific mAbs are
Made up of parts of two different mAbs which allows them to attach to two different proteins at the same time. This brings immune cells and cancer cells together which causes the immune system to attack the immune system.
77
Name a drawback to mAbs
They can cause allergic reactions
78
What are the two classes of anti-angiogenics?
1) Drugs that block blood vessel growth factors such as VEGF
2) Drugs that block signalling within the cell such as Tyrosine Kinase receptors
79
How do tumours increase angiogenesis?
tumour cells produce and release pro-angiogenic factors such as VEGF, that act on endothelialcells found lining the blood vessels. This encourages the vessels to grow towards, and supply blood to, the tumour
80
What is the idea of synthetic lethality?
loss of cellular viability occurs when the interaction between two genes is disruptedsimultaneously but cells survive when either gene alone is disrupted
81
What is an example of a cancer treatment utilising the concept of synthetic lethality?
PARP inhibitors in patients with BRCA1/BRCA2 deleted or mutated cancers
82
How is synthetic lethality related to cancer therapy?
Synthetic lethality is a genetic concept to identify new cancer treatment targets. It is ideal for disrupting altered genes in cancer cells whilst leaving healthy cells unaffected.
83
Give an example of synthetic lethality with tumour cells, imagining gene A and gene B
Tumour cell with mutated gene A cannot survive when gene B’s protein product is bound to by a drug, leading to loss of function. The normal cell can survive with disrupted gene B as they have a normally functioning gene A.
84
What is PARP involved in?
base excision repair
85
What can PARP inhibition in cancer cells with BRCA mutations lead to?
DNA breaks which can result in cell death due to DNA damage. The accumulation of SSBs causes the stalling of replication forks which leads to cytotoxic DSBs which cannot be repaired as BRCA is mutated.
86
Name a PARP inhibitor undergoing clinical trials
Olaparib/Lynparza
87
In what cancers have there been positive results with using PARP inhibitors (Olaparib) in?
Germline BRCA mutations of breast, ovarian, pancreatic and prostate cancers
88
What has Olaparib been found useful in?
BRCA mutated HER2- metastatic breast cancer that had been previously treated with chemotherapy. It has recently been EMA and FDA approved.
89
What side effects were seen in triple negative breast cancer patients?
Myelosuppression and CNS side effects
90
When does resistance to PARP inhibitors occur?
when cancer cells can restore Homologous Repair in tumour cells although the exact mechanism is not fully understood
91
What can PARP inhibitors be combined with in therapy?
- PARPi with ATR inhibitors which further prevent DNA repair
| - immunotherapy (antibodies)
92
Stratified trials have also shown that PARP inhibitors are more useful in tumours with what?
DNA damage repair pathway mutations.
