CBIO 8: Cancer Therapy Flashcards
1
Q
Observe the learning outcomes of this session
A
2
Q
What are the five pillars of cancer treatment?
A
- surgery
- radiotherapy
- chemotherapy
- immunotherapy
- targeted therapy
3
Q
What is the purpose of cancer treatment?
A
- prolong survival time
- improve quality of life
4
Q
What are the three key goals of cancer treatment?
A
- cure
- control
- palliative care
The aim is always to eliminate cancer cells and reduce the chance of recurrence but in cases where cancer cannot be cured, palliative treatment is important.
5
Q
What type of treatment is most commonly used in the UK?
A
- surgery
6
Q
Give an example of the treatment strategy for breast cancer
A
7
Q
Define neoadjuvant therapy
A
- treatment given to shrink the tumour before the primary treaatment
8
Q
Define adjuvant therapy
A
- treatment given in addition to the primary treatment
9
Q
Define cancer stage
A
- describes the size of tumour and how far it has spread from the original site
10
Q
Define cancer grade
A
- described the appearance of tumour compared to original normal cells
11
Q
Describe complete remission
A
- treatment has eliminated cancer as measured by medical tests
- does not mean a cure
12
Q
Define anti-angiogenic
A
- drugs to stop tumours growing their own blood vessels
13
Q
What are the different functions of surgery in cancer treatment?
A
- cancer prevention
- diagnosis
- staging
- primary treatment
- debulking
- relieving symptoms or side effects
14
Q
Describes the aims of surgery in cancer treatment
A
- Surgery is often used with curative intent.
- It is usually the first line of treatment for many patients that have localised solid tumours, or tumours caught at an early stage of development.
- However it is not suitable if the cancer is systemic such as in leukaemia (haematological cancer) or lymphatic cancer.
- It is also less suitable for metastasised cancer, or in case the tumour is near a risky or delicate area, such as a major blood vessel.
- The aim of surgery is to remove the tumour mass or the whole host organ, sometimes including the surrounding lymphatic system.
- A margin of healthy tissue is also removed to reduce the chance of recurrence.
- Surgery alone can be used as cancer treatment, but it’s often used in combination with other modalities.
- For example, surgery can be performed before chemotherapy or radiotherapy as an adjuvant treatment, or radiation can be given to reduce the tumour size and then surgery can be performed to remove it (neoadjuvant treatment).
- Surgery can also be performed to control symptoms or extend life/improve quality of life, for example to remove the tumour even though it is not a cure.
15
Q
Describe the different types of surgery in cancer treatment
A
- debulking:
- Refers to 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.
- laparoscopic surgery:
- This type of surgery is less invasive as it is carried out through smaller incisions.
- Also referred to as ‘keyhole’ surgery, laparoscopic surgery uses a 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.
- radical surgery:
- To lower the chance of recurrence, radical surgery will remove all nearby tissue including lymph nodes, muscles and nerves, for example radical mastectomy is the removal of the breast and surrounding tissue.
- see image
- preventative (prophylactic) 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).
16
Q
What are the main risks associated with cancer surgery?
A
- Bleeding
- Blood clots
- Damage to nearby tissues, nerves
- Adverse reactions to drugs used in surgery
- Damage to other organs
- Pain
- Infections
- Slow recovery of other body functions
17
Q
What is radiotherapy?
A
- Radiotherapy uses ionising radiation (IR), normally delivered by a linear accelerator, to cause DNA damage and kill malignant cells.
- Radiotherapy can be curative in many cases where the tumour is localised and it can be used instead of surgery to remove a tumour in cases where the patient is too weak to undergo surgery.
- Radiation is delivered to match the 3D shape of the tumour so that intense radiation is delivered to tumour cells with less exposure to the surrounding healthy tissue.
- Not all cancer can be treated with radiotherapy - some cancers are radio-resistant, such as renal cell carcinoma.
- Metastatic cancer is also less suitable for radiotherapy treatment due to its systemic nature.
- Radiotherapy is usually given as doses over days, allowing time in between treatments for the normal cells that have been exposed to IR to repair and recover (reduce side effects).
- It can also be adjuvant or neoadjuvant with other cancer therapies.
18
Q
Describe the types of radiotherapy used in cancer treatment
A
- 3DCRT (three-dimensional conformal radiotherapy):
- This is the most commonly used radiotherapy
- It uses computer programmes to analyse and design radiation beams to match the shape of the tumour.
- IMRT (intensity-modulated radiation therapy):
- Uses linear accelerators to deliver precise radiation doses to the 3D shape of the tumour.
- The 3D shape of the tumour is divided into segments and during treatment different intensities of radiation are delivered to each segment via computer-controlled modulation of multiple radiation beams.
- IGRT (image guided radiotherapy):
- Is used to treat tumours in areas that move, such as the lungs or close to critical organs.
- Therefore frequent imaging is taken before and during radiotherapy to assist precise delivery of irradiation to the tumour.
- SBRT (stereotactic body radiation therapy):
- Uses imaging and computer programmes to precisely deliver a higher dose (higher than other types of radiotherapy) of radiation.
- It is usually given in a single or small number of treatments, where delivery is accurate to within one to two millimetres.
- It is also used as an alternative to open surgery for removal of small to moderately-sized cancers.
- brachytherapy:
- A radioisotope source in a sealed container such as a capsule is placed in or near the tumour.
- see image
19
Q
How does radiotherapy work to kill cancer cells at the molecular level?
A
- Ionising radiation consists of particles, X-rays, or gamma rays with sufficient energy to cause ionisation.
- This means that during an interaction with an atom, it can remove tightly bound electrons from the orbit of the atom, causing the atom to become charged or ionised.
- During radiotherapy, using photons, protons or particle radiation, the ionising radiation can damage the DNA directly.
- It can also have indirect effects such as affecting water molecules, which become free radicals that can themselves damage the DNA (see diagram below).
- Although cells have mechanisms in place to repair DNA damage, these are often significantly disrupted in cancer cells.
- As a consequence, DNA damage is more likely to trigger cell death signals in cancer cells.
- Also, the sheer amount of DNA damage induced can overwhelm the repair machinery.
- Whilst IR causes several types of DNA damage including single-stranded DNA breaks, it is the double stranded DNA breaks that are responsible for inducing cell death.
- IR induces several cell death mechanisms
- apoptosis and mitotic catastrophe are the main mechanisms, but necrosis, IR-induced senescence followed by apoptosis, and IR-induced autophagy followed by apoptosis are also triggered by IR.
20
Q
Define mitotic catastrophe
A
- a type of cell death that occurs during mitosis
- results from premature or inappropriate entry of cells into mitosis
- can be caused by chemical or physical stresses
- it is unrelated to programmed cell death or apoptosis
21
Q
Define senescence
A
- cells cease to divide and grow
22
Q
Define autophagy
A
- A natural process to self-degrade cellular components, important for balancing energy during critical times such as nutrient stress.
23
Q
What happens to healthy cells adjacent to cancer cells exposed to IR?
A
- Healthy cells adjacent to cancer cells or in the path of radiation are exposed to some IR.
- These normal cells proliferate more slowly and therefore have time to repair DNA damage before replication.
- They can also repair themselves at a faster rate and retain their normal function more effectively than cancer cells.
- However, even though healthy tissue is better at recovering from IR it can nevertheless be damaged resulting in short or long term side-effects.
24
Q
What are some general side effects of radiotherapy?
A
- Sore, red skin
- Feeling tired most of the time (due to low red blood cells or body is using most energy to repair healthy tissue)
- Hair loss in the area being treated (IR affects cells that proliferate at a faster rate, such as hair folicles)
- Feeling sick
- Loss of appetite
- A sore mouth
- Diarrhoea
- Lymphoedema (swelling of limbs due to damage to the lymphatic system that normally regulates body fluid)
28
Q
Is chemotherapy given alone or in combination with other treatments?
Give some examples
A
- Chemotherapy can be given alone or as an adjuvant or neoadjuvant treatment and the patient is usually given several drugs in combination.
- Occasionally it is also combined with other medicines, such as steroids or biological therapies.
29
Q
Describe the chemotherapy: alkylating agents
A
- Nitrogen mustards were the first alkylating agent used medically and also the first chemotherapy drug.
- Alkylating agents add alkyl (CNH2N+1) groups to guanine residues in DNA which causes cross-linking of DNA strands thus preventing DNA from uncoiling at replication.
- The replication arrest activated by checkpoint pathways triggers apoptosis.
- Pseudo-alkylating agents add platinum to guanine residues in DNA, which activate the checkpoint and trigger apoptosis.
- Most of the alkylating agents are also carcinogenic as they encourage mispairing during DNA repair.
- They are toxic to normal cells, particularly cells that divide frequently, such as those in the gastrointestinal tract, bone marrow, and in the testicles and ovaries, which can cause loss of fertility.
33
Q
Describe the chemotherapy: anti-microtubule agents
A
- Antimicrotubule agents are originally derived from natural sources.
- They inhibit cell proliferation by binding to microtubules and suppressing microtubule dynamics during the particularly vulnerable mitotic stage of the cell cycle.
- Vinca alkaloids and taxanes are the two main groups of anti-microtubules.
- They work by inhibiting assembly (vinca alkaloids) or disassembly (taxanes such as Paclitaxel) of mitotic microtubules.
- This causes dividing cells to undergo mitotic arrest which activates cell death.
- Antimicrotubules are also antiangiogenic which means they prevent tumour vasculature forming and have vascular-disrupting effects.
35
Q
Describe the chemotherapy: topoisomerase inhibitors
A
- Topoisomerases are enzymes that regulate the unwinding of DNA.
- They are required to prevent DNA torsional strain during DNA replication and transcription.
- They induce temporary single-strand (topoisomerase I) or double-stranded (topoisomerase II) breaks in the phosphodiester backbone of DNA.
- Topoisomerase I cuts one of the DNA strands, relaxes the strand and then re-ligates the strand.
- Topoisomerase II cuts a double-stranded break in one DNA segment, to allow another DNA segment to pass through, and re-ligates the first DNA segment.
- Topoisomerase inhibitors are drugs that bind to the enzyme and prevent the re-ligation, which means DNA remains cut.
- There are DNA repair mechanisms in place within cells for double-stranded breaks, such as the Non-Homologous End Joining pathway (NHEJ).
- However, chemotherapeutic topoisomerase inhibitors will cause significant single- and double-stranded DNA breaks that will overwhelm the repair mechanisms and therefore trigger apoptosis of the cancer cells.
44
Q
Briefly describe the tyrosine kinase inhibitor: Gleevec
A
- Gleevec was the first “targeted therapy” (also known as Glivec and Imatinib).
- In 1973, the human geneticist Dr Janet Rowley became the first scientist to identify a chromosomal translocation as the cause of cancer in patients with chronic myeloid leukaemia.
- The chromosomal translocation was found to create its own unique fusion protein called Bcr-Abl, an enzyme which drives over-production of white blood cells (see diagram below).
- This is an example of “Oncogene Addiction” – a uniquely hyperactive oncogene driving a tumour (Achilles’ heel).
- In 1996 Buchdunger et al published data on a drug that could specifically target Bcr-Abl (and not affect other proteins).
- Fantastic clinical results (90% complete response rates in patients with CML) heralded the departure from “conventional cytotoxics” into a new era of “targeted therapies”.
- In 2017, a 10 year follow-up study reported that the overall survival rate was 83.3%.
45
Q
How does Gleevic inhibit Bcr-Abl enzyme activity?
A
- The 9;22 chromosome translocation is named the Philadelphia chromosome.
- The translocation creates the fusion protein Bcr-Abl which is a membrane-associated protein with ‘always on’ tyrosine kinase activity.
- It speeds up cell division through the regulation of cell cycle proteins.
- Gleevec works by binding close to the ATP binding site of Bcr-Abl, preventing the enzyme binding to ATP and inhibiting the enzyme activity.
- Gleevec is quite selective for Bcr-Abl, though it does also inhibit other targets such as c-Kit and the PDGF-Receptor.
- C-Kit is mutated in gastrointestinal stromal tumours (GIST) and Gleevec is used in therapy, however resistance to Gleevec unfortunately occurs (75% at 2.5 years).
49
Q
Describe the targeted therapy: anti-angiogenic therapy
What are the two types?
A
- When a tumour has reached 1 to 2 mm across it requires its own blood supply.
- Therefore in order to survive, tumour cells produce and release pro-angiogenic factors such as VEGF, that act on endothelial cells found lining the blood vessels.
- This encourages the vessels to grow towards, and supply blood to, the tumour
- Drugs that block blood vessel growth factors are called anti-angiogenics.
- There are two types of anti-angiogenics:
1. Drugs that block blood vessel growth factor, for example by preventing VEGF from binding to the blood vessel cell receptors
2. Drugs that block signalling within the cell, these are the tyrosine kinase inhibitors
50
Q
What is synthetic lethality?
A
- Synthetic lethality is a simple genetic concept to help identify new cancer treatment targets.
- The concept originated in genetic studies of model organisms such as fruit flies.
- The idea is that loss of cellular viability occurs when the interaction between two genes is disrupted simultaneously but cells survive when either gene alone is disrupted.
- This is ideal for cancer treatment as cancer cells usually harbor genetically altered genes that are not present in healthy cells.
- Since the synthetic lethality concept was proposed 20 years ago there is only one successful story that has been translated into clinical therapy.
- This is the use of PARP inhibitors (PARPi) in patients with BRCA1/BRCA2 deleted or mutated cancer.
51
Q
How do PARP inhibitors work?
A
- Poly (ADP-ribose) polymerases (PARPs) constitute a large family of 18 proteins.
- PARP1 and PARP2 are enzymes, activated by DNA damage, and facilitate DNA repair of single-strand breaks (SSBs) and base excision repair (BER).
- Suppression of PARP leads to stalling of replication forks due to the accumulation of unrepaired SSBs.
- The stalled replication forks degrade into highly cytotoxic double strand breaks (DSBs) which are normally repaired by homologous recombination (HR), considered to be the most precise DSB repair mechanism.
- BRCA-mutated cells (either germline or somatic) are incapable of HR, therefore PARP inhibition results in genomic instability and cell death.
57
Q
Describe the emerging cancer therapy: PROTACs
A
- PROTAC: PROteolysis TArgeting Chimera
- Targets cellular proteins for degradation by co-opting the ubiquitin-proteasome system
-> chemical knockdown approach
- Improved selectivity compared to classic inhibitors
- Higher sensitivity to drug resistant targets
- PROTACs have been successfully developed for >50 cancer relevant proteins
- Clinical trials ongoing
58
Q
Describe the emerging cancer therapy: DNA cages
A
- Nanostructures modified with lipid-like molecules – DNA origami
- Lipids can act like sticky patches that come together and create a “handshake” inside the DNA cube, creating a core that can hold cargo such as drug molecules
- A DNA cube can carry drug cargo to a diseased cell environment.
- This triggers the release of the drug when it encounters particular DNA sequences
• Can also be used for in vivo imaging
60
Q
Describe the emerging cancer therapy: Gut microbiome
A
- Increasing evidence that gut microbiome influences both susceptibility to certain cancers as well as response to therapy
- This influence has most convincingly been shown in immunotherapy
- Therapeutic strategies to target the gut microbiome include lifestyle changes, administration of probiotics and fecalmicrobiota transplant
62
Q
Describe the emerging cancer therapy: Cryotherapy
A
- Cryotherapy is a treatment that uses extreme cold to destroy cancer cells
Some facts about cryotherapy:
- Cryotherapy can be used to treat different types of cancer and precancerous conditions
- Cryotherapy is a local treatment
- After cryotherapy the body’s immune system gets rid of the dead tissue
- For cryotherapy of cancers inside the body, a small probe (cryoprobe) is inserted next to or inside the tumour that is attached to a supply of liquid nitrogen
- Depending on the treatment area, cryotherapy can take a few minutes to a couple of hours
- Cryotherapy can be administered through the skin (percutaneously) or through a scope
