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Cellular and Molecular pathology > 18. Cancer Therapy > Flashcards

18. Cancer Therapy Flashcards

1. Review different methods employed to eradicate cancer 2. To understand how knowledge of molecular and cellular biology helps develop novel therapies for cancer 3. General therapies 4. Targeted and personalised therapies 5. Continuing challenges

1
Q

What do the hallmarks of cancer provide?

A

Targets for therapies to prevent and treat cancer

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2
Q

What are the hallmarks of cancer?

A
  1. resisting cell death
  2. inducing angiogenesis
  3. enabling replicative immortality
  4. activating invasion and metastasis
  5. evading growth suppressors
  6. sustaining proliferative signalling
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3
Q

How is surgery used to treat cancer?

A

To remove primary tumours and lymph nodes.

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4
Q

How is radiotherapy used to treat cancer?

A
  1. high energy x-rays to kill cancer cells
  2. can be used in combo with chemo
  3. shrink tumours before surgery
  4. palliative care to reduce physical burden due to increased tumour mass
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5
Q

How is chemotherapy used to treat cancer?

A
  1. To target faster replicating cells like cancer cells.
  2. for the whole body and disseminated disease
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6
Q

What do all current cancer treatments have?

A

detrimental side effects due to effects on normal cells.

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7
Q

What does chemotherapy focus on?

A
  1. Points in the central dogma that can be targeted.
  2. These cancer cells need more energy, amino acids and nucleic acids.
  3. The majority of cancer therapies target DNA replication.
  4. And signalling pathways that can be inhibited like kinases and inducers of differentiation.
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8
Q

What is mitosis normally?

A

Very carefully orchestrated and controlled.

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9
Q

What is mitosis in cancer cells?

A
  1. The bulk of cancer cells undergo mitosis very quickly.
  2. These means that we can target these.
  3. Many of these treatment do not target cancer stem cells that don’t replicate very fast.
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10
Q

What is Taxol?

A
  1. A chemotherapy drug that disrupts mitosis by interfering with the polymerisation and depolymerisation of microtubules.
  2. Identified by botanists as it is from the bark of yew trees.
  3. acts similarly to Vinca alkaloid.
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11
Q

What does the experimental drug YK-4-279 do?

A
  1. It has a dramatic effect on the organisation of chromosomes during replication.
  2. This leads to cell death.
  3. This drug act very quickly to keep up with mitosis.
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12
Q

What are topoisomerases?

A
  1. They release the torsional stress on the DNA.
  2. This is needed to unwind the DNA and make it more accessible to allow replication.
  3. It does this by creating a nick in the DNA which enables the DNA to rotate in the helix.
  4. Once replication is complete the nick is sealed and the topoisomerase is released.
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13
Q

How are topoisomerases bound to the DNA?

A

Covalently

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14
Q

What does the topoisomerase 1 inhibitor, camptothecin, do?

A
  1. Camptothecin binds to the topoisomerase DNA complex and stabilises it.
  2. This causes double stranded DNA breaks in S-phase.
  3. These are cytotoxic.
  4. They are not repaired due to the loss of G2/M checkpoint in most cancer cells.
  5. This causes catastrophe and leads to cell death.
  6. They have off target effects in other replicating cells.
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15
Q

What does Cisplatin and Mitomycin-C do?

A
  1. They are cross-linking agents.
  2. They can cause inter or intra strand linkage.
  3. This causes dsDNA breaks and cytotoxic cell death.
  4. This also relies on there being no G2/M checkpoint.
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16
Q

How can lack of differentiation cause cancer?

A

Neuroblastoma is bought about by blocking the normal differentiation of neural crest cells.
This can be caused by MYCN blocking differentiation.

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17
Q

How does retinoic acid differentiation therapy work?

A
  1. It pushes the cells through the differentiation pathway.
  2. Pushes it to the endpoint of apoptosis.
  3. It does this because retinoic acid decreases MYCN transcription.
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18
Q

What is differentiation therapy normally used for?

A

relapsing cases or minimal residual disease

19
Q

What are the 2 types of radiotherapy?

A

photon and proton radiotherapy

20
Q

What happens in photon radiotherapy?

A
  1. High energy light is directed at the tumour.
  2. The energy decreases as it travels through the body but some still passes through the cancer and damages other cells.
  3. More side effects
21
Q

What happens in proton radiotherapy?

A
  1. High energy light is directed at the tumour.
  2. The energy decreases as it travels through the body.
  3. It stops when it hits the tumour.
  4. Only extra damage to the cells in front of the tumour.
  5. still some side effects
22
Q

Why are brain tumours mainly treated with radiotherapy?

A
  1. They are challenging to treat with chemo due to the blood brain barrier.
  2. Chemo cannot effectively treat brain tumours but radiotherapy can.
  3. some specialist drugs can treat brain tumours.
23
Q

How can radiopharmaceutical drugs be used to treat neuroblastoma?

A
  1. MIBG is a noradrenaline analogue that is taken up by neuroblastoma cells.
  2. This is due to the sympathetic origin of neuroblastoma.
  3. Drugs labelled with radioactive iodine are taken up is massive amounts by the cancer.
24
Q

What are most cancer therapies currently?

A

Very broad and leave lots of healthy cells damaged.

25
Q

What do targeted therapies need?

A
  1. Knowledge of the molecular basis of the tumour.
  2. disease stratification.
  3. target identification.
26
Q

What things can personalised therapies target?

A
  1. Gain of function mutations in oncogenes.
  2. Over expression of regulators.
  3. deregulated pathways.
27
Q

What is the RAS-RAF-MEK-ERK signalling pathway?

A
  1. A commonly disrupted pathway in cancer.
  2. A tyrosine kinase pathway.
  3. Signalling through Ras but mutations can lock it in an active state and cause uncontrolled signalling.
  4. Especially with the loss of tumour suppressor NF1.
  5. Activates A-RAF, B-RAF, C-RAF signalling.
  6. Activates MEK1/2 and ERK1/2 which disrupt gene expression
28
Q

How many melanoma patients have a BRAF mutation?

A

60%

29
Q

How can the RAS-RAF-MEK-ERK signalling pathway be inhibited?

A
  1. The BRAF-v600 is a very common gain of function mutation.
  2. Vemurafenib can block the signalling.
  3. Trametinib can selectively inhibit MEK kinases.
  4. The problem is cancers can gain resistance to these.
30
Q

What does the DNA-damage response involve?

A
  1. Activation of repair
  2. transcription regulation
  3. cell cycle control and apoptosis
  4. also senescence
  5. Highly specific and highly sensitive interactions
31
Q

What does the PARP repair pathway do?

A
  1. Repair single stranded breaks.
  2. uses base excision repair.
32
Q

What does the BRCA repair pathway do?

A
  1. Repair double stranded breaks.
  2. uses HR and NHEJ
33
Q

How can we take advantage of cancer cells DNA repair deficiencies?

A
  1. Normal cells will have 2 or more DNA repair pathways.
  2. Cancer cells will have lost most of these DNA damage repair pathways.
  3. This leads to over reliance on1 repair pathway.
  4. If we use inhibitors for these pathways we can cause the cancer cells to die.
34
Q

What is an example of taking advantage of cancer DNA repair deficiencies?

A
  1. Some breast cancers have lost the repair pathway BRCA.
  2. They over rely on PARP repair.
  3. We use olaparib to treat this as it is a PARP inhibitor.
  4. This causes the cancer cells to die.
35
Q

How inhibiting certain DNA repair pathways cause selective lethality?

A
  1. A cancer is treated with a DNA repair inhibitor like olaparib.
  2. The cancer cells die due to the loss of other DNA repair pathways and impaired HR repair.
  3. The normal cells still have other DNA repair pathways and functioning HR repair so these cells survive.
36
Q

How can new immunotherapies provide personalised treatment?

A
  1. Screening of patients for specific abnormalities so treatment can be tailored and reduce side effects.
  2. For example some breast cancers overexpress HER2 which leads to increased HER2 kinase activity and growth.
  3. Herceptin is a monoclonal antibody to HER2 and it blocks this kinase activity.
  4. It is only effective on breast cancers that overexpress HER2.
37
Q

What are common problems with immunotherapy?

A
  1. Drug resistance and relapse.
  2. Cancer stem cells with different phenotype/replication.
  3. drug delivery can be hard due to blood brain barrier.
  4. Intratumoral heterogeneity
  5. Cost of drug discovery and development.
38
Q

What is intratumoral heterogeneity?

A
  1. A tumour is made up of lots of different cells with different mutations.
  2. Some cells may be more responsive to treatment than others.
  3. We cannot ensure that the therapies will kill all the cancer cells.
39
Q

Cancer’s developing drug resistance: on target mutations

A

A mutation on the target protein that makes it insensitive to the action of the inhibitor.
eg mutations in binding sites to prevent inhibitors binding.

40
Q

Cancer’s developing drug resistance: parallel pathway activation

A

A different receptor or activator triggers the same pathway causing the same effects. Basically bypassing the inhibitor.

41
Q

Cancer’s developing drug resistance: Downstream pathway activation

A

The cell has gained a mutation in the pathway downstream of the inhibitor causing the pathway to still be active and signalling.

42
Q

Cancer’s developing drug resistance: Alternative pathway activation

A

Activation of a different pathway that causes the same effects but uses totally different molecules and receptors.

43
Q

What are the mechanisms of cancer drug resistance?

A

After initial inhibitor treatment a secondary mutation occurs. This causes:
1. increased expression of multi drug resistance proteins that can pump out the drugs reducing its effects.
2. OR altering of the target molecule.

44
Q

How can money be saved for drug development?

A

By repurposing existing drugs.
eg.
1. viagra for angina and erectile dysfunction
2. Arsenic for syphilis and now leukaemia
3. Metformin for diabetes and now cancer

Cellular and Molecular pathology (25 decks)

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