Edmead Past Paper Questions

Question 1

What are the 10 hallmarks of cancer and how are they mitigated/treated?

Answer 1

1. Growth signal autonomy (sustained proliferative signalling)
   Normal cells require signals from growth factors to stimulate proliferation and growth. Cancer cells are not dependent on this growth factor signalling as mutations have occurred perhaps leading to constitutive activation of the GFRs, resulting in unregulated growth.
   Treated via SMI such as Iressa or tarceva for EGFR.
2. Evasion of growth inhibitory signals
   Normal cells respond to inhibitory signals and are not actively growing, cancer cells however do not respond to these signals.
   Treated via cyclin dependent kinase inhibitors such as Palbociclib.
3. Avoiding immune destruction
   Immune surveillance is a theory that immune cells can recognise and eliminate cancer cells, therefore the only cancer cells in the body should be those that can evade detection or interfere with the immune response to avoid destruction.
   Treated via Ipilimumab, MM, CTLA-4 treatment etc.
4. Unlimited proliferative potential
   Normal cells have the Hayflick limit, a finite number of cell replications before they become senescent. This is due to shortening of the chromosomal ends, telomeres, during each round of replication as DNA polymerase cannot copy all the way to the ends of each chromosome. This results in a loss of 100-200 base pairs with each replication cycle. Cancerous cells maintain the length of their telomeres so are able to continue to replicate.
   Telomerase inhibitors: Imetelstat a 13-mer oligonucleotide inhibitor of RNA component of human telomerase.
5. Tumours promoting inflammation
   Virtually all tumours contain immune inflammatory cells, these can release RoS that are mutagenic and also provide growth factors/enzymes that promote angiogenesis and invasion. Metastatic cells capable of travelling to a distant site and invading do this via same mechanisms that immune cells use to get to the sites of infection.
   Treated via normal anti-inflammatory drugs?
6. Invasion and metastasis
   Normal cells generally maintain their location in the body and do not migrate to other regions. Cancerous cells, however, can move to other parts of the body (metastasis) and this can be due to alterations to their genome causing expression of modified e-cadherins etc. responsible for cell-cell adhesion.
   Treated via inhibitors of HGF/c-met
7. Angiogenesis
   Angiogenesis is tightly controlled via negative factors (endostatin, angiostatin) and positive factors (VEGF [triggered by oncogenes and HIF], PDGF, GFs, FGF). Normally only occurs in embryogenesis, wound healing and during the menstrual cycle.
   Treated via avastin, anti VEGFA antibody [not long term due to impairing wound healing, doesn’t work on established tumours]. Sunitinib and Sorafenib: VEGF receptor inhibitors. Vitaxin is an antiangiogenic humanised Ab against Avb3 integrin expressed on cancer cells. We can also use antineovascular therapy which is based around the use of drug delivery systems such as liposomes to transport cytotoxic drugs to integrins. (also Vasc gene therapy: use of retroviruses to target E selectin adhesion molecule.)
8. Genome instability and mutation
   Acquiring the hallmarks of cancer depends on genomic alterations occurring and one major cause of this is faulty DNA repair pathways.
   Treated via the use of PARP inhibitors, many cancer cell lines utilise overexpression of PARP to repair their damaged DNA (from chemo, radio etc).
9. Evasion of cell death
   Cancer cells often evade apoptotic signals and have turned off their apoptotic pathways.
   Treated via proapoptotic BH3 mimetics which activate BCL-2 proapoptotic protein family.
10. Reprogramming energy metabolism
    Treated via glycolysis inhibitors:
    “In oncology, the Warburg effect is the observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells.”

Question 2

How is growth signal automony treated?

Answer 2

Normal cells require signals from growth factors to stimulate proliferation and growth. Cancer cells are not dependent on this growth factor signalling as mutations have occurred perhaps leading to constitutive activation of the GFRs, resulting in unregulated growth.
Treated via SMI such as Iressa or tarceva for EGFR.

Question 3

How is the evasion of growth inhibitory signals treated?

Answer 3

Normal cells respond to inhibitory signals and are not actively growing, cancer cells however do not respond to these signals.
Treated via cyclin dependent kinase inhibitors such as Palbociclib.

Question 4

How can cancer cells avoiding the immune system be treated?

Answer 4

Immune surveillance is a theory that immune cells can recognise and eliminate cancer cells, therefore the only cancer cells in the body should be those that can evade detection or interfere with the immune response to avoid destruction.
Treated via Ipilimumab, MM, CTLA-4 treatment etc.

Question 5

How can the unlimited proliferative potential of cancer cells be treated?

Answer 5

Normal cells have the Hayflick limit, a finite number of cell replications before they become senescent. This is due to shortening of the chromosomal ends, telomeres, during each round of replication as DNA polymerase cannot copy all the way to the ends of each chromosome. This results in a loss of 100-200 base pairs with each replication cycle. Cancerous cells maintain the length of their telomeres so are able to continue to replicate.
Telomerase inhibitors: Imetelstat a 13-mer oligonucleotide inhibitor of RNA component of human telomerase.

Question 6

How can the inflammation produced by cancer cells be treated?

Answer 6

Virtually all tumours contain immune inflammatory cells, these can release RoS that are mutagenic and also provide growth factors/enzymes that promote angiogenesis and invasion. Metastatic cells capable of travelling to a distant site and invading do this via same mechanisms that immune cells use to get to the sites of infection.
Treated via normal anti-inflammatory drugs?

Question 7

How can the invasion and metastasis of cancer be treated?

Answer 7

Normal cells generally maintain their location in the body and do not migrate to other regions. Cancerous cells, however, can move to other parts of the body (metastasis) and this can be due to alterations to their genome causing expression of modified e-cadherins etc. responsible for cell-cell adhesion.
Treated via inhibitors of HGF/c-met

Question 8

How can angiogenesis be treated?

Answer 8

Angiogenesis is tightly controlled via negative factors (endostatin, angiostatin) and positive factors (VEGF [triggered by oncogenes and HIF], PDGF, GFs, FGF). Normally only occurs in embryogenesis, wound healing and during the menstrual cycle.
Treated via avastin, anti VEGFA antibody [not long term due to impairing wound healing, doesn’t work on established tumours]. Sunitinib and Sorafenib: VEGF receptor inhibitors. Vitaxin is an antiangiogenic humanised Ab against Avb3 integrin expressed on cancer cells. We can also use antineovascular therapy which is based around the use of drug delivery systems such as liposomes to transport cytotoxic drugs to integrins. (also Vasc gene therapy: use of retroviruses to target E selectin adhesion molecule.)

Question 9

How can faulty/overexpression of DNA repair pathways be treated?

Answer 9

Acquiring the hallmarks of cancer depends on genomic alterations occurring and one major cause of this is faulty DNA repair pathways.
Treated via the use of PARP inhibitors, many cancer cell lines utilise overexpression of PARP to repair their damaged DNA (from chemo, radio etc).

Question 10

How can the evasion of death pathways be treated?

Answer 10

Cancer cells often evade apoptotic signals and have turned off their apoptotic pathways.
Treated via proapoptotic BH3 mimetics which activate BCL-2 proapoptotic protein family.

Question 11

How can the reprogramming of energy metabolism be treated?

Answer 11

Treated via glycolysis inhibitors:
“In oncology, the Warburg effect is the observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells.”

Question 12

Using a named example, describe the mutagenic changes that occur resulting in the expression of an oncogene.

Discuss the contributory effects this has to the development of cancer and where relevant discuss a therapeutic approach to the treatment of cancers bearing this mutation.

Answer 12

1. Oncogene: gain of function results in either increased quantity of the gene products or contitutive activity etc.
   1a. Oncogene products are usually present at low levels in cells or not at all.
2. Cell needs >3 mutations to become cancerous (CSCH).
3. Example: EGFR, can become oncogenic by three mechanisms:
   3a: Overexpression of EGFR due to template slipping and point mutation, mutations resulting in consitutive dimerisation of the kinases and chromosomal translocations resulting in high activity promoter rather than low activity.
4. Overexpression of EGFR results in uncontrolled cellular proliferation: EGFR is a tyrosine kinase which is responsible for the signalling of MEK/ERK and PI3K pathways.
5. SOS -> MEK/ERK -> Ras (phosphorylation via GTP) -> Raf -> phosphorylation of Mek -> Erk.
6. Erk will then induce TG such as c-fos and c-jun which cause transcription of AP1 and Cyclin D, STAT and CDKs.
7. Targeted via monoclonal antibodies (Cetuximab: colon cancer, Vectibix).
8. Targeted via SMIs of the cytoplasmic kinase portions (erlotinib, geftinib) and third generation: Osimertinib is used to treat locally advanced or metastatic non-small-cell lung cancer (NSCLC), when the cancer has the specific T790M mutation in the gene coding for epidermal growth factor receptor.
9. Vaccines: CimaVax-EGF, an active vaccine targeting EGF as the major ligand of EGF, uses a different approach, raising antibodies against EGF itself, thereby denying EGFR-dependent cancers of a proliferative stimulus. NSCLC in Cuba.
10. EGFR targeting will not be effective in patients with a downstream mutation such as in Ras, this can be found out via micro-array technology. Ras will be overexpressed and therefore its miRNAs will be overexpressed and therefore will show up on a microarray.

Question 13

Why does overexpression of EGFR lead to uncontrolled cell growth?

Answer 13

1. Oncogene: gain of function results in either increased quantity of the gene products or contitutive activity etc.
   1a. Oncogene products are usually present at low levels in cells or not at all.
2. Cell needs >3 mutations to become cancerous (CSCH).
3. Example: EGFR, can become oncogenic by three mechanisms:
   3a: Overexpression of EGFR due to template slipping and point mutation, mutations resulting in consitutive dimerisation of the kinases and chromosomal translocations resulting in high activity promoter rather than low activity.
4. Overexpression of EGFR results in uncontrolled cellular proliferation: EGFR is a tyrosine kinase which is responsible for the signalling of MEK/ERK and PI3K pathways.
5. SOS -> MEK/ERK -> Ras (phosphorylation via GTP) -> Raf -> phosphorylation of Mek -> Erk.
6. Erk will then induce TG such as c-fos and c-jun which cause transcription of AP1 and Cyclin D, STAT and CDKs.
7. Targeted via monoclonal antibodies (Cetuximab: colon cancer, Vectibix).
8. Targeted via SMIs of the cytoplasmic kinase portions (erlotinib, geftinib) and third generation: Osimertinib is used to treat locally advanced or metastatic non-small-cell lung cancer (NSCLC), when the cancer has the specific T790M mutation in the gene coding for epidermal growth factor receptor.
9. Vaccines: CimaVax-EGF, an active vaccine targeting EGF as the major ligand of EGF, uses a different approach, raising antibodies against EGF itself, thereby denying EGFR-dependent cancers of a proliferative stimulus. NSCLC in Cuba.
10. EGFR targeting will not be effective in patients with a downstream mutation such as in Ras, this can be found out via micro-array technology. Ras will be overexpressed and therefore its miRNAs will be overexpressed and therefore will show up on a microarray.

Question 14

How can EGFR overexpression or constitutive activation be targeted?

Answer 14

1. Oncogene: gain of function results in either increased quantity of the gene products or contitutive activity etc.
   1a. Oncogene products are usually present at low levels in cells or not at all.
2. Cell needs >3 mutations to become cancerous (CSCH).
3. Example: EGFR, can become oncogenic by three mechanisms:
   3a: Overexpression of EGFR due to template slipping and point mutation, mutations resulting in consitutive dimerisation of the kinases and chromosomal translocations resulting in high activity promoter rather than low activity.
4. Overexpression of EGFR results in uncontrolled cellular proliferation: EGFR is a tyrosine kinase which is responsible for the signalling of MEK/ERK and PI3K pathways.
5. SOS -> MEK/ERK -> Ras (phosphorylation via GTP) -> Raf -> phosphorylation of Mek -> Erk.
6. Erk will then induce TG such as c-fos and c-jun which cause transcription of AP1 and Cyclin D, STAT and CDKs.
7. Targeted via monoclonal antibodies (Cetuximab: colon cancer, Vectibix).
8. Targeted via SMIs of the cytoplasmic kinase portions (erlotinib, geftinib) and third generation: Osimertinib is used to treat locally advanced or metastatic non-small-cell lung cancer (NSCLC), when the cancer has the specific T790M mutation in the gene coding for epidermal growth factor receptor.
9. Vaccines: CimaVax-EGF, an active vaccine targeting EGF as the major ligand of EGF, uses a different approach, raising antibodies against EGF itself, thereby denying EGFR-dependent cancers of a proliferative stimulus. NSCLC in Cuba.
10. EGFR targeting will not be effective in patients with a downstream mutation such as in Ras, this can be found out via micro-array technology. Ras will be overexpressed and therefore its miRNAs will be overexpressed and therefore will show up on a microarray.

Question 15

SMIs for EGFR mutations

Answer 15

1. Oncogene: gain of function results in either increased quantity of the gene products or contitutive activity etc.
   1a. Oncogene products are usually present at low levels in cells or not at all.
2. Cell needs >3 mutations to become cancerous (CSCH).
3. Example: EGFR, can become oncogenic by three mechanisms:
   3a: Overexpression of EGFR due to template slipping and point mutation, mutations resulting in consitutive dimerisation of the kinases and chromosomal translocations resulting in high activity promoter rather than low activity.
4. Overexpression of EGFR results in uncontrolled cellular proliferation: EGFR is a tyrosine kinase which is responsible for the signalling of MEK/ERK and PI3K pathways.
5. SOS -> MEK/ERK -> Ras (phosphorylation via GTP) -> Raf -> phosphorylation of Mek -> Erk.
6. Erk will then induce TG such as c-fos and c-jun which cause transcription of AP1 and Cyclin D, STAT and CDKs.
7. Targeted via monoclonal antibodies (Cetuximab: colon cancer, Vectibix).
8. Targeted via SMIs of the cytoplasmic kinase portions (erlotinib, geftinib) and third generation: Osimertinib is used to treat locally advanced or metastatic non-small-cell lung cancer (NSCLC), when the cancer has the specific T790M mutation in the gene coding for epidermal growth factor receptor.
9. Vaccines: CimaVax-EGF, an active vaccine targeting EGF as the major ligand of EGF, uses a different approach, raising antibodies against EGF itself, thereby denying EGFR-dependent cancers of a proliferative stimulus. NSCLC in Cuba.
10. EGFR targeting will not be effective in patients with a downstream mutation such as in Ras, this can be found out via micro-array technology. Ras will be overexpressed and therefore its miRNAs will be overexpressed and therefore will show up on a microarray.

Question 16

Monoclonal antibodies for EGFR mutations

Answer 16

1. Oncogene: gain of function results in either increased quantity of the gene products or contitutive activity etc.
   1a. Oncogene products are usually present at low levels in cells or not at all.
2. Cell needs >3 mutations to become cancerous (CSCH).
3. Example: EGFR, can become oncogenic by three mechanisms:
   3a: Overexpression of EGFR due to template slipping and point mutation, mutations resulting in consitutive dimerisation of the kinases and chromosomal translocations resulting in high activity promoter rather than low activity.
4. Overexpression of EGFR results in uncontrolled cellular proliferation: EGFR is a tyrosine kinase which is responsible for the signalling of MEK/ERK and PI3K pathways.
5. SOS -> MEK/ERK -> Ras (phosphorylation via GTP) -> Raf -> phosphorylation of Mek -> Erk.
6. Erk will then induce TG such as c-fos and c-jun which cause transcription of AP1 and Cyclin D, STAT and CDKs.
7. Targeted via monoclonal antibodies (Cetuximab: colon cancer, Vectibix).
8. Targeted via SMIs of the cytoplasmic kinase portions (erlotinib, geftinib) and third generation: Osimertinib is used to treat locally advanced or metastatic non-small-cell lung cancer (NSCLC), when the cancer has the specific T790M mutation in the gene coding for epidermal growth factor receptor.
9. Vaccines: CimaVax-EGF, an active vaccine targeting EGF as the major ligand of EGF, uses a different approach, raising antibodies against EGF itself, thereby denying EGFR-dependent cancers of a proliferative stimulus. NSCLC in Cuba.
10. EGFR targeting will not be effective in patients with a downstream mutation such as in Ras, this can be found out via micro-array technology. Ras will be overexpressed and therefore its miRNAs will be overexpressed and therefore will show up on a microarray.

Question 17

Vaccines for EGFR mutations

Answer 17

1. Oncogene: gain of function results in either increased quantity of the gene products or contitutive activity etc.
   1a. Oncogene products are usually present at low levels in cells or not at all.
2. Cell needs >3 mutations to become cancerous (CSCH).
3. Example: EGFR, can become oncogenic by three mechanisms:
   3a: Overexpression of EGFR due to template slipping and point mutation, mutations resulting in consitutive dimerisation of the kinases and chromosomal translocations resulting in high activity promoter rather than low activity.
4. Overexpression of EGFR results in uncontrolled cellular proliferation: EGFR is a tyrosine kinase which is responsible for the signalling of MEK/ERK and PI3K pathways.
5. SOS -> MEK/ERK -> Ras (phosphorylation via GTP) -> Raf -> phosphorylation of Mek -> Erk.
6. Erk will then induce TG such as c-fos and c-jun which cause transcription of AP1 and Cyclin D, STAT and CDKs.
7. Targeted via monoclonal antibodies (Cetuximab: colon cancer, Vectibix).
8. Targeted via SMIs of the cytoplasmic kinase portions (erlotinib, geftinib) and third generation: Osimertinib is used to treat locally advanced or metastatic non-small-cell lung cancer (NSCLC), when the cancer has the specific T790M mutation in the gene coding for epidermal growth factor receptor.
9. Vaccines: CimaVax-EGF, an active vaccine targeting EGF as the major ligand of EGF, uses a different approach, raising antibodies against EGF itself, thereby denying EGFR-dependent cancers of a proliferative stimulus. NSCLC in Cuba.
10. EGFR targeting will not be effective in patients with a downstream mutation such as in Ras, this can be found out via micro-array technology. Ras will be overexpressed and therefore its miRNAs will be overexpressed and therefore will show up on a microarray.

Question 18

_________ is used to treat locally advanced or metastatic non-small-cell lung cancer (NSCLC), when the cancer has the specific ______mutation in the gene coding for epidermal growth factor receptor.

Answer 18

Osimertinib is used to treat locally advanced or metastatic non-small-cell lung cancer (NSCLC), when the cancer has the specific T790M mutation in the gene coding for epidermal growth factor receptor.

Question 19

________, is an active vaccine targeting EGF as the major ligand of EGF, uses a different approach, raising antibodies against EGF itself, thereby denying EGFR-dependent cancers of a proliferative stimulus. ______ in Cuba.

Answer 19

CimaVax-EGF, an active vaccine targeting EGF as the major ligand of EGF, uses a different approach, raising antibodies against EGF itself, thereby denying EGFR-dependent cancers of a proliferative stimulus. NSCLC in Cuba.

Question 20

Discuss the impact advances in the area of targeted therapies has had on the survival rates of patients with relevant cancers.

Answer 20

1. DNA-damaging/cytotixic nature of non-targeted chemotherapy results in widespread killing of normal cells.
2. FEC100 causes alopecia, Doxorubicin promotes dose dependent cardiotoxicity: HF.
3. Examples of targeted therapy: Herceptin against HER2 (EGFR) in breast cancers.

We can use immunohistochemistry or FISH analytical techniques to see how much receptor is overexpressed (>3).

4. Herceptin modes of action:
   a) blocks interaction of ligand
   b) antibody fc mediated cytotoxicity
   c) Increased PTEN
   d) downreg Src
   e) cell cycle arrest and apoptosis.

Herceptin only works against Her2+ cells, not other cancer cells.

5. Tamoxifen and aromotase inhibitors such as anastrozole another example in breast cancer cells.
6. Ipilimumab in MM. CTLA-4.
7. Pembrolizumab PD-1 inhibitor of the action of Programmed death receptor and its two ligands, takes breaks off immune system.

Question 21

If cancer is shown to originate from stem cells, discuss one potential molecular target for novel therapeutic approaches to cancer treatment.

Answer 21

1. CSCH:
   Long life span allows accumulation of mutations.
   Differentiation potential allows for hetergenicity of tumours.
   Telomerases = immortal.
   Self-renew and clonal nature.
   Assymetric division.
   Ability to escape niche and metastasise.
   Adapt to a different niche.
2. Stem cell renewal is under the control of Wnt.
   Wnt3a binds to frizzled activating LRP via phosphorylation by GSK3.

This causes recruitment of APC away from the degradation complex (GSK3, APC, AXIN, CKI) which normally breaks down B-catenin. (a TF responsible for self-renewal)

[APC = colon cancer via, FAP?]

3. B-catenin can then bind to TCF, displacing it from the groucho repressor complex.

This causes transcription if TCF dependent genes such as cyclin D: drive cell through G1 phase.

4. It is possible to target Wnt signalling via targeting the downstream elements (need the upstream ones for other valuable processes).
5. Stem cells also involve the HH signalling pathway:
   (three ligands, SHH, IHH, DHH).

Shh binds to the PTCH receptor releasing the inhibition on Smoothened which drives GLI1, GLI2, GLI3 which cause clioma.

6. Vismodegib is the first treatment targeted at HH signalling in basal cell skin carcinoma.
7. Metastasis targeting via MMP inhibitors like Marimastat, c-met inhibitors like Cabosantinib.
8. TELOMERASES:
   IMTELESTAT- 13 mer oligonucleotide for targeting RNA component of human telomerase.
9. Target stem cell niches and induce differentiation to prevent proliferation.

Question 22

What are the advantages and limitations of targeted approaches over standard chemotherapy in the treatment of cancers?

Answer 22

Advantages:
1. Reduced side effects: chemo can lead to reduced life expectancy or cause cessation of chemo treatment due to side effects before cancer is removed. Example: Doxorubicin, an anthracycline based regimen, is known to be cardiotoxic at high doses. Same with FEC100 and its side effects.

2. Reduced cytotoxic effects on surrounding tissues.
3. More likely to treat the cancer: research into ADC, herceptin as a warhead fo the delivery of the toxic emtansine drug: a DM1 inhibitor which will bind to tubulin.
4. Overcoming resistance: Platinum resistance can occur. We can overcome this by targeting the platinum to the cancer cells due to the EPR effect: ProLindac: a platinum drug with large lipophillic side chains: increased tumour retention.

Limitations:
1. SEs still occur etc tumour flare from abiratoreno.

2. Expensive
3. Resistance can still occur: Glivec vs leukamia and GIST (c-kit).

Question 23

Discuss the chromosomal changes that underlie many types of leukaemia and discuss the mechanism of action and effects of therapeutic agents targeting these cancers.

Answer 23

Leukaemia: chromosomal translocations, when part of the chromosome becomes translocated with another on a different part of the chromosome.

BCR-ABL: Break point cluster region is translocated next to the kinase part of the Abl gene on the adjacent chromosome (9,22) causing a fusion tyrosine kinase with constitutive activity.

Bcr-Abl fusion product causes Ras, PI3K and STATs overactivation.

Normal function of c-ABL is to interact with Rb and p53 to regulate gene transcription and this function is lost.

Glivec is a SMI to inhibit the proliferation of chronic myeloid leukeami cells by blocking the activity of Abl tyrosine kinase and also PDGFbR and C-kit (GIST).

TEL-PDGFR occurs in CMML, another example of a chromosomal translocation between 5 and 12. Also inhibited by Glivec.

Glivec resistance has occured: overamplification of BCR-ABL or point mutation changing structure, Dasatinib and nilotinib bind to only the active conformation. Dont work against T1351 tho, VX-680 did, 3rd gen JAK inhibitor.

Question 24

Functional p53 has been shown to be important in the prevention of cancer. Discuss the importance of the molecule in maintaining cellular integrity and discuss approaches for restoring p53 function in cancer cells.

Answer 24

The importance of p53:
‘Guardian of the Genome’ acts via control of the cell cycle: when DNA damage is detected (oncogenic signals, Hypoxia etc) in the G1 phase it will cause cell cycle arrest while DNA repair occurs or induce apoptosis if not possible via upregulation of pro-apoptotic pathways (such as Bad).

p53 regulates the expression of p21 CDKI which is a promoter of cell cycle arrest, MDM2 (inhibitor of p53) and Bax, proapoptosis.

How loss of p53 occurs:
p53 is a tetramer so unlike normal TSGs, it is an example of halpoinsufficiency: one mutated p53 can act as a dominant negative to prevent proper function of other 3 parts.

Li Fraumeni syndrome is where there is a mutated p53 and recurring tumours occur. p53 is mutated in 60% of lung and many liver cancers.

How we can restore p53 function or target p53 deficient tumours:
1. Advexin: delivery of wild-type RNA p53 via retroviruses via adenoviruses for head and neck cancers.

2. Cyclotherapy: normal cells surrounding a tumour can be placed into a transient cell cycle by the activation of p53 via MDM2 inhibitors.

p53 mutant tumour cells will be unaffected and continue to proliferate - we then use a PLK1 inhibitor, or any other mitotic inhibitor to target these still proliferating cancer cells. This can be a way of bypassing the side effects of normal chemo.

There are however other ways that loss of function to p53 can occur other than mutations to the DNA binding region (aa subs) or mutations in coding region leading to incorrect structure etc.

a) mutations that cause overexpression of MDM2 or MDMx.
b) mutations in uprstream regulators that prevent p53 activation.

Question 25

Describe three mutations, which, when occuring in a single cell, could cause it to become malignant.

Answer 25

Activation of a proto-oncogene into an oncogene.
Example of HER2 receptor commonly overexpressed in BC.
Caused by over-expression of receptor, point mutation or constitutive receptor dimerisation. Lung cancer: point mutation.

Mutations to HER2/EGFR cause oncontrolled cell growth via activation of SOS -> Ras via GTP phosphorylation -> kinase cascade -> Raf -> MEK -> ERK -> transcription of cell growth factors.

Loss of tumour suppressor genes:
p53 (MDM2), pRB -> e2f etc.

There could be a chromosomal translocation.
Chromosomal translocation where one part of the chromosome is exchanged with another part of the chromosome. An example of this is in chronic myeloid leukaemia (CML) or chronic myelomonocytic leukaemia (CMML). In CML; the BCR is exchanged with the c-Abl which is a non-receptor tyrosine kinase. The kinase domain of the c-abl is attached to BCR which causes activation of many down stream signalling targets such as PI3K and STAT which causes the cell to divide uncontrollable.