Cancer and Stratified Medicine:
Lecture 1: What is Cancer?
Cancer results from the uncontrolled division of cells
A single cell was the most life on earth for a long time, then there was a multi-cellular
organism. Eventually, there was the presence of gem cells (sperm and egg). These germ cells
came together to form a soma. The Soma evolved in different ways, eventually becoming
homosapiens. The only role of the same is to deliver the germ cell, but this is a risk because
as soon as multicellular cells are present cancer can occur. Cancer starts from one cells and
undergoes uncontrolled replication due to dysfunction of cell cycle checkpoints.
Cancer can destroy the germline - how can it be controlled?
We can develop an adult that does not have dividing cells.
Problems - cannot repair tissue.
However, we have cells that can divide and repair.
Current lifetime risk of cancer is 45% in men and 39% in women.
Why is cancer so uncommon?
The complexity of the metazoan (multicellular organ)
• We have 1014 cells
• Estimated to undergo 1024 cell divisions in a lifetime
• May be up to 20,000 breaks in DNA in each cell division
Your body has made:
• 300 million new red blood cells
• 12,000 million new gut cells
• 40,000 new skin cells
The evolution of protection against cancer:
• Selection for tumour suppressor genes so a cell stops going under unprotected
proliferation.
• Multiple systems for DNA repair - to stop the development of cancer.
• Immune control of transformed cells. There is evidence that immune system undergoing
constant surveillance.
Tumour suppressor genes:
Main Tumour Suppressor Genes = p53. It is mainly inactivated in most cancer.
• Induces apoptosis or senescence - cell death or put to sleep so they have control
proliferating cells. Eventually the senescent cells are killed.
• Probably accelerate ageing if overexpression of p53 is present.
• May be selected to prevent cancer before reproductive age then reduce effect thereafter
As the number of cells increases, so does the number of tumour suppressor genes.
Most commonly diagnosed cancers in the world:
- Lung
- Breast
- CRC
- Stomach
, - Prostate
- Liver
-
Most common causes of death from cancer:
- Lung
- Stomach
- Liver
- CRC
- Breast
- Esophagus
Most common causes of cancer deaths in the UK – Male:
- Lung
- Prostate
- CRC
- Oesphagus
Most common causes of cancer deaths in the UK – Female:
- Lung
- Breast
- CRC
- Ovary
- Pancreas
Cancer is a disease of aging
There are acquisitions of mutations as the individual gets older due to environmental stress.
Overtime they add up, there are many different mutations that accumulate together.
Changes in the types of cancers present are due to the presence of different environments.
How does cancer develop?
Cancer is caused when there is damage to this genetic material. Mutations happen to the
DNA and that can be hereditary.
Emerging Hallmarks of cancer cells:
- Deregulation of cellular energetics
- Avoiding immune destruction
Enabling Characteristics of cancer cells:
- Genome instability and mutation
- Tumour promoting inflammation
There is a combination of both genetic susceptibility and environmental factors that
determines whether someone will develop cancer.
The Germline:
• We all carry individual risk of developing of developing cancer
• There are several genetic disorders that predispose to cancer - mainly affect DNA
repair
• Fanconi anaemia
• Ataxia telangiectasia
,The Environment:
• At least 40% of common epithelial tumours are preventable by changes in lifestyle
such as diet and activity
• Smoking decreases life expectancy by 7.5 years.
Smoking rates are dropping and alongside so is the prevalence of lung cancer
• Obesity - a new epidemic
• Body Mass Index (Kg / m2)
• 22-25 - Ok
• 25-30 - Overweight
• 30+ - Obese
Increasing weight predisposes to many types of cancers
• Infection – causes 20% of all cancers. It is mainly found in less developed countries
(EBV and HPV)
30% of EBV cases cause Hodgkin Lymphoma and glandular fever. They spread down the
lymph node. EBV lymphoma is not curable.
Development of Cancer Therapy:
1. Acute lymphoblastic Leukaemia:
most common in children
The discovery of chemotherapy agents:
- Alkylating agents were identified through poisoning effect of mustard gas. Mustard
gas killed of haematopoiesis. Alkylating agents treats leukaemia.
- Folate antagonists from treatment of anaemia - during pregnancy.
Development of chemotherapy:
1946
- Folic acid was good for anaemia and so was given to children with leukaemia but
caused an acceleration of symptoms because it helped the cancerous cells to divide.
- Folic acid antagonists were developed and used as chemotherapy
- 80-90% of children were cured
2. Breast Cancer
• Risk factors for development of breast cancer
- Alcohol - 5000 cases /year
- HRT - 1000 cases /year
- Obesity - 4000 cases/year
Pregnancy can protect from breast cancer
“Occupational disease of nuns” - Nuns do not have children and so that there was an
increased risk in these.
- Each pregnancy reduces risk by 9% but the mechanism is not clear
Mortality rates from breast cancer is falling. This is because there is improvement been seen
in the treatment of breast cancer (Combination of different treatments)
- Surgery
, o Less Extensive
- Radiotherapy
o Addition to lumpectomy
- Adjuvant Chemotherapy
o 10% reduction in mortality with CMF (3 combination treatment of
cyclophosphamide, methotrexate, 5 fluorouracil)
o 10% more reduction in mortality with epirubicin
- Hormonal Therapies
o Best Prognostic factor is ER+ due to tamoxifen
3. Chronic Myeloid Leukaemia
It is a rare cancer. W want to develop specific treatment to kill specific cells and we
can do that with this cancer.
CML is characterized by the Philadelphia Chromosome, which has a translocation between
chromosome 9 and 22. When two of the genes come together, one of the proteins are highly
activated. BCR and ABL genes fused and causes cancer since it is a tyrosine kinase that
causes cancer.
We can design a drug that blocks the action of the fused protein e.g. STI571. Survival in
response to this is very good.
Imatinib as a cure for CML: Imatinib is a kinase inhibitor.
CML is a chronic disease and therapy resembles the early treatments of HIV. We need a
combination therapy to prevent the cancer mutating.
Cancer immunotherapy:
- Role of the immune system in the control of cancer has been controversial for many
decades
- Major advances in the last 5 years
o Co-stimulatory blockade
o Chimeric antigen receptors
Our immune system is fighting cancer.
T Cell Co-Stimulation:
T cell recognise antigens of a virus or bacteria on the MHC Class I/II using TCR. It can also
recognise peptides on cancer cells. However, cancer cells interfere with the T cell recognition
thorough using PD1 and CTLA-4 which give inhibitory signals, so the T cells are not primed
against the cancer cell.
Blockade of T cell Co-stimulation:
Blocking CTAL-4 and PD1 means that the inhibitory signals are not present, and the T cells
can be primed towards the cancer cells and kill it.
Challenges in Cancer Treatment:
Pancreatic Cancer – no improvement in pancreatic cancer surivival in the last 5 years
Future prospects in the management of cancer:
Prevention
Lecture 1: What is Cancer?
Cancer results from the uncontrolled division of cells
A single cell was the most life on earth for a long time, then there was a multi-cellular
organism. Eventually, there was the presence of gem cells (sperm and egg). These germ cells
came together to form a soma. The Soma evolved in different ways, eventually becoming
homosapiens. The only role of the same is to deliver the germ cell, but this is a risk because
as soon as multicellular cells are present cancer can occur. Cancer starts from one cells and
undergoes uncontrolled replication due to dysfunction of cell cycle checkpoints.
Cancer can destroy the germline - how can it be controlled?
We can develop an adult that does not have dividing cells.
Problems - cannot repair tissue.
However, we have cells that can divide and repair.
Current lifetime risk of cancer is 45% in men and 39% in women.
Why is cancer so uncommon?
The complexity of the metazoan (multicellular organ)
• We have 1014 cells
• Estimated to undergo 1024 cell divisions in a lifetime
• May be up to 20,000 breaks in DNA in each cell division
Your body has made:
• 300 million new red blood cells
• 12,000 million new gut cells
• 40,000 new skin cells
The evolution of protection against cancer:
• Selection for tumour suppressor genes so a cell stops going under unprotected
proliferation.
• Multiple systems for DNA repair - to stop the development of cancer.
• Immune control of transformed cells. There is evidence that immune system undergoing
constant surveillance.
Tumour suppressor genes:
Main Tumour Suppressor Genes = p53. It is mainly inactivated in most cancer.
• Induces apoptosis or senescence - cell death or put to sleep so they have control
proliferating cells. Eventually the senescent cells are killed.
• Probably accelerate ageing if overexpression of p53 is present.
• May be selected to prevent cancer before reproductive age then reduce effect thereafter
As the number of cells increases, so does the number of tumour suppressor genes.
Most commonly diagnosed cancers in the world:
- Lung
- Breast
- CRC
- Stomach
, - Prostate
- Liver
-
Most common causes of death from cancer:
- Lung
- Stomach
- Liver
- CRC
- Breast
- Esophagus
Most common causes of cancer deaths in the UK – Male:
- Lung
- Prostate
- CRC
- Oesphagus
Most common causes of cancer deaths in the UK – Female:
- Lung
- Breast
- CRC
- Ovary
- Pancreas
Cancer is a disease of aging
There are acquisitions of mutations as the individual gets older due to environmental stress.
Overtime they add up, there are many different mutations that accumulate together.
Changes in the types of cancers present are due to the presence of different environments.
How does cancer develop?
Cancer is caused when there is damage to this genetic material. Mutations happen to the
DNA and that can be hereditary.
Emerging Hallmarks of cancer cells:
- Deregulation of cellular energetics
- Avoiding immune destruction
Enabling Characteristics of cancer cells:
- Genome instability and mutation
- Tumour promoting inflammation
There is a combination of both genetic susceptibility and environmental factors that
determines whether someone will develop cancer.
The Germline:
• We all carry individual risk of developing of developing cancer
• There are several genetic disorders that predispose to cancer - mainly affect DNA
repair
• Fanconi anaemia
• Ataxia telangiectasia
,The Environment:
• At least 40% of common epithelial tumours are preventable by changes in lifestyle
such as diet and activity
• Smoking decreases life expectancy by 7.5 years.
Smoking rates are dropping and alongside so is the prevalence of lung cancer
• Obesity - a new epidemic
• Body Mass Index (Kg / m2)
• 22-25 - Ok
• 25-30 - Overweight
• 30+ - Obese
Increasing weight predisposes to many types of cancers
• Infection – causes 20% of all cancers. It is mainly found in less developed countries
(EBV and HPV)
30% of EBV cases cause Hodgkin Lymphoma and glandular fever. They spread down the
lymph node. EBV lymphoma is not curable.
Development of Cancer Therapy:
1. Acute lymphoblastic Leukaemia:
most common in children
The discovery of chemotherapy agents:
- Alkylating agents were identified through poisoning effect of mustard gas. Mustard
gas killed of haematopoiesis. Alkylating agents treats leukaemia.
- Folate antagonists from treatment of anaemia - during pregnancy.
Development of chemotherapy:
1946
- Folic acid was good for anaemia and so was given to children with leukaemia but
caused an acceleration of symptoms because it helped the cancerous cells to divide.
- Folic acid antagonists were developed and used as chemotherapy
- 80-90% of children were cured
2. Breast Cancer
• Risk factors for development of breast cancer
- Alcohol - 5000 cases /year
- HRT - 1000 cases /year
- Obesity - 4000 cases/year
Pregnancy can protect from breast cancer
“Occupational disease of nuns” - Nuns do not have children and so that there was an
increased risk in these.
- Each pregnancy reduces risk by 9% but the mechanism is not clear
Mortality rates from breast cancer is falling. This is because there is improvement been seen
in the treatment of breast cancer (Combination of different treatments)
- Surgery
, o Less Extensive
- Radiotherapy
o Addition to lumpectomy
- Adjuvant Chemotherapy
o 10% reduction in mortality with CMF (3 combination treatment of
cyclophosphamide, methotrexate, 5 fluorouracil)
o 10% more reduction in mortality with epirubicin
- Hormonal Therapies
o Best Prognostic factor is ER+ due to tamoxifen
3. Chronic Myeloid Leukaemia
It is a rare cancer. W want to develop specific treatment to kill specific cells and we
can do that with this cancer.
CML is characterized by the Philadelphia Chromosome, which has a translocation between
chromosome 9 and 22. When two of the genes come together, one of the proteins are highly
activated. BCR and ABL genes fused and causes cancer since it is a tyrosine kinase that
causes cancer.
We can design a drug that blocks the action of the fused protein e.g. STI571. Survival in
response to this is very good.
Imatinib as a cure for CML: Imatinib is a kinase inhibitor.
CML is a chronic disease and therapy resembles the early treatments of HIV. We need a
combination therapy to prevent the cancer mutating.
Cancer immunotherapy:
- Role of the immune system in the control of cancer has been controversial for many
decades
- Major advances in the last 5 years
o Co-stimulatory blockade
o Chimeric antigen receptors
Our immune system is fighting cancer.
T Cell Co-Stimulation:
T cell recognise antigens of a virus or bacteria on the MHC Class I/II using TCR. It can also
recognise peptides on cancer cells. However, cancer cells interfere with the T cell recognition
thorough using PD1 and CTLA-4 which give inhibitory signals, so the T cells are not primed
against the cancer cell.
Blockade of T cell Co-stimulation:
Blocking CTAL-4 and PD1 means that the inhibitory signals are not present, and the T cells
can be primed towards the cancer cells and kill it.
Challenges in Cancer Treatment:
Pancreatic Cancer – no improvement in pancreatic cancer surivival in the last 5 years
Future prospects in the management of cancer:
Prevention
