Cancer Genes And Growth FactorsPresentation Transcript
What is cancer?
The phenomenon of cancer can be defined on various levels. On the most basic level, cancer represents the collapse of the cooperation between the ten million cells of human being . This results in the selfish, uncontrolled growth of cells within the body which eventually leads to the death of the organism.
History of Cancer :-
Cancer as described by the ancient Egyptians (3000 BC to 1500 BC):-
The oldest known description of human cancer is found in an Egyptian seven papyri or writing written between 3000-1500 BC . Two of them, known as the "Edwin Smith" and "George Ebers" papyri .
The Edwin Smith Papyrus describes eight cases of tumors or ulcers of the breast.
The document acknowledged that there is no treatment for this condition and recommended cauterization as a palliative measure.
The ancient Egyptian medicine mixed medicine and religion.
Hieroglyphic inscriptions suggest that ancient physicians were able to distinguish between benign and malignant tumors .
Origin of the word carcinoma:-
Hippocrates , the great Greek physician considered the father of medicine , is though to be the first person to clearly recognize difference between benign and malignant tumors .
Hippocrates noticed that blood vessels around a malignant tumor looked like the claws of crab . He named the disease karkinos (the Greek name for crab)
In English, this term translates to carcinos or carcinoma.
Later in the course of history, the cause of cancer was explained as the result of an excess of black bile .
Autopsies , performed by Harvey in the 17th century, gave an insight in to the circulation system . By about the same period Gaspare Aselli discovered the lymphatic system
New theory suggested that abnormalities in the lymph and lymphatic system as the primary cause of cancer .
Discovery of anesthesia in 1844 by Wells allowed surgery to flourish and the classic cancer operations such as radical mastectomy were developed.
The discovery of microscope by Leeuwenhoek in the late 17th century added momentum to the quest for the cause of cancer.
By late19th century , with the development of better microscopes to study cancer tissues.
These studies showed that cancer cells are markedly different in appearance compared to the surrounding normal cells
Rudolf Virchow , who is often called the founder of cellular pathology , provided the scientific basis for the modern pathologic study of cancer and correlated the clinical course of illness with microscopic findings .
This approach led to the development of modern cancer surgery
** Cancer is a genetic disorder:-
Four lines of evidence converged to demonstrate that cancer is a genetic disease:-
1- Chromosomal anomalies in cancer:-
in chronic myelogenous leukemia ( CML ) translocation between chromosome 9 & chromosome 22 forming Philadelphia chromosome
2- Families in which cancer is transmitted as a genetic trait e.g. Li-Fraumeni Syndrome , inherited as autosomal dominant trait .
3- Overlap between carcinogens & mutagens .
4- Individuals with DNA repair deficiency syndrome are at increased risk of cancer e.g Xeroderma pigmentosum , inability to repair DNA damage done by U.V exposure leads to high incidence of cancer skin .
What Are Mutations?
Mutations are changes in the arrangement of the bases that make up a gene .
A mutated (altered or changed) gene may tell the cell to make an abnormal protein, which no longer functions properly
This may not have any effect at all, or it may lead to a disease.
Some diseases like sickle cell anemia are caused by gene mutations
Types of mutations:-
are gene changes (mutations) that come from a parent and therefore exist in all cells of the body, including reproductive cells .
passed from generation to generation
These are also called germline mutations . This type of mutation is a major factor for 5% to 10% of cancers.
2- Acquired mutations:-
occurs when DNA in a cell changes during the person’s life.
caused by environmental influences such as exposure to radiation or toxins.
they are not in the reproductive cells.
They are not in every cell of the body like the hereditary mutations but only in the tumor or cancer cells. called sporadic or somatic mutations.
mutations in our cells happen all the time
our genes can recognize and repair the abnormality
If it can’t be repaired, the cell will actually begin a process called apoptosis that leads to its death.
If the mutation occurs in a gene that helps control how often a cell divides or one that checks for errors in cell division, it may contribute to a person developing cancer .
cancer may also occur because the mutation happens in a gene that normally causes a defective cell to die.
Most scientists today believe that cancer develops in a process that involves more than one mutations
person may inherit a form of one or more genes that makes him or more likely to develop a specific type of cancer.
On top of this, he may acquire other mutations because of exposure to cigarette smoke, excess sunlight, or viruses.
Therefore, some people may be more likely to develop cancer than others simply because they were born with mutations in their genes.
Gene Mutations That Can Lead to Cancer:-
The 2 main types of genes that are now recognized as playing a role in cancer are oncogenes and tumor suppressor genes .
** What Are Oncogenes?
- Oncogenes are mutated forms of genes that cause normal cells to grow out of control and become cancer cells.
- They are mutations of certain normal genes of the cell called proto-oncogenes .
Proto-oncogenes are the genes that normally control how a cell divides and the degree to which it differentiates
When a proto-oncogene mutates into an oncogene , it becomes permanently " turned on " or activated
When this occurs, the cell divides too quickly, which can lead to cancer
think of a cell as a car :- A proto-oncogene normally functions in a way that is similar to a gas pedal An oncogene could be compared to a gas pedal that is stuck down, -> cell to divide out of control
Pathway of normal cell growth:-
starts with growth factor , which locks onto a growth factor receptor .
The signal from the receptor is sent through a signal transducer .
A transcription factor is produced, which causes the cell to begin dividing.
More than 100 oncogenes are now recognized Scientists have divided oncogenes into the 5 different classes
These oncogenes produce factors that stimulate cells to grow.
The best known of these is called sis
It leads to the overproduction of a protein called platelet-derived growth factor ( PDGF ) , which stimulates cells to grow.
Vascular endothelial growth factor (VEGF) & Fibroblast growth factor ( FGF ) are other growth factors.
2- Growth factor receptors
Normally turned " on " or " off " by growth factors. When they are " on ," they stimulate the cell to grow. They may become always in the on state in 2 cases:-
a- Certain mutations in the genes that produce them.
b- gene amplification :
This means that instead of the usual 2 copies of the gene, there may be several extras, resulting in too many growth factor receptor molecules.
The best-known examples of growth factor receptor gene amplification are erb B and erb B-2 .
3- Signal transducers
These are the intermediate pathways between the growth factor receptor and the cell nucleus where the signal is received.
Like growth factor receptors, these can be turned on or off. When they are abnormal in cancer cells, they are turned on
Two well-known signal transducers are abl and ras . Abl is activated in chronic myelocytic leukemia and is the target of the most successful drug for this disease, imatinib or Gleevec . Abnormalities of ras are found in many cancers.
4- Transcription factors
These are the final molecules in the chain that tell the cell to divide.
These molecules act on the DNA and control which genes are active in producing RNA and protein .
The best known of these is called myc . In lung cancer, leukemia, lymphoma , and a number of other cancer types, myc is often overly activated and stimulates cell division.
5- Programmed cell death regulators:
These molecules prevent a cell from committing suicide when it becomes abnormal
When these genes are overactive , they prevent the cell from going through the suicide process. This leads to an overgrowth of abnormal cells , which can then become cancerous .
The most well described one is called bcl-2 . It is often activated in lymphoma cells .
Tumor suppressor genes
What Are Tumor Suppressor Genes?
are normal genes that slow down cell division, repair DNA mistakes, and tell cells when to die (apoptosis or programmed cell death) .
When tumor suppressor genes don’t work properly, cells can grow out of control, which can lead to cancer.
About 30 tumor suppressor genes have been identified, including p53, BRCA1, BRCA2, APC, and RB1 .
A tumor suppressor gene is like the brake pedal on a car
An important difference between oncogenes and tumor suppressor genes is that oncogenes result from the activation ( turning on ) of proto-oncogenes , but tumor suppressor genes cause cancer when they are inactivated ( turned off ).
Another major difference is that while the overwhelming majority of oncogenes develop from mutations in normal genes (proto-oncogenes) during the life of the individual ( acquired mutations ), abnormalities of tumor suppressor genes can be inherited as well as acquired .
Types of Tumor Suppressor Genes
1- Genes that control cell division :-
The RB1 (retinoblastoma ) gene is an example of such a gene. Abnormalities of the RB1 gene can lead to (retinoblastoma ) in infants
there are always 2 copies of each gene. But the inherited RB1 mutation only affects one of the gene pairs
during the infant’s development, a random mutation can occur in the normal copy of the RB1 gene. Scientists call this process loss of heterozygosity (LOH)
2- Genes that repair DNA
when a cell prepares to divide into 2 new cells, it must duplicate its DNA. copying errors sometimes occur but cells have DNA repair genes , which make proteins that proofread DNA
The genes responsible for HNPCC (hereditary nonpolyposis colon cancer) are examples of DNA repair gene defects. When these genes do not repair the errors in DNA, HNPCC can result. HNPCC accounts for up to 5% of all colon cancers and some endometrial cancers.
3- Cell "suicide" genes :-
If there is too much damage to a cell’s DNA couldn't be repaired by DNA repair system
Cell is directed to be destroyed what is called ( programmed cell death or apoptosi s )
the p53 tumor suppressor gene is responsible for this apoptosi s
If the p53 gene is not working properly, cells with DNA damage that has not been repaired continue to grow and can eventually become cancerous
Abnormalities of the p53 gene are sometimes inherited, such as in the Li-Fraumeni syndrome (LFS) .
People with LFS have a higher risk for developing a number of cancers, including soft-tissue and bone sarcomas, brain tumors, breast cancer, adrenal gland cancer, and leukemia.
Many sporadic ( not inherited ) cancers such as lung cancers, colon cancers, breast cancers as well as others often have mutated p53 genes within the tumor.
Inherited Abnormalities of Tumor Suppressor Genes
In addition to mutations in p53, RB1 , and the genes involved in HNPCC, several other mutations in tumor suppressor genes can be inherited.
A defective APC gene causes familial polyposis , a condition in which people develop hundreds or thousands of colon polyps
Abnormalities of the BRCA genes account for 5% to 10% of breast cancers .
Non-inherited mutations of tumor suppressor genes
Mutations of tumor suppressor genes have been found in many cancers.
abnormalities of the p53 gene have been found in over 50% of human cancers.
Acquired mutations of the p53 gene appear to be involved in a wide range of cancers, including lung, colorectal, and breast cancer
acquired changes in many other tumor suppressor genes also contribute to the development of sporadic (not inherited) cancers.
Certain types of kidney cancers VHL Kidney cancer Small numbers of colon cancers, melanomas, neuroblastoma NF1, NF2 Nerve tumors, including brain Wilms tumors WTI Wilms Tumor Only rare ovarian cancers BRCA1, BRCA2 Breast and/or ovarian Colorectal, gastric, endometrial cancers MLH1, MSH2, or MSH6 Colorectal cancer (without polyposis) Most colorectal cancers APC Colorectal cancer (due to familial polyposis) Many different cancers INK4a Melanoma Many different cancers P53 Li-Fraumeni Syndrome (sarcomas, brain tumors, leukemia) Many different cancers RBI Retinoblastoma Other non-inherited cancers seen with this gene Abnormal gene Inherited cancer
How Can Oncogenes and Tumor Suppressor Genes Be Used to Help Prevent Cancer?
Several mutations in oncogenes and tumor suppressor genes useful in helping decide which people are at higher risk for developing cancers .
Genetic testing can be used to look for such mutations.
The testing is often expensive
Finding a genetic mutation can have a significant impact on a person’s life , as well as the lives of other family members .
How Can Oncogenes and Tumor Suppressor Genes Be Used to Help Guide Treatment of Cancer?
specific gene changes help predict either patients have a better or worse prognosis or which patients are likely to benefit from certain treatments.
women with breast cancer that contains the HER2/neu (erbB-2) mutation tend to fare worse than women without the mutation .
Some tests for certain gene mutations are very sensitive in finding cancer that persists or returns after treatment. This type of test identify patients at risk of relapse , who might benefit from additional chemotherapy .
Colorectal cancers APC Colorectal cancers MLH1, MSH2 Brain tumors, skin cancers, lung cancer, head and neck cancers, others p53 Burkitt lymphoma, others C-myc Ewing tumor EWS Neuroblastoma N-myc Breast cancer, ovarian cancer, others HER2/neu (erbB-2) B-cell lymphoma bcl-2 Chronic myelogenous leukemia bcr-abl Breast and ovarian cancer BRCA1, BRCA2 Related Cancers Oncogene/Tumor Suppressor Gene
How Can Oncogenes and Tumor Suppressor Genes Be Used to Treat Cancer?
humanized monoclonal antibodies that acts on the HER2
eu (erbB2 ) receptors.
as inhibition of cell growth by trastuzumab is limited to HER2-positive cancers , testing tumors for HER2 expression became integral to selecting patients
HER2 testing of breast cancer patients becomes a routine
Mechanism of action:-
How it is given ?
Herceptin is given by a drip (infusion )
The first dose is given slowly, usually over about an hour and a half . After this, doses normally take about 30 minutes . The drug may be given once a week or once every three weeks .
If Herceptin is given together with Taxol or Taxotere, they are given in the normal way, which is usually every three weeks.
Herceptin is used mainly to treat women with breast cancer
It may be used in the early stages to increase the chances of a cure
It also used in metastatic breast cancer
In most cases it is used in combination with chemotherapeutic agents paclitaxel or docetaxel
1- Effects on the heart:
Herceptin may lead to cardiomyopathy or congestive heart failure sprcially if taken with carboplatin , it is recommended that Herceptin is not given to people with a history of heart disease or high blood pressure.
2- Flu-like symptoms
This includes a high temperature ( fever ) and chills, shortly after the drug is given.
3- Tumour pain:
Some people may experience mild pain in parts of the body to which the breast cancer has spread.
6- Allergic reactions :
This is a rare side effect of Herceptin. Signs of this include skin rashes and itching , wheezing, difficulty breathing, and breathlessness.
a monoclonal antibody , In the UK it is currently used to treat cancer of the colon and rectum specially advanced or metastatic cancer.
cetuximab is given in combination with the drug irintocan . Cetuximab is also used with radiotherapy to treat locally advanced head and neck cancer.
Cetuximab is also being used in research trial to treat other types of cancer, including non-small cell lung cancer (NSCLC ) and breast cancer.
Mechanism of action:
Cetuximab attaches to the EGFRs and prevents the receptors from being activated.
This stops the cells from dividing. therefore stop the cancer cells from growing.
Cetuximab also make the cancer cells more sensitive to chemotherapy and radiotherapy
Tests may be done to find the level of EGFR in the tumour cells before cetuximab is given.
Dosage and administration :
Cetuximab is a colourless liquid
Cetuximab is given by a drip into the vein ( intravenously ) through cannula. The first dose is given slowly , usually over two hours.
After this, doses are given weekly and this normally takes about an hour . The first dose is usually larger than the weekly maintenance treatments.
Possible side effects :-
1- Allergic reactions skin rashes and itching, a feeling of swelling in the tongue or throat antihistamines can be given
2- nausea and less commonly vomiting
3- Diarrhea This can usually be controlled with medicine
4- Fever and chills
5- dyspnea Some people may become breathless
also called 2C4 , formerly known as Omnitarg is a monoclonal antibody . The first of its class in a line of agents called " HER dimerization inhibitors ".
By binding to HER2, it inhibits the dimerization of HER2 with other HER receptors, which is hypothesized to result in slowed tumor growth .
Early clinical trials of pertuzumab in prostate, breast, and ovarian cancers have been met with limited success .
It is used in treating chronic myelogenous leukemia ( CML ), gastrointestinal stromal tumors ( GISTs ) and a number of other malignancies.
It is the first member of a new class of agents that act by inhibiting particular tyrosine kinase enzyme , instead of non-specifically inhibiting rapidly dividing cells.
Mechanism of action:
Imatinib is specific for the TK domain in abl (the Abelson proto-oncogene), and PDGF-R (platelet-derived growth factor receptor).
In chronic myelogenous leukemia , the philadelphia chromosome leads to a fusion protein of abl with bcr ( breakpoint cluster region ), termed bcr-abl . As this is now a continuously active tyrosine kinasae, imatinib is used to decrease bcr-abl activity.
1- Imatinib is used in chronic myelogenous leukemia
2- gastrointestinal stromal tumors (GISTs)
3- 3- number of other malignancies as certain brain tumors such as high grade gliomas including recurrent glioblastoma
4- Recent mouse animal studies at Emory Univerty in Atlanta have suggested that imatinib may be useful in treating Small pox
edema , nausea , rash and musculoskeletal pain are common but mild .
Severe congestive heart failure is an uncommon but recognised side effect of imatinib and mice treated with large doses of imatinib show toxic damage to their myocardium.
Gefitinib is used alone (monotherapy ) for the treatment of patients with a certain type of lung cancer ( non-small cell lung cancer or NSCLC) that has not responded to chemotherapy.
mechanism of action:
When the epidermal growth factor (EGF) attaches to the receptor, it causes an enzyme called tyrosine kinase (TK) to trigger chemical processes inside the cell to make it grow and divide.
Iressa attaches itself to the EGF receptor on the cell and prevents the receptor from being activated. This stops the cells from dividing.
Iressa is taken as a tablet once a day .
The tablet should be taken at roughly the same time each day.
Side effects :
1- Diarrhea 2- Acne-like rash
3- Loss of appetite 4-nausea & vomiting
5-Change in blood pressure Iressa may make your blood pressure rise,
6-Breathing problems A rare side effect of gefitinib is inflammation of the lungs
Gene Therapy for Cancer
Cancer gene therapy:-
four separate pathways have developed, namely :-
2- introduction of tumor suppressor genes induction of apoptosis
3- enzyme prodrug therapy
4- inhibition of tumors angiogenesis.
I- immunotherapy :-
tumors do express antigen that can be recognized by the immune system:-
A- unique antigen expressed only by individual types of tumor (e.g bcrabl in CML )
B- shared tumor specific antigens (e.g CEA )
C- tissue specific antigen expressed by both the tumor & the healthy tissue ( e.g tyrosinase in melanoma)
D- viral antigens in known viral associated tumors ( e.g human papilloma virus E6 protein in cervical cancer )
tumor cells are able to evade the immune system through several mechanisms:-
1- Secretion of inhibitory factors such as transforming growth factor β (TGFβ)
2- down regulation of MHC class I & II
3- disrupted antigen-presentation pathway
4- the ability to induce T-cell apoptosis
immunotherapy the induction of cytokine Genetic modification of lymphocytes Tumor antigen vaccines
A) Induction of cytokine or co-stimulatory molecule expression :-
The frequently employed cytokines include interleukin2 ( IL-2 ), interleukin 12 ( IL-12 ) & granulocyte-macrophage colony-stimulating factor (GM-CSF ).
Many clinical protocols involve an ex vivo approach
excision of a single tumor nodule, viral transduction in vitro, followed by selection for the transgene, irradiation of the modified cells & finally re-implantation.
The hope is that a generalized antitumour immune response will be elicited.
In theory, the cytokines could be administered systemically , removing the need for viral modification. However, the level of systemic cytokine required to induce an antitumour response inevitably produces systemic toxicity .
The ex vivo approach permit the local production of high concentration cytokine within the microenvironment of the tumor, without significant systemic level being produced .
1- interleukin 2 ( IL-2)
secreted mainly by activated T-helper ( Th) cells
stimulates the proliferation & activation of a wide variety of cells including cytotoxic T lymphocytes ( CTLs ), natural killer ( NK ) cells & lymphokine-activated killer ( LAK ) cells
induction of IL-2 expression by a variety of tumor cells leads to tumor rejection mediated by CLTs & NK cells .
2- interleukin 12( IL-12)
expressed mainly be activated macrophages
its main function is the promotion of a Th1 - like response via the secretion of interferon γ ( IFNγ ) , IL-2 , and tumor necrosis factor α ( TNFα ) this is in turn promotes cell-mediated immunity .
induction of IL-12 secretion can result in regression of a wide variety of tumors with the development of protective immunity against re-challenge.
The main function of GM-CSF is to cause maturation of Antigen-presenting cells (APCs).
APCs detect antigens released by tumor cells processing them & presenting them in association with class I & class II MHC to T-cells in local lymph nodes there by eliminating the need for the tumor to present antigens directly by itself .
B) Genetic modification of lymphocytes:-
The strategy here is to modify the lymphocytes, rather than the tumor cells
Currently extremely popular is the modification of denderitic cells (DCs)
DCs cells are bone marrow-derived cells function as extremely potent APCs and capable of activating T-cells.
Intratumoural injection of DCs modified with an adenovirus encoding CD40 ligand led to significant tumor regression in a murine model
II- Introduction of tumor suppressor genes & induction of apoptosis:-
multiple genes are involved in carcinogenesis, but mutations of the p53 gene are the most frequent abnormality identified in human tumors
Preclinical studies both in vitro and in vivo have shown that restoring p53 function can induce apoptosis in cancer cells.
High levels of p53 expression and DNA-damaging agents like cisplatin and ionizing radiation work synergistically to induce apoptosis in cancer cells.
Phase I clinical trials now show that p53 gene replacement therapy using both retroviral and adenoviral vectors is feasible and safe.
In addition, p53 gene replacement therapy induces tumor regression in patients with advanced non-small-cell lung cancer (NSCLC ) and in those with recurrent head and neck cancer.
III- Virus-directed enzymeprodrug therapy:-
The principle is to achieve tumor cell–selective activation of prodrugs and to produce tumor-specific cytotoxicity
Potentially, one of several "vectors " (antibodies, viruses, or neural progenitor cells) can be used to deliver a prodrug-activating enzyme selectively to tumor foci in vivo
the elevated level of enzyme at the tumor foci produce high local concentrations of active drug, increasing the antitumor effect and decreasing the toxicity of the systemically given prodrug.
The search for more efficient prodrug-activating enzymes/prodrugs for the treatment of cancer has led to investigations of a variety of combinations, including :