Cancer 3 Flashcards
3 components of fighting against cancer
- Prevention ⇒ such as avoiding carcinogens
- Early diagnosis ⇒ the earlier it is found the easier it is to treat
- Treatment
why are mutations bad but still important?
important for our cells and evolutionary drive
how much of cancer is attributed to modifiable risk?
40%
- cigarette smoking
- excess body weight
- Alcohol
- UV
- inactivity
- etc.
how do cell errors eventually cause cancer?
errors in DNA replication accumulate each time a cell divides
- Eventually enough of these mutations occur in checkpoints or repair mechanisms that cells become cancerous
there is a positive correlation between step cell divisions and what?
incidence of cancer in a certain cell type
- a significant component of cancer risk is inherent and due to bad luck through these accumulated mutations
what are highly environmental cancers?
Mesothelioma (asbestos exposure), lung cancer (smoking), cervical cancer (HPV)
Medium environmental ⇒ risk is increased by environmental factors but also driven by intrinsic risk
Colorectal carcinoma, breast cancer, pancreatic cancer
Low environmental impact ⇒ mostly intrinsic in nature
Prostate cancer, brain cancer, non hodgkin’s lymphoma
Least environmental impact ⇒ hereditary or genetic in nature
Retinoblastoma, pediatric neuroblastoma, acute lymphoblastic leukemia
what is a 3rd component of cancer?
hereditary mutations can increase your risk of developing cancer
Li Fraumeni syndrome
inherited mutations in P53 leading to increased risk of all cancers
BRCa2 deficiency
mutations in a tumor suppressor gene are increased risk of breast and ovarian cancer
how does heterozygosity work for tumor suppressor genes?
if the remaining ones become mutated will lead to cancer
- Should be reviewed by genetic counselors to figure out variants in genomes
what environmental effects affect cancer? (3)
- Carcinogen activation
- Ionizing radiation
- UV radiation
what is carcinogen activation; most potent carcinogens?
a few carcinogens act directly on DNA and the most potent carcinogens are initially chemically inert and only becoming damaging after metabolic processes in the liver
Cytochrome P-450 oxidases
normally convert toxins into harmless molecules but certain chemicals can be converted to highly mutagenic products
how do aflatoxin and cytochrome P-450 interact?
aflatoxin derived from mold that grows on grains and peanuts when stored under humid tropical conditions and cytochrome P-450 can catalyze aflatoxin B1 to aflatoxin 2-3 epoxide to become a carcinogen in DNA
ionizing radiation and components (5)
x-rays and other scans can directly affect DNA and can generate reactive oxygen species
- Cross linking
- Breaks
- Base modifications
- May directly affect DNA
- Can drive oncogenic processes ⇒ migration, invasion, angiogenesis
UV radiation and components (3)
induces formation of pyrimidine (cytosine and thymine) dimers so they link together on the same strand and is a significant risk factor for developing melanoma
- Causes crosslinking between bases and distorts the DNA double helix
- Interferes with polymerases generating errors in transcription and replication
- Primarily resolved through nucleotide excision repair
how is inflammation involved in cancer?
inflammation is pro-oncogenic
what % of cancer is oncoviruses responsible for; what are examples?
20%
1. direct
- Epstein barr virus
- Human papillomavirus
- Human T-lymphotropic virus
2. indirectly
- Hepatitis B and C
Human papillomavirus (HPV)
primary cause of uterine cervix carcinoma and agent of genital warts
- Infection usually lasts approximately 2 years
- Highly effective vaccine available => referred to as a cancer vaccine
how does HPV work?
infects the basal layers of cervical epithelial cells
- Maintained in latent phase as extra chromosomal plastids ⇒ stays with the DNA
- Produce infectious progeny in the outer layer of epithelial cells
- Express proteins that interfere with cell cycle arrest of the host cell in outer layer ⇒ excess proliferation of cells
- This produces benign warts that allow release of viral progeny and spread of the disease
what does the presence of the extra chromosomal DNA lead to in HPV?
integration into the host genome via recombination ⇒ break in host genome and homologous recombination occurs
- This can lead to uncontrolled production of viral proteins in the basal layer cells ⇒ mitotic cells
- These genes act as oncogenes ⇒ directly leading to oncogenesis and proliferation
what is integration in the basal layer a problem?
it will express proteins responsible for cell growth and result in invasion from the epithelial layer leading to cervical cancer
Adult T-cell lymphoma virus type 1
human retrovirus that infects lymphocytes with a lifelong infection ⇒ normally asymptomatic
- 5% of infected individuals will develop adult t-cell lymphoma
- Transmission occurs through breast milk, sexual contact, intravenous drug use (needle sharing)
how does TLV-1 oncogenesis work?
viral proteins directly interfere with processes to favor and maintain viral infection and persistence as a retrovirus
- Much of this has been traced to the viral oncogene Tax
Tax
a viral oncogene that interferes with cell processes so the virus maintained and spreads
components of Tax (3)
- Dysregulation of cell cycle
- Inhibition of apoptosis
- Alterations in gene expression
Epstein-Barr virus (EBV)
causative agent of mononucleosis (mono)
- Vast majority of individuals will experience a 4-6 week infection or no symptoms at all
- 90% + of adults exposed
- Infection is lifelong, virus remains dormant in tissues and can become reactivated in times of stress, infection, or immunocompromised
how does EBV cause cancer
EBV can cause cancer in multiple tissue types
- EBV viral genes are directly oncogenic
ex: Burkitt’s lymphoma
EBNA1
viral protein binds to host genome on chromosome 11
- Region has homology to EBV genome
- Binding leads to double stranded breaks in a region responsible for regulating cell growth
- Induces rearrangement to stimulate Myc expression
Hepatitis B/C
chronic infections that lead to chronic liver inflammation and eventually cirrhosis
- Hepat: liver
- Itis: inflammation of
- lifelong infections, controllable with medication but incurable ⇒ vaccine available for B but not C
how can Hep B and C cause cancer?
hepatitis B and C can cause cancer through indirect mechanisms but not through integration of expression of viral oncogenes
- The sustained damaging and inflammatory environment promotes tumor growth
- Damage to cells leads to DNA damage and mutations
- Inflammation triggers healing and cell growth, immunosuppression, angiogenesis
- Proper treatment limits risk of oncogenesis
what are available effective vaccines
- Hepatitis B
- HPV
- Others under development
what is the mainstay of curative cancer treatment?
surgical resection followed by chemotherapy
requirements of surgical resection? What type of cancers have become increasingly treatable?
This requires early diagnosis before metastasis has occurred
- Blood cancers have become increasingly treatable and curable
- early diagnosis and treatment is strongly correlated with favorable outcomes
4 cancers with regular screening guidelines
- Breast
- Cervical
- Colorectal
- Lung
what percent of cancers don’t have a screening test?
57%
typically found in patients who are symptomatic which may be indicative of late stage disease
what are methods of detection? (3)
- screening
- molecular markers
- imaging
screening types (3)
- Colonoscopy
- Physical examination
- Mammography
molecular markers (2)
- Overexpression of certain proteins ⇒ PSA in prostate cancer
- Blood and fecal tests
imaging types (3)
- X-ray
- MRI
- Contrast tomography (CT)
Positron emission tomography (PET)
scan commonly used to identify and track cancerous lesions
- Utilizes radioactively labeled molecules to highlight regions of the body (glucose)
Warburg effect
cancer cells use aerobic glycolysis even when oxygen is abundant from mTOR activation
- Consume large amounts of glucose
- Regions with high metabolic activity light up in a PET scan
is there too much screening
there is such a thing as too much screening and overdiagnosis
Contrast
how much a given therapy affects cancerous cells vs healthy cells
3 types of treatments
- primary treatments
- adjacent therapy
- palliative care
Primary treatment
completely remove cancer from your body and kill all cancer cells
Adjuvant therapy
kill any cancer cells remaining after treatment ⇒ or neo before the primary treatment
Palliative care
to relieve and improve QOL without curative intent
what cancers tend to be highly treatable
Early stage and blood cancers
- Metastatic or unresectable solid tumors much less so
how does survival work with cancer therapy?
- Overall survival ⇒ % survival over a time frame
- Progression free survival
response related endpoints for measuring cancer therapy
- Tumor volume reduction
- Cure fraction
cure fraction
the proportion of patients that survive due to the treatment therapy over an extended period of time
traditional therapies
- surgical resection
- radiation
- chemotherapy
surgical resection; what does removing a tumor do?
involves the removal of cancerous tissue
- Often only beneficial to overall survival if the tumor is not yet metastatic or if metastases are responding well to treatment
- removal of a tumor may take away your body’s antitumor ability by taking out the main tumor ⇒ it will not fight against the rest of the metastasis in the body
what is needed for surgical resection (2)
- Accessible
- not spread to critical areas
radiation
cancer cells often have defective repair mechanisms, they are generally more susceptible to radiation induced DNA damage than healthy cells
what are negative effects of radiation?
- Increases the risk of secondary malignancies from treatment itself which induces a second cancer type
- Tumor must be accessible to radiation
what are benefits to radiation?
- Cancer either directly or indirectly kills cells or induces antitumor immunity or apoptosis
- can be effective as adjunct therapy or for tumors that are not resectable
chemotherapy
non-specific cytotoxic drugs that target various aspects of cell growth and homeostasis
- Generally function under the principle that cancer cells will be more affected by the effects than healthy cells
components of chemotherapy? (2)
- Often rapidly dividing cells are often affected
- Dosing is limited by systemic toxicity
classes of chemotherapy drugs? (4)
- Alkylating agents
- Anti-metabolites
- Plant alkaloids
- Antitumor antibiotics
Alkylating agents
attach alkyl groups to DNA interfering with replication and transcription
Anti-metabolites
substitute for nucleotides, interfere with replication and transcription
Plant alkaloids
inhibit mitosis ⇒ microtubule formation in taxanes
Antitumor antibiotics
bind to DNA and inhibit transcription, cause fragmentation
Paclitaxel
taxmen that stabilize microtubules preventing their degradation
- Stabilizes GTP bound tubulin
- Inhibits chromosome segregation during M-phase
- Triggers mitotic spindle checkpoint
what is the class of Paclitaxel?
plant alkaloid, mitotic inhibitor
Spindle assembly checkpoint
unattached kinetochores causes ubiquitinated cyclin B1 and you cannot proceed through M phase
- The cell will return to G1 or it will goto mitotic exit
- sometimes it will try to redo the process but this won’t work
5-fluouracil
Pyrimidine analog of uracil and Inhibits thymidylate synthetase
- Starves cell of thymine needed for replication
- Secondarily substitutes for uracil in mRNA and thymine in DNA interfering with transcription, translation, replication
what class if 5-flurouracil
antimetabolite
what is the 5-FU mechanism of action?
Ends up with low thymine and you can no longer replicate the genome to fill in the T spots
Targeted therapies
can target cancer cells directly but often require identifications of specific mutations ⇒ sequence, find mutations, analyze lifestyle factors, etc.
- non specific therapies have limited contrast and high systemic toxicity
target therapies (6)
- Hormonal
- Antibody drug conjugates
- Immunotherapy
- CarT cell therapy
- Oncolytic viral therapy
- Small molecules
Small molecules
drugs that specifically target cancerous cells but spare healthy cells ⇒ inhibit specific molecules of a pathway specifically dysfunctional in a certain cancer type
- This leads to higher potency and lower toxicity than traditional chemotherapies
what are small molecule applicabilities?
these are less broadly applicable to all cancers and tend to work on specific types, tend to be highly effective in some patients and ineffective in others
- Can also be conjugated to antibodies to enhance targeting, useful for cell surface markers
- more useful for doing stuff in a cell than antibodies which target the surface
immunotherapies
seek to either use immune system components to directly target cancer cells or to stimulate the hosts anti-tumor immunity
- Antibodies targeted to cancer antigens can inhibit cancer signaling or trigger elimination
- molecules/receptors overexpressed in cancer will be targeted
what can certain cancer mutations do in regards to the immune system?
evade immune surveillance
what is the early stage breast cancer driver?
estrogen receptor signaling
- Estrogen freely diffuses the cell and binds to the estrogen receptor in the cytoplasm
- Complex translocates to the nucleus where it binds to the estrogen response element leading to cell growth and proliferation
Tamoxifen
specifically binds to the estrogen receptor in breast tissue
- Prevents estrogen from binding and activating transcription
- Estrogen signaling in other tissues remains active
- Highly effective treatment for breast cancer so long as other mutations do not arise
- inhibits co-activator in breast tissue specifically
Ras-Mapk pathway & mutations
RTK signaling activates Ras and GTP bound form is active
- at some point GTP is removed and ras is inactivated
- Results in downstream signaling that promotes survival and proliferation
- Mutations in Ras can prevent GTP from being hydrolyzed rendering Ras permanently active ⇒ doesn’t require RTK signaling
- Ras activates Raf activates Mek activates Erk/MapK
drugs ending in nib are what?
small molecule inhibitors
drugs ending in mab are what?
antibodies
why is Ras difficult to inhibit?
its affinity for GTP is very high so GTP will always bind instead of a different molecule
- It doesn’t have many grooves for binding to Ras
small molecule inhibitor targets in the ras pathway(3)
- Raf inhibitors ⇒ mostly small molecule inhibitors
- Mek ⇒ mostly small molecule inhibitors
- RTK ⇒ mix of small molecule inhibitors and antibody techniques
are cyclin dependent kinases functional in cancer?
often dysfunctional in cancer and become overactive
- CDKs regulate cell cycle progression
- Often dysfunctional in cancer
what are effective inhibitors for CDKs
Small molecule inhibitors are effective for certain cancers by preventing progression through the cell cycle
why is p53 a problematic target?
At first glance appears a prime target for molecular therapies but much more difficult to correct a nonfunctional protein than to inhibit an overactive one
- Inhibiting p53 would make the problem even worse
what are advanced car-T therapies
- Car-T cell therapy
- Oncolytic viral therapy
Car-T cell therapy
chimeric antigen receptor T-cells ⇒ engineered T cells that can target specific antigens
- Can be engineered to target tumor antigens
- Highly specific and extremely potent
what are downsides of Car-T cell therapy?
- Extreme potency may limit practical applications via targeting of non cancerous cells that express low levels of the same markers
- Extremely expensive to administer
- can be problematic because there are no breaks once these are released
oncolytic viral therapy
utilizes viruses to target cancer cells ⇒ measles, adenovirus, HSV-1, etc.
- Can be engineered to specifically target and replicate in cancer, express therapeutic transgenes
how does viral lysis work in oncolytic viral therapy?
Viral lysis kills cells and releases viral progeny and tumor antigens stimulating host anti-tumor immunity ⇒ directly kills the cancer cell and then spreads the progeny of the virus
- Tumor antigens are also being released at the same time which stimulates the hosts anti-tumor immunity on a second level
what is great about oncolytic viral therapy?
this therapy type can be engineered to only replicate in tumor cells with certain promoters so it does not lyse the other cells
