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PHRM30003 > Cancer > Flashcards

Cancer Flashcards

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1
Q

Solid cancer

A

lung, breast, and colon cancers= solid tumours

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2
Q

Liquid cancers

A

leukaemias, lymphomas, and multiple myelomas (blood cancers)=liquid cancers. Cancers of the blood, circulate.

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3
Q

Cancers

A

1.Arise by genomic mutation and chromosomal instability affecting cell phenotype and fusion.

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4
Q

Cancers have a high

A

spontaneous mutation rate + can bypass processes usually used to remove mutated-> multiply into more cells able to by-pass destruction. Highly heterogeneous even within tumour types

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5
Q

Main risk factor

A

age

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6
Q

Other proven causes

A

cigarette smoke, obesity, environmental and occupational exposures, radiation, some viruses and bacteria. Many are of an unknown cause, other can be heritable

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7
Q

Mostly cancer kills by

A

spreading=metastasis. Movement from primary sites to secondary organs

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8
Q

Risks

A

The mutations that give rise to instability can occur early in life and then combine with the normal accumulations of mutations that occur as people age to cause cancer. Carcinogenic compounds increase risk of cancer in later life

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9
Q

In the case of smoking

A

progenitors (parent cells) that are mutated through smoking stay mutated forever-> higher than normal risk of cancer even though absolute risk decrease upon stopping. Increased relative risk increases with number of cigarettes smoked per day

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10
Q

How does lung cancer cause death?

A

1.Lung cancer typically kills through moving (metastasis) to the brain/bone marrow/liver and causing organ failure in these organs 2.Due to capillary networks in the lung-> there is a connection between lung and brain

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11
Q

Bowel cancer in situ

A

1.Villi in gut (food exchange areas) at the base are crypt/progenitor cells where cancer begins-> always replenishing the epithelium 2.If they become mutated-> dysplasia (abnormal structures) occurs-> these areas can progress on to become true tumours. If cancer continues to progress will invade + metastasise.

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12
Q

Lung cancer, How easily a melanoma can spread throughout the lung

A

the lung acts as a filter-> if cells are sticky will often be retained in the lung, and can move into the brain from here,

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13
Q

Chromosomal aberrations

A

genomic instability. Mutations can be individual but may also include truncations (missing bits) or translocation

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14
Q

Translocation

A

oncogene translocated to promoter region that is always expressed will lead to high expression of the oncogene= amplification

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15
Q

Cancer in gut + liver

A

1.Crypt cells/progenitor cells -> In colon lumen, cells absorb food in a capillary network that goes to the liver 2.At the bottom of the crypt are constantly dividing stem cells-> give rise to tissue that moves up along the way to replace other cells 3.Where mutations occur, a polyp may form 4.This leads to abnormality + growth of polyps causing adenomas-> cancerous head (tumour) can attach to adenoma 5.Cancer can mutate and become invasive-> moving into the tissue 6.First draining point from the gut is the liver-> so gut cancers often metastasise to the liver

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16
Q

Cancer progression in normal tissues

A

period of initiation (carcinogens) + effect of age + other insults (normal time will give a mutation rate) + anything else that increases cell division (more cell division=shorter telomeres + more room for mutations during the replication)-> pre-cancer->slow but progressive change in appearance of the cancer-> invasive + metastatic cancer

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17
Q

Inflammation is almost always associated with

A

an increased risk of cancer-> inflammation triggers greater rate of cell division. Stem cells bought out of acquiescence to replicate + divide to close wounds

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18
Q

Cells within a tumour

A

Not all tissue is the same-> stem cells dividing to produce clones, clones expand and are genomically unstable + can give rise their own subclones

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19
Q

Cells undergo relapse

A

some clones survive therapies, residual resistant clones that cannot be eliminated although tumour gets smaller. These clones are already multi-drug resistant, will grow to become the source of another cancer.

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20
Q

Sequencing of tumours

A

tumours can be sequenced for molecular defects, new drugs can them be matched (EGFR, KRAS)

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21
Q

EGFR

A

cancer arises from lining of the lung, highly overexpressed in lung cancers. If EGFR inhibitors are used in lung cancer patients who are secondary-smokers there is a positive impact. EGFR is a protein involved in a cell signalling pathway that controls cell division and survival-> mutations may cause overexpression, leading to greater and more rapid division

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22
Q

KRAS

A

1.Membrane bound G-protein with intrinsic GTPase activity 2.Most frequently mutated oncogene 3.KRAS signalling triggers downstream activation of the RAF/MEK/ERK and PI3K/AKT/mTOR pathways amongst others 4.Oncogenic KRAS mutations prevent the inactivation of the KRAS protein, resulting in uncontrolled cell proliferation and unregulated cell survival

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23
Q

Selective KRAS inhibitors target

A

cancer cells, but not other cells

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24
Q

The cell cycle

A

1.Stem cells sit until they are promoted-> they sense nutrients and receive signals 2.There are lots of checks in the DNA cycle to make sure replication is occurring correctly-> issue almost always trigger apoptosis. There are natural safe guards that protect against cancer

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25
Tyrosine Kinase receptors
are a large target due to their role in regulating the cell cycle
26
Factors that influence the cel cycle clock
1.tyrosine kinase receptors 2.G-protein coupled receptors 3.TGF-B receptors 4.integrins 5.nutrient status
27
Cells can either be in
1.a quiescent state (Go) or 2.enter into active cell cycle
28
G1
DNA damage checkpoint. entrance into S can be blocked. period during which cells are response to mitogenic GFs and TGF-B
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S
DNA damage checkpoint. DNA replication haltered if genome is damaged
30
G2
entrance into M blocked if DNA replication is not completed
31
M
anaphase blocked if chromatids are not properly assembled on mitotic spindle
32
P53
universal guard in the cell cycle
33
p53 senes issues
lack of nucleotides, UV radiation, ionising radiation, oncogene signalling, hypoxia, blockage of transcription. Is activated by this DNA damage
34
P53 in response coordinates
1.Cell cycle arrest 2.DNA repair 3.Block of angiogenesis 4. Apoptosis
35
Mutations in p53
have a large impact + can be involved in different cancers. One or both copies of p53 can be compromised. P53 has a number of target genes that can be impacted (including apoptotic factors, factors that inhibit DNA synthesis, cell cycle factors).
36
The window of opportunity for many cancer drugs is
in the cell replication stage, DNA damage + checkpoints that read damage are active during division process-> when these drugs work. This means these drugs do not work on work on quiescent (cell outside of the cell cycle, but has capacity to divide) cells-> cannot get the long term stable apoptosis resistant cells. Cancer drugs often work on growth factors/checkpoints, and I guess that's why many of these drugs require cancer cells to be dividing actively to target them
37
Checkpoints in apoptosis
anti-apoptosis factors are balanced by pro-apoptotic (BCL-2) factors. Apoptosis plays an important role in inflammation and normal growth and development.
38
Hanahan and Weinberg-> Hallmarks of cancer
1.Sustaining proliferating signalling 2.Evading growth suppressors 3.Activating invasion and metastasis 4.Enabling replicative immortality 5.Inducing angiogenesis 6.Resisting cell death
39
Emerging hallmarks
7.Deregulating cellular energetics 8.Avoiding immune destruction
40
Enabling characteristics
9.Genome instability and mutation 10.Tumour-promoting inflammation (vasodilation + leaky blood vessels) (angiogenesis)
41
Inflammation will promote
progression from pre-cancerous state to pro-cancerous state
42
Currently cancer has moved towards
true cures (testicular cancers), + selective inhibitors (genome sequencing, molecular profiling and target specific screening)
43
How are treatment responses measured?
1.progression free survival (tumour reduction- but OS not improving) 2.overall survival 3.(amount of) residual disease- ideally minimal 4.side effect profile
44
In treatments you are trying to avoid
a banana curve, in which there is progression free survival and tumour is reduced, but overall survival does not improve. Drugs should allow for true survival
45
Cancer staging (lung cancer)
What can be achieved through therapy depends on the stage of cancer-> size + location (if it is in lymph node-> will send nodes into lymph and eventually blood)
46
Nodes can now be biopsied
first nodes biopsied to determine the presence of any cancer cells-> if there is presence the nodes can be removed
47
An indication of a particularly severe/dangerous cancer is
Metastasis to a secondary location (in M1b and M1c), very large tumour (>7 in T4 or any tumour with invasion of heart, spine etc) + high lymph node involvement (cancer can travel through the lymph)
48
Alkylating agents
BIND DNA-> ALKYLATE IT-> CHANGE STRUCTURE-> TRIGGERS APOPTOSIS + ENDUCES FURTHER OXIDATIVE STRESS. Works in all phases of the cell cycle
49
Mechanism of action
1.bind to DNA and alkylate it-> alkylating agents have have two DNA binding spots-> binding at both points, causes DNA to link together and form a covalent bond=cross-link sensed as damage. Can also cause abnormal DNA pairing, or DNA strand breaks=cell cannot divide. ALSO creates further lesions from oxidation in DNA that can be sensed as damage
50
examples of alkylating agents
1.Nitrogen mustards (cyclophosphamide) 2.Alkyl sulfonates (carmustine) 3.Triazines (temozolamide) 4.Ethylenimines
51
Issues with alkylating agents
Not curative-> does not work on quiescent stem cells-> but can be given in doses that WILL destroy the bone marrow (stem cell location) before a transplant. Resistance can occur (nucleotide excision repair)
52
Sulphur Mustard: Causes
1.damage to DNA, RNA, membranes and proteins 2.production of reactive oxygen species, changes in signal transduction and cell cycle regulation. This leads to apoptosis (tissue damage + decreased repair)
53
Antimetabolite
Interfere with DNA and RNA growth by substituting for the normal building blocks of RNA and DNA. Damage cells during the S phase when chromosomes are usually copied. They enter structure during DNA replication-> affecting ability to grow and reproduce as the structure is recognised as incorrect-> leads to apoptosis
54
Antimetabolites also
reduce the number of macrophages- by decreasing macrophage progenitors
55
Antimetabolites examples
5-Fluorouracil (5-FU) and Methotrexate-> can also be used in serious inflammatory conditions. used to treat leukemias, breast cancer, cancer of the ovary and intestinal tract.
56
Anti-tumour 'antibiotics'
They interfere with DNA replication-> errors in DNA replication will trigger apoptosis. Does it kill bacteria? Fungus? But were found to be too toxic for routine anti-infective agents'
57
(antibiotic) Anthracyclines
antitumor antibiotics that interfere with enzymes involved in DNA replication (one error in DNA replication fork will trigger apoptosis). they work at all phases of the cell cycle->>used for a variety of cancers (will not work on quiescent cells)
58
Issues with Anthracyclines
cannot be used often-> can cause toxicities. Can permanently damage the heart if given in high doses=lifetime dose limit
59
Example of Anthracycline
Doxorubicin
60
Topoisomerase inhibitors
Interfere with topoisomerases (help separate strands of DNA in the S phase-Allow for DNA to be separated, cut, and replicated). This stops DNA replication . Used to treat certain leukemias, as well as lung, ovarian, GI and other cancers.
61
Issues with topoisomerase inhibitors
Topoisomerase II inhibitors-> can increase risk of a second cancer (acute myelogenous leukemia- 2 to 3 years after the drug is given)
62
Mitotic inhibitors
(Often plant alkaloids). Work by stopping mitosis in the M phase of the cell cycle, but can damage cells in all phases by keeping enzymes from making the proteins needed for cell reproduction.
63
Mitotic inhibitors used to treat
breast, lung, lymphomas, and leukemias
64
Issues with Mitotic inhibitors
Can cause nerve damage=limit on how much can be given
65
Examples of Mitotic inhibitors
vinblastine
66
RTKs
1.Blood cell growth factors-> can cause leukemia when working too rapidly 2.RTKs are dimeric receptors- when dimerised by an external ligand they come together and have intrinsic phosphorylation activity via phosphorylating each other 3.This allows molecules to dock-> turning on a cascade of signal transduction 4. This signalling allows for growth and survival-> the signal is relayed by activated signalling proteins in the cell interior which are bound to phosphorylated tyrosine
67
RTKs can be targeted by
Targeted molecular therapies that target specific RTKs + their mutations
68
RTK inhibitors may be
1.Selective active site inhibitors 2.Drugs that block ligands/receptor dimerization 3.Drugs that bind to receptors encouraging cell destruction
69
Imatinib/Gleevec
Targets the ABL (BCR-Abl) kinase through active site binding but has broad spectrum activities that hit other kinases. Has shown to have a long-term survival rate-> first time there has been a flat line drug. Types of leukemia that respond to this drug rarely mutate the binding site.
70
The ABL kinase in cancer
The ABL kinase becomes a translocated growth factor that drives blood cells to proliferate-> when a chromosome breaks the Abl kinase ends up placed at a promoter region-> leads to persistent activation=chronic fatal leukemia.
71
Issues with RTK inhibitors
Their effectiveness can be reduced due to mutation of the binding site-> however, can develop different generations of drugs
72
Differentiating agents
Act on cancer cells to make them mature into normal cells. Mostly used on blood cancers
73
Differentiating agents example
Retinoids, tetimoin, bexarotene
74
Combination regimes (CHOP)
#ERROR!
75
CHOP consists of
1.Cyclophosphamide-> alkylating agent which damages DNA by binding to it and causing the formation of cross links 2.Hydroxydaunorubicin-> intercalating agent which damages DNA by inserting itself between DNA bases 3.Vincristine-> prevents cells from duplicating by binding to the protein tubulin 4.Prednisone-> corticosteroid
76
Issues with CHOP
Leads to bone marrow failure + damage to the gut due to damage to mucus. Anaemia, difficulty eating
77
Kras
an regulator of cell growth and differentiation-> common gene mutation linked to cancer (oncogene). It is a GTPase-> so converts another molecule (GTP) into GDP to convey a signal. In cancer cells there are variations in the RAS active site-> Mutant KRAS protein can cause increased cellular proliferation=cancer
78
Sotorasib (and Adagrasib)
small molecule inhibitors that covalently bind to the KRAS G12C oncoprotein (mutant KRAS protein). Interacts with the cysteine residue introduced by the mutation (not present in normal KRAS so does not impact this protein)-> Binding in the pocket locks the protein in the inactive GDPbound conformation of KRAS-> This prevents interactions with downstream effectors=inhibited cell proliferation
79
KRAS inhibitor example
SOTORASIB
80
Small molecules ancillary therapy
Helper-therapies: make small molecule therapy more tolereance. Includes Anti-emetics (5HT3 (prevent vomiting), NK1 receptor)
81
Hormone therapy
Many cancers (breast + prostate) are driven by sex hormones (oestrogen + testosterone). These hormones can be targeted in cancer therapy-> Anti-oestrogens (effective in breast cancer) + Anti-androgens
82
Benefits of hormone therapy
more targeted-> less adverse effects-> targets hallmarks)
83
Biological
Traditionally, refers to any natural product. Now used to denote drugs made using recombinant DNA technology (for nucleotide-based drugs)
84
B-cell Immunity/clonal selection theory
1.from stem cells, lymphocytes are generated-> each with a single type of receptor for an antigen 2.mature inactive lymphocytes are produced-> primarily to non-self of foreign antigens 3.when activated by a foreign antigen, B cells specific to the antigen form an expanded clone of antigen specific lymphocytes 4.'Self' antigens from the body's own tissue delete self-reactive lymphocytes
85
Monoclonal antibodies
Immortal (myeloma) cells can be fused with antibody producing b-cells specific to the antigen-> this produces hybridoma cells capable of making large amounts of immunoglobulin-> hybridoma cells are cultured + selected to positive cells -> monoclonal antibodies are harvested
86
Structure of biologicals
Mutation and recombination occurs in VDJ gene to generate CDR diversity (site where foreign particle binds) 1.4 different types of IgG 2.IgG typically have a long half-life
87
sub-type of IgG can be selected as needed
some IgG (4) does not induce compliment activation-> thus can select antibodies that will just block OR that will activate compliment proteins (attracting immune cells to destroy the target)
88
Mechanisms for Anti-cancer treatment
1.receptor blocking 2.ligand blocking 3.Antibody dependant cellular cytotoxicity 4. compliment-dependant cytotoxicity 5.antibody dependant cellular phagocytosis
89
Receptor and ligand blocking
apoptosis
90
ADCC
Natural Killer cell attachment-> release of cytotoxic granules from NKCs that cause tumour cell lysis (antibody-dependant cytotoxicity)
91
CDC
compliment cascade leading to cell lysis
92
ADCP
Antibody dependant cellular phagocytosis-> antibody induces phagocytosis by macrophage
93
Evolution of antibody therapies
1.Murine antibodies (Human anti-mouse antibodies~ often rejected) 2.Re-engineered chimeric antibodies-> variable regions from mouse antibodies while the rest/the constant regions of the antibody is human~ still triggers a human reaction against mouse-antibody 3.CDR-drafted antibodies contain only 5% mouse sequences
94
Issues with monoclonal antibodies
Serum sickness (individuals became sick after receiving infusion of serum containing antibodies from vaccinated horses). Today, Use of mouse B cells to produce the antibodies can lead to serum sickness (immune response towards foreign mouse antibody)
95
HPV vaccines:
Protect against infection with HPV (various strains of HPV directly causes cervical, anal, oropharyngeal, penile, vulvar and vaginal cancer). HPV vaccines using Virus-like particles covering strains found to cause these cancers are highly effective in preventing cancer
96
Rituximab
Chimeric, AntiCD20 . B cell leukemias express CD19/CD20 receptors (functional surface molecules). Rituximab is a killing antibody against CD20-> can be used to eliminate resistant clones
97
Actions of Rituximab
1.Harvests natural defences (NK, macrophages + complement reactions) 2.Targets normal + cancer cells expressing this protein, however the protein may found in higher than normal quantities on cancer cells 3.Leads to apoptosis, antibody dependant cellular cytotoxicity
98
Leukomas
involve growth of uncontrolled proliferation of white cell lineages)
99
HER-2 and Trasuzumab (Herceptin)
HER-2 is a growth factor TKR that is overexpressed in ovarian and breast carcinomas. It hetero-dimerises with other growth factors to enhance their activation 1.There is no known ligand 2.In the mutated, cancerous form, the variant kinase does not express extracellular domain but remains active internally with signals (enzymatic function)
100
Antibodies targeting HER2
inhibit heterodimerization and internalization.
101
EGFR
epidermal growth factor receptor protein is involved in cell signaling pathways that control cell division and survival. Sometimes, mutations (changes) in the EGFR gene cause epidermal growth factor receptor proteins to be made in higher than normal amounts on some types of cancer cell
102
Cetuximab
Induces apoptosis in EGFR+ tumour cells by blocking ligand binding + receptor dimerization. Ligand binding usually->dimerization->receptor activation->cellular growth/proliferation
103
VEGF
growth factor for blood vessels. Makes them leaky. Can target theses (circulating) growth factor proteins
104
Bevacizumab (Avastin)
inhibit VEGF to cause metastasis + stops tumour growth by preventing VEGF from binding (antibody binds to VEGF)
105
VEGF/metastasis is a cycle
Cancer cells need blood vessels-> slight inflammation from cancer brings in macrophages which are involved in vessel dilation-> this creates a supportive environment-> blood vessels form (angiogenesis)-> allows tumour progression
106
Imiquimod
anticancer mechanism that helps stimulate the immune system. Primes the immune system to active attack surface antigens over-expressed on the cancer surface-> causes cells to be re-activated (can just sit there passively)-> stimulates the immune system
107
Imiquimod activates
1.Adjuvant effects through Toll like receptor (TLR7) 2.Natural killer cells, macrophages and lymphocytes including interferon-a (INF-a), IL-6 and tumour necrosis factor-a (TNA-a) 3.Langerhans cells (an APC) that can migrate to local lymph nodes to trigger adaptive immunity
108
Checkpoing inhibitors
T cell receptors, CTLA-4 and PD-1 determine cell destruction (checkpoint inhibitors)
109
Over-expression of these checkpoint inhibitors (tell the immune system not to kill the cell)
over-expression means that even if co-stimulation does occur-> T cell activation will not happen. tumours evolve these checkpoint inhibitors that means even when the cells are presenting lots of 'not-me' antigens~ T cells will still not attack because tumours have evolved to over-express theses checkpoint inhibitors
110
Checkpoint inhibitors
Monoclonal antibodies can be used to block these checkpoint inhibitors. Effective!! Lucrative!!
111
PD1 blockers
Nivolumab: PD1 + Pembrolizuma. PD1(genetic smoking signature positively associated with benefit with treatment). The more mutations that had occurred due to smoking=better response to PD-1 blockers
112
CAR-T therapy
1.Active virus used to insert genes into the T cell 2.The genes cause the T cell to make special CAR receptors on their surfaces- these receptors target investigated antigens on the tumour 3.Modified T cells are multiplied 4.Car T cells are placed back into the body to target cancer cells-> identify cancer cells + kill them even if usual activation factors are not present
113
Issues with CAR-T therapy
Can cause of cytokine storm (Often paired with IL-6 antibodies (IL-6 heavily involved in cytokine storm) to protect the body-> IgG 4 subtype (non-complement fixing->neutralise the IL-6) + glucocorticoid steroids)
114
CAR-NK therapy is due to issues with CAR-T
In CAR T, T cells need to be autologous . Own T cells are MHC (recognised my immune cells as 'own' compatible-> so must take them from your own body~ can't engineer therapies from others. NKC kills in a way that is not MHC restricted (CD-20 killer?) that could be stored + ready to go
115
CAR-NK cells in the body
1.NKC binds to cancer cell (immune synapse)-> few other molecules involved 2.Binding + activation leading to NKC secreting perforins + granzymes (same are CART cells) 3.Target cells undergoes apoptosis
116
immune system activation therapy
Taking tumours out (heterogenous 4/5 major clones)-> sequencing of tumour-> vaccine combined with immunotherapy

PHRM30003 (3 decks)

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