Other Tumour Targeting Strategies

Describe features of vascular targeting strategies

Solid tumours require a functioning network of blood vessels to sustain growth (oxygen/nutrient supply, removal of metabolic waste). Aim to target tumour angiogenesis

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What are the two main approaches of vascular targeting? (1)

Anti-angiogenic agents (for small solid tumours with new blood vessels, anti-angiogenic agents have ab effect on the tumour periphery, inhibiting endothelial proliferation and migration)

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What are the two main approaches of vascular targeting? (2)

Vascular disrupting agents (for larger solid tumours with established blood vessels, VDAs have an effect on the central part of the tumour causing vessel occlusion and necrosis)

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Give an example of an anti-angiogenic agent

Bevacizumab (Avastin) - MOA (binds to VEGF to prevent Flt-1/KDR receptor interaction) small survival benefit in colorectal cancer, demonstrates proof of concept (more anti-angiogenic agents both antibody based and small molecules being developed)

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What is pharmacokinetic trapping?

Use of VDAs. Cytotoxic drugs in the tumour, schedule VDA to close the tumour blood vessels after cytotoxic agents have been administered

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Describe features of combetastatins

Cis-stilbene compounds (SAR studies - Z-configuration if essential for antitumour activity) - clinical trials

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Describe features of bioreductive agents (1)

Low oxygen levels (hypoxia) make cells resistant to being killed by radiation and chemotherapy, thus reducing the efficacy of treatment. Hypoxic cells - quiescent (not replicating, less vulnerable to antiproliferative agents)

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Describe features of bioreductive agents (2)

If drugs could be designed to be optimally effective at low oxygen levels, then they would be useful for killing tumour cells in the centres of larger tumours and those that remain after radiotherapy.

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Describe features of bioreductive agents (3)

Can put a needle into a tumour (during biopsy) and measure oxygen tension in different points in the tumour

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Describe features of bioreductive agents (4)

Drug triggered by low oxygen tension – want drug which stays in inactive form in normal oxygen levels but prodrug converts into active drug at low oxygen levels

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Describe features of mitomycin C (1)

Components - quinone, aziridine, carbamate (MOA - DNA cross linking, involves bioreductive step) - bioreductive agent

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Describe features of mitomycin C (2)

Ddministered in quinone form, once injected, undergoes enzymatic reduction to form quinol, occurs best in hypoxic conditions (low oxygen tension), occurs to a greater extent in the centre of a large tumour where oxygen tension is low

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Describe features of mitomycin C (3)

Electrophilic centres cross links with DNA (guanine-guanine)

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Describe features of AQ4N (Banoxantrone) - 1

Intercalator (slide in between base pairs of DNA), attachment of N-oxides, molecule is overall neutral – goes across cell membranes, if cell had low oxygen tension/hypoxic/centre of large tumour, N-oxides become reduced and are removed

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Describe features of AQ4N (Banoxantrone) - 2

Diethylamines become protonated – won’t go across cell membranes easily, stuck inside cell/trapped inside cell

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What are the three main uses of polymers, liposomes and nanoparticles in drug delivery?

Polymer-drug conjugates, encapsulated nanoparticle technologies, PDEPT (polymer directed enzyme prodrug therapy)

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Describe features of the enhance permeation and retention effect

Properties of solid tumours - enhanced vascular permeability, limited macromolecular recovery via post-capillary venules, poor lymphatic drainage (optimum size range of macromolecules for this effect - 40-70 kDa)

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What are the advantages of encapsulated nanoparticle technologies? (1)

Long circulation time in blood/stability in biological fluids. Appropriate size (10-30 nm) to escape renal excretion but to allow for extravasation at tumour site (EPR effect)

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What are the advantages of encapsulated nanoparticle technologies? (2)

Simple to incorporate drug compared to covalent bonding of agent to polymeric carrier. Drug delivery is independent of drug characteristics

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Describe the definitions of particles and sizes

Fine particles (100-250 nm). Ultrafine particles (1-100 nm). Nanoparticles (1-100 nm, size restricted to 2D, e.g. needles/rods)

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Give examples of liposomes and nanoparticles in formulations (1)

Caelyx, Myocet (incidence of cardiotoxicity is lowered as well as the potential for local necrosis at the site of administration), Doxil. Abraxane (Taxol-Albumin nanoparticles, Taxol attached to albumin, drug attached via chemical linker, EPR)

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Give examples of liposomes and nanoparticles in formulations (2)

Irinotecan Liposome Formulation (Onivyde®) - extends patient's life by ~ 2 months

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Describe features of polymer-drug conjugates

Based on EPR effect. Linker between drug and polymer which can be cleaved with enzymes to release drug to tumour site, avoiding toxicity associated with wider distribution of active agent. PEG used

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Describe features of PDEPT

Two component system. Polymer-linked drug and polymer-linked enzyme, both administered and accumulate in tumour. Enzyme cleaves linker to release drug at tumour site

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What is another novel approach target tumours via EPR effect?

Uptake of drug using carbon nanotubes

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Describe features of enzyme based strategies

Use of enzyme expressed by tumour cells (but not healthy cells) to activate prodrug. Systemic administration of enzyme asparaginase (Erwinase) to break down asparagine in blood/tissues. Asparagine is required for survival by leukaemia cells

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What are the challenges when designing a prodrug to be activated by over-expressed tumour enzymes?

Identify a suitable enzyme or enzyme family. Design prodrugs that are not toxic to normal tissues but can be converted to cytotoxic species by the relevant enzymes

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Describe features of the choice of enzyme

Focus on CYP450 enzymes. CYP1B1 thought to be over-expressed

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Describe features of CYP mediated activation of Bizelesin prodrug to parent molecule

Bizelesin prodrug – formed without OH group, in some cells, the OH group is added back on the compound (drug becomes cytotoxic)

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What are the problems with constitutive enzyme expression therapy? (1)

Highly unlikely that all tumour cells in a tumour mass will robustly over-express the chosen enzyme and will therefore succumb to released drug (may be alleviated using bystander effect)

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What are the problems with constitutive enzyme expression therapy? (2)

Unlikely that the chosen enzyme is expressed exclusively in the tumour tissue, and it is probably always expressed elsewhere in the body. Narrow therapeutic index

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Describe features of Erwinase (1)

Tumour cells cannot synthesis asparagine, give the enzyme asparaginase via systemic injection, asparaginase breaks down asparagine, depleted in plasma/healthy tissue, tumour cells, healthy tissue can synthesis asparagine more

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Describe features of Erwinase (2)

But tumour cells cannot synthesis asparagine, tumour cells die, used for leukaemia

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Describe features of PDT (photoactivated prodrugs) - 1

Administration of a non-toxic prodrug that can be activated selectively at the tumour site by light of a specific wavelength. Used to treat psoriasis, uses 8-methoxypsoralen

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Describe features of PDT (photoactivated prodrugs) - 2

This agent is relatively non-toxic until exposed to UV light, when it then cross-links DNA at thymine sites, causing distortion of the DNA helix with consequent toxicity toward the psoriatic cells.

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Describe features of PDT (photoactivated prodrugs) - 3

Porfimer sodium, temoporfin. After systemic administration, these drugs accumulate in malignant tissue and can then be activated by laser light to produce cytotoxic effects. Indications limited

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What are the challenges with PDT? (1)

Broaden the use of this therapy is that the shorter wavelengths of light required to activate the present generation of photoactivated agents do not penetrate tissues very effectively

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What are the challenges with PDT? (2)

New agents that can be activated at longer wavelengths are required for deeper penetration of light sources

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Describe features of ADC/phototherapy approach - Aspyrian therapeutics (1)

Near infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment based on an antibody-photosensitizer conjugate (APC). The photosensitizer, IRDye700DX, which is a water soluble silica- phthalocyanine dye is conjugated to an antibody to form APC

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Describe features of ADC/phototherapy approach - Aspyrian therapeutics (2)

APC binds to its cell surface target and induces cytotoxicity after exposure of NIR light at a wavelength 690 nm.

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Describe features of Boron Neutron Capture Therapy (1)

Bombarded with neutrons, generate alpha particles (radiation), limited range of depth into tissue, technology delivered for brain tissues (target damaged brain tissue, localised) - mechanism of selective tumour toxicity e.g. p-Boronophenylalanine

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Describe features of Boron Neutron Capture Therapy (2)

Availability of neutron source is a limiting factor

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Knowledge and experience from which areas have been used to develop novel approaches?

Nanotechnology, advanced polymer chemistry, electronic engineering - gene therapy, nanotechnology, novel polymers, ultrasound

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Describe features of intracranial delivery

Limitation of treating brain tumours - lack of suitable method to delivery therapeutic agents directly to tumour. Need to develop drugs which can cross BBB and brain-tumour barrier to allow higher concentrations to be obtained within the tumour bed

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Describe features of Gliadel

Local delivery, controlled delivery of carmustine by a biodegradable polymer implanted at the tumour site after surgical resection

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Describe features of ultrasound targeting

Efficacy of cancer chemotherapy is often limited by the toxic effects of the current generations of drugs. One approach - sequester drug into package which interacts minimally with healthy cells, keep drug contained until release at tumour site

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Describe features of ultrasound-sensitive liposomes (1)

Systemic administration of a micellar drug carrier with a hydrophobic core containing an effective amount of an anticancer drug. Ultrasonic energy is then applied to the tumour site to release the drug from the hydrophobic core of the micelles

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Describe features of ultrasound-sensitive liposomes (2)

Can be combined with imaging techniques. E.g. ABA triblock polymers, AB diblock copolymers, mixtures, PEGlyated diacylphospholipids

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Describe features of infrared-activated nanoshells (1)

The photothermal cancer treatment uses nanoshells that are tuned to respond to near-infrared light. Located just outside the visible spectrum, near-infrared light passes harmlessly through soft tissue

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Describe features of infrared-activated nanoshells (2)

In the treatment, nanoshells convert this light into heat that destroys nearby tissue adjacent to the tumour. tumour cells. The heating is highly localized and does not affect healthy tissues adjacent to tumour

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Describe features of microwave technologies (1)

Microwave treatment for prostate cancer. Insert catheter, inflate balloon, piece of metal sits inside prostate gland, rest of the catheter has an outer sleeve, cooling liquid (cooling of urethra), fire microwave radiation at prostate tissue

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Describe features of microwave technologies (2)

Heats up and kills tumour cells surrounding prostate gland, rest of the urethra remains cool. Potential to apply microwave technologies to other cancers e.g. pancreatic cancer via hepatic portal vein

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Describe features of radioactive glass beads (microspheres)

Radioactive element into beads, injected locally into tumour, clinical trials carried out, beads placed in liver, give off radiation

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Describe features of anti-metastatic agents

Potential to cure cancer, no good anti-metastatic agents currently. Still need to understand how metastatic tumours develop in different locations in the body (no particular part of the body), don’t know about the enzymes involved

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Describe features of metalloproteinase (MMP) enzymes as a drug target

MMP enzyme used by tumours (embed in matrix to help with formation of tumour) e.g. Marimastat (MMP inhibitor)

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Describe features of lysyl oxidase as a drug target

LOX (lysyl oxidase) works by sending out signals to prepare a new area of the body for the cancer to set up a camp - potential drug target

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Describe features of gene therapy (1)

Involves the use of a viral vector to deliver a working version of a mutated gene known to be associated with the tumour. Replacement of mutated tumour suppressor gene e.g. p53

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Describe features of gene therapy (2)

Or delivery non-human gene that can produce enzyme which can activate prodrug e.g gene directed enzyme prodrug therapy (utilise carboxypeptidase or nitroreductase enzymes, local drug action at tumour site, Aziridine activated – bind to DNA)

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What are the concerns in the gene therapy area?

Safety (in long term use). Highly unlikely that vectors can be targeted completely specifically to tumours, organs, or tissues, and some degree of collateral delivery to healthy cells is always likely. Could lead to cancer of healthy tissues.

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Describe features of vaccines (1)

Vaccination against cancer has the objective of either activating or inducing a host response to tumour-associated antigens

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Describe features of vaccines (2)

Treatment vaccines – cells extracted from patient, genetically engineered (incorporated antigen from cancer/tumour cell), inserted back into patient, immune system responds to antigen attached to T-cell. Issue - cost/benefit ratio

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Give examples of prophylactic vaccines

HPV vaccine. HBV vaccine

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Give examples of treatment vaccines

Provenge (prostate cancer). BCG vaccine (bladder cancers). Imlygic (melanoma)

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Describe features of growth factors (1)

Growth factors/cytokines are proteins which affect cell growth and maturation. Recombinant technology has allowed the production of large amounts of cytokines. G-CSF and GM-CSF used to overcome myelosuppressive S/E associated with anticancer agents

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Describe features of growth factors (1)

Inhibiting growth factors can lead to useful antitumour activity, and known inhibitors include octreotide (Sandostatin®) which is in clinical use, and suramin (a polysulphonated naphthylurea).

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Describe features of small molecule immunomodulation

Thalidomide (potential mechanisms e.g. myeloma cell growth inhibition, anti-angiogenesis, suppress production of TNFα etc.)

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What are the issues with the new types of agents in this society

Health service (NHS) funded by taxpayers, insurance system, charitable funding, pay privately

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Give examples of biological immunomodulatory agents

Nivolumab and Ipilimumab

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Describe features of hormonal selectivity (1)

Selectivity can be gained by targeting hormone-sensitive tumours. Estrogen ablation in ovarian and breast tumours. Testosterone ablation in prostrate tumours.

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Describe features of hormonal selectivity (2)

Hormonal selectivity – e.g. prostate cancer (most treatments involve blocking testosterone, prostate cancer stops growing due to cutting off testosterone supply), Zoladex, Zytig, Erleadaa

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Describe features of hormonal selectivity (3)

S/E of testosterone ablation – weight gain, depression, loss of libido. Block oestrogen, Herceptin (selective), beta-estradiol, tamoxifen, atamestane, anastrozole

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How do tumours develop resistance against anti-cancer drugs?

Tumour cells develop resistance to drugs – find an alternative signalling pathway to achieve the same activity (e.g. development of tumour)

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Describe features of structural proteins (1)

Binding of the vinca alkaloids to the tubulins that make up the spindle interferes with and “weakens” the microtubule assembly, causing damage to the mitotic spindle apparatus and preventing chromosomes from traveling out to form daughter cell nuclei

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Describe features of structural proteins (2)

Other natural products include colchicine and paclitaxel. Epothilones

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Describe features of signalling pathways (1)

New class of anticancer agents known as Growth Factor, signal-transduction or secondary message inhibitors have been developed. They are sometimes collectively called “molecularly targeted agents”, kinase inhibitors are contained within this group

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Describe features of signalling pathways (2)

Due to up-regulation and/or greater dependence on some of these pathways in tumour cells, inhibition should lead to an anticancer effect

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Describe the classification of protein kinases (1)

Enzymes within cells that act by attaching phosphate groups to amino acid residues. Acts as a molecular on-off switch to trigger a cascade of cellular events and as a connector that binds proteins to each other to facilitate signalling

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Describe the classification of protein kinases (2)

Protein kinases play a primary role in the complex signalling system that transfers information between and within cells.

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Describe the classification of protein kinases (3)

Classifications - based on specificity for target amino acids (serine, threonine, tyrosine, mixed function kinases), based on structure and cellular localisation (receptor kinases, non-receptor kinases)

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What is the typical signalling pathway?

Activation of receptor when ligand binds. Signal transmitted through membrane to intracellular kinase. Intracellular kinase activated. (Ligand can be EC, IC, transmembrane domain)

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What are the main types of agents?

Iressa (EGFR, lung cancer). Gleevec (BCR-ABL, leukaemia). Herceptin (HER-2, breast cancer). Avastin (VEGF, anti-angiogenic agent)

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What are the consequences of the mutation of tyrosine kinases?

Mutation of BCR-ABL, mutation of RET tyrosine kinase, EGFR mutations - significant changes in signalling, development of disease

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Co-expression of which protein kinases is linked to the pathogenesis of several human caners?

EGFR, PDGF, PDGFR, SRC kinase activity, HER2/neu receptor tyrosine kinase

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Give examples of drugs which target protein kinases (1)

Vemurafenib (targets mutated B-RAF found only in melanoma cells and not healthy cells). Crizotinib (licenced for advanced non-small cell lung cancer (NSCLC) whose tumours are ALK-positive). Alectinic (for ALK+ lung cancer)

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Give examples of drugs which target protein kinases (2)

Ibrutinib, Osimertinib, Neratinib

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Describe features of cell cycle inhibitors (1)

The D-type cyclins and their kinase partners (CDK4 and CDK6) phosphorylate the tumour suppressor protein pRb during the G1 phase of the cell cycle and contribute to its inactivation

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Describe features of cell cycle inhibitors (2)

Cyclin D1 expression can be stimulated by the RAS signalling pathway, and most human cancers contain mutations that affect either cyclins, CDK4, CDK6, their regulators or pRB

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Describe features of cell cycle inhibitors (3)

Develop inhibitors of the D-type cyclins and their kinase partners such as CDK4 and CDK6 e.g. flavone, olomoucine, Paullones, alsterpaullone, Palbociclib

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Describe features of proteosome inhibitors

Ubiquitin pathway plays a significant role in neoplastic growth and metastasis.

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Give an example of proteosome inhibitor

Bortezomib (Bortezomib bound to the core particle in a yeast proteasome, catalytic threonine residue activity is blocked by the presence of bortezomib)

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Describe features of mTOR inhibitors (1)

mTOR is a cellular enzyme that plays a key role in cell growth and proliferation as part of the mTOR signalling pathway (tumour cells, angiogenesis)

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Describe features of mTOR inhibitors (2)

Inhibition of mTOR delivers the false signal that the cell is starved of nutrients and lacks growth factor stimulation.

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Describe features of mTOR inhibitors (3)

This initiates the cellular starvation response, which includes dramatic metabolic reprogramming, prevention of cell growth, and arrest of cell division. E.g. rapamycin and analogues

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Describe features of chromatin remodelling agents (1)

Chromatin re-modelling agents act on chromatin epigenetically, altering its degree of compaction (rather than DNA sequence), and therefore controlling gene expression, DNA replication, DNA repair, and chromosome segregation

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Describe features of chromatin remodelling agents (2)

Fusion of ALL1 protein deregulates target genes (encoding transcription factors). Drugs in development - DNA methyltransferase inhibitors, histone deacetylase inhibitors, aurora kinase inhibitors

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Describe features of chromatin remodelling agents (3)

Epigenetic mechanisms (transcription- de-methylation, acetylation, no transcription - methylation, de-acetylation). HDACs -

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Describe features of chromatin remodelling agents (4)

Causes a decreased affinity of the histones for DNA. Deacetylation by HDACs removes these charge-neutralizing acetyl groups. Protein becomes more +ve, causing an increased affinity of histones for DNA, leading to transcriptional repression

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Describe features of apoptosis regulators (1)

Apoptosis is triggered via two major pathways: Extrinsic (through Death Receptors) and Intrinsic (through the mitochondria).

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Describe features of apoptosis regulators (2)

Several investigations have been carried out to exploit the apoptotic pathways in an effort to induce cell death and to arrive at a suitable anticancer drug through targeting either BCL-2 protein or the caspases. Naitoclax

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Describe features of RAS inhibitors (1)

RAS proteins, which are associated with the cell membrane and pass signals to a number of downstream molecules, are examples (mutations of RAS involved in cancers).

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Describe features of RAS inhibitors (2)

Inhibition of farnesyl transferase can, in theory, prevent RAS protein from associating with the membrane and from picking up a growth signal. Lonafarnib and tipifarnib are two such inhibitors that have been trialled.

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Give other examples of pathways and inhibitors of potential interest

Chaperone Protein Folding Inhibitors (e.g., HSP90). Metabolic Pathways. TGFbeta Pathway. WNT Pathway. NFkB Pathway. STAT3. JAK/STAT Pathway. p53 Pathway. Notch Pathway. Hedgehog Pathway. PPAR Pathway. Oxidative Stress Pathways. Hypoxia Pathways

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Other Tumour Targeting Strategies

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