clinical oncology 1: cancer treatment

Question 1

what are the main anti-cancer treatment modalities?

Answer 1

surgery
radiotherapy
chemotherapy
immunotherapy

Question 2

what are the types of genetic mutations that can cause cancer?

Answer 2

• chromosome translocation
• gene amplification (copy number variation)
• point mutations within promoter or enhancer regions of genes
• deletions / insertions
• epigenetic alterations to gene expression
• inherited

Question 3

what are the types of systemic cancer therapies?

Answer 3

cytotoxic chemotherapy

targeted therapies

Question 4

what are some types of cytotoxic chemotherapies used?

Answer 4

• alkylating agents
• antimetabolites
• anthracyclines
• vinca alkaloids & taxanes
• topoisomerase inhibitors

Question 5

what are the types of targeted therapies?

Answer 5

small molecule inhibitors

monoclonal antibodies

Question 6

how do cytotoxic chemotherapies work?

Answer 6

select’ rapidly dividing cells by targeting their structures (mostly DNA except taxanes affect microtubules)

Question 7

how & when is cytotoxic chemotherapy given?

Answer 7

IV or orally

can be given:

• adjuvant (post-op)
• neoadjuvant (pre-op)
• as monotherapy or in combination
• with curative or palliative intent

Question 8

what are the side effectes of cytotoxic chemotherapy and why do they arise?

Answer 8

• hair loss
• mucositis
• immunnosuppression
• nausea & vomiting
• diarrhoea
• nephrotixicity
• neurotoxicity
• tiredness
• systemic effects mean all rapidly dividing cells in body are affected

Question 9

how do alkylating agents work?

Answer 9

• add alkyl groups to guanine residues in DNA
• cross-link DNA strands and prevents DNA from uncoiling at replication
• trigger apoptosis (via checkpoint pathway)
• encourage mis-pairing (oncogenic)

Question 10

what are some examples of alkylating agents?

Answer 10

chlorambucil
cyclophosphamide
decarbazine
temozolomide

Question 11

how do pseudo-alkylating agents work?

Answer 11

add platinum to guanine residues in DNA

- same mechanism of cell death as alkylating agents

Question 12

what are some examples of pseudo-alkylating agents?

Answer 12

carboplatin
cisplatin
oxaliplatin
(basically anything with platin in the name)

Question 13

how do anti-metabolites work?

Answer 13

masquerade as purine / pyrimidine residues -> inhibition of DNA synthesis, DNA double strand breakage, apoptosis

Question 14

what are some examples of anti-metabolites?

Answer 14

• methotrexate (folate)
• 6-mercaptopurine
• decarbazine
• fludarabine
• 5-fluorouracil
• capecitabine
• gemcitabine

Question 15

what are the side effects of anti-metabolites?

Answer 15

• hair loss
• bone marrow suppresion -> anaemia & thrombocytopenia
• increased risk or neutropenic sepsis
• nausea, vomiting
• mucositis & diarrhoea
• palmar-plantar erythrodysesthesia
• fatigue

Question 16

how do anthracyclines work?

Answer 16

inhibit transcription & replication by intercalating nucleotides within the DNA/RNA strand

• also block DNA repair (mutagenic)
• create DNA and damagine free oxygen radicals

Question 17

what are some examples of anthracyclines?

Answer 17

• doxorubicin

- epirubicin

Question 18

what are the side effects of anthracyclines?

Answer 18

• cardiax toxicity
• alopecia
• neutropenia
• nausea & vomiting
• fatigue
• skin changes
• red urine

Question 19

how do vinca alkaloids & taxanes work?

Answer 19

inhibit assembly (VA) or disassembly (taxanes) or mitotic microtubules -> dividing cells undergo mitotic arrest

Question 20

what are some side effects of vinca alkaloids & taxanes?

Answer 20

• nerve damage (peripheral neuropathy, autonomic neuropathy)
• hair loss
• nausea & vomiting
• bone marrow suppression
• arthralgia
• allergy

Question 21

how do topoisomerase inhibitors work?

Answer 21

topoisomerases regulate torsional strain within DNA during replication & transcription by inducing temporary breaks in phosphodiester backbone of DNA -> specific topoisomerase inhibitors alter binding of complex to DNA -> DNA breaks permanently

Question 22

wha are some examples of topoisomerase inhibitors?

Answer 22

• topotecan & irinotecan (topo I)

- etoposide (topo II)

Question 23

what are some side effects of topoisomerase inhibitors?

Answer 23

• acute cholinergic type syndrome (diarrhoea, abdominal cramps, diaphoresis - managed with atropine)
• hair loss
• nausea & vomiting
• fatigue
• bone marrow suppression

Question 24

what are some mechanisms for cell resistance to cancer drugs?

Answer 24

DNA repair mechanisms upregulated & increased dna damage repair -> less likely for dna double strand to break

• DNA adducts replaced by base excision pair
• drug effluxed from the cell by ATP-binding cassette (ABC) transporters

Question 25

what are the pros and cons of dual kinase inhibitors?

Answer 25

reduce chance of alternate pathways continuing when one pathway is blocked - however increased toxicity

Question 26

what are the 10 hallmarks of the cancer cell?

Answer 26

1. self-sufficient 2. insensitive to anti-growth signals 3. anti-apoptotic 4. pro-invasive and metastatic 5. pro-angiogenic 6. non-senescent 7. disregulated metabolism 8. evades immune system 9. unstable dna 10. inflammation

Question 27

how are normal cells stimulated to grow?

Answer 27

growth signals transmitted into cell via growth factors binding transmembrane receptors -> activates downstream signalling pathways

Question 28

how can signal amplification be increased in cancer cells?

Answer 28

- overexpressoin of receptors (HER2, EGFR) - overexpression of ligand (eg VEGF in prostate, kidney + breast) - ligand independent receptor activation (eg EGFR (lung), FGFR (head+neck))

Question 29

how can receptors on cancer cells be targeted?

Answer 29

monoclonal antibodies

Question 30

what do the suffixes of monoclonal antibodies mean?

Answer 30

momab = derived from mouse ximab = chimeric (murine component of variable region of fab is maintained integrally) zumab = humanised (murine regions interspersed within light + heavy chains of fab portion) mumab = fully human

Question 31

how do monoclonal antibodies work?

Answer 31

neutralise ligand -> receptor doesn’t dimerise -> no downstream signalling - target extracellular component of receptor - cause internalisation of receptor - complement-dependent cytotoxicity -> immune response

Question 32

what are some examples of monoclonal antibodies used in oncology?

Answer 32

bevacizumab (binds and neutralises VEGF) - improves survival in colorectal cancer) cetuximab (targets EGFR)

Question 33

what do small molecule inhibitors do?

Answer 33

bind to kinase domain of tyrosine kinase within the cytoplasm -> blocks autophosphorylation & downstream signalling

Question 34

what is glivec?

Answer 34

small molecule inhibitor that targets ATP binding region within kinase domain

Question 35

what are some examples of SMIs inhibiting receptors?

Answer 35

erlotinib gefitinib lapatinib sorafinib

Question 36

what are some examples of SMIs inhibiting intracellular kinases?

Answer 36

sorafinib, dasatinib

Question 37

what are some advantages of MABs?

Answer 37

- high target specificity - cause ADCC, complement mediated cytotoxicity + induce apoptosis - can be radiolabelled - cause target receptor internalisation - long half-life - liked by regulatory authorities

Question 38

what are some disadvantages of MABs?

Answer 38

- large with complex structure -> low tumour / BBB penetration - less useful against bulky tumours - only work against targets with extracellular domains - cause immunogenicity, allergy - parenteral administration - expensive

Question 39

what are some advantages of SMIs?

Answer 39

- can target TKs without extracellular domain / which are ligand activated - oral administration - good tissue penetration - cheap

Question 40

what are some disadvantages of SMIs?

Answer 40

- short half-life -> more frequent administration | - more unexpected toxicity

Question 41

what are some resistance mechanisms to targeted therapies?

Answer 41

- mutations in ATP binding domain - intrinsic resistance - intragenic mutations - upregulation of downstream / parallel pathways

Question 42

what are anti-sense oligonucleotides?

Answer 42

single-stranded chemically modified DNA-like molecule - complementary nucleic acid hybridisation to target gene hinders translation of specific mRNA - good for 'undruggable targets'

Question 43

what is RNA interference?

Answer 43

single stranded complementary RNA

Question 44

what is nivolumab?

Answer 44

anti PD-1 antibody - big success in treatment of melanoma

Question 45

what are some examples of new ways that cancer treatment can be delivered?

Answer 45

- nanotherapies - virtual screening technologies - immunotherapies using antigen presenting cells to present 'artificial antigens' - targeting cancer metabolism