Extra Reading

Question 1

Lecture 2 - EGFR Mutations

Answer 1

• T790 critical for the binding of erlotinib to EGFR. Thre –> Met introduces bulkier amino acid side chain than threonine –> steric hindrance which interferes with the binding of erlotinib.

Question 2

Lecture 3 - P53 treatments

Answer 2

• PRIMA-1 in combination with pembrolizumab
• Wee1: Synthetic lethality to p53. Used in resistant ovarian cancer and metastatic CRC. Enhances carboplatin sensitivity

Question 3

Lecture 3 - pRb treatments

Answer 3

CDK4/6 inhibitors for blockade of RB phosphorylation.

Question 4

Lecture 4 - Resistance to imatinib

Answer 4

• Common Imatinib resistance mutations in BCR-ABL replaces threonine –> isoleucine in the ABL tyrosine kinase domain
• leading to a structural change similar to EGFR T790M

Question 5

Lecture 5 - Sonic Hedgehog targeting therapies

Answer 5

• Arsenic trioxide
• Can suppress pathway at the level of the GLI proteins

Question 6

Lecture 6 - Combination therapies

Answer 6

• Bevacizumab in combo with irinotecan, fluorouracil, and leucovorin improves survival for metastatic colorectal cancer

Question 7

Lecture 9 - DPD targeting therapies

Answer 7

• Capecitabine
• 5-FU pro-drugs to avoid DPD-mediated degradation in the liver.

Question 8

Lecture 10 - Antimitotic drugs for angiogenesis

Answer 8

• Combrestatin in clinical trial as angiogenesis drug
• acts as a vascular targeting agent to rapidly depolymerise MT of newly formed vasculature to shut down blood supply to tumours.

Question 9

Lecture 11 - Mustards in the clinic

Answer 9

Chlorambucil –> CLL
Cyclophosphamide –> multiple myeloma and breast cancer
Estramustine –> metastatic prostate cancer

Question 10

Lecture 12 - Telomerase inhibitors mouse model

Answer 10

• Mouse model limited for studying telomerase inhibitors
• inbred mouse strains have longer telomeres and mouse telomerase widely expressed in adult tissue.

Question 11

Lecture 13 - Combination of decitabine and cisplatin

Answer 11

• In gastric cancer induce Sox2 DNA demethylation to promote expression of the Sox2 gene –> anti-tumour activity

Question 12

Lecture 14 - Other TOP-2 therapies

Answer 12

Etoposide

Question 13

Lecture 2 - Other Ras Therapies

Answer 13

• Deltarasin
• Needs further clinical testing to see toxicity and efficacy
• impair the RAS protein stimulation at the membrane and suppressing signalling

Question 14

Lecture 2 - Sotorasib MOA

Answer 14

• covalently binds to a pocket of the switch II region that is present only in the inactive GDP-bound conformation
• trapping in the inactive state

Question 15

Lecture 2 - Detection of EGFR

Answer 15

• Amplicon-based NGS and ddPCR assays used to detect T790M
• ctDNA isolation from liquid biopsies allows identification of cancer-related mutations –> when tissue biopsies not avaliable