Cancer Pharmacogenomics Flashcards
1
Q
Genetic Variations
A
- Differences in DNA sequence between people
- NOT mutations
2
Q
Examples of Genetic Variations
A
- Insertions (Indels)
- Deletions (Indels)
- Inversions
- Amplifications
- Duplications
- Single Nucleotide Polymorphisms (SNPs)
- Translocations
3
Q
Possible Consequences of Genetic Variations
A
- Translocations (dysregulated gene expression, chimeric proteins)
- Copy number variants (more copies)
- Non-coding region variants
- Coding Region variants
4
Q
Coding Region SNPs may result in…
A
- Reduced protein activity compared to common variant
- Increased enzyme activity
- No change in enzyme activity
- Must do functional assay to determine effect
5
Q
Non-coding Region Variants
A
- Changes in enzyme levels
- Reduced levels of gene expression, decreased activity
- Increased levels of gene expression, increased activity
6
Q
Somatic Mutations
A
- Neoplasms are heritably altered
- Genetic changes in cancer are mutations (not born variants)
- Mutations can create specific targets for cancer treatment or can make it resistant to treatments
7
Q
EGFR Inhibitors
A
- EX: Cetuximab and Panitumumab
- Monoclonal antibodies used to treat mCRC
- Bind to extracellular EGFR domain to inhibit downstream signaling
- Only 10-20% benefit from anti-EGFR
- EGFR doesn’t correlate with clinical benefit
8
Q
KRAS
A
- NRAS, HRAS, and KRAS are 3 family gene members
- KRAS is most frequently found mutated in human cancers
- Belongs to gene family of oncogenes encoding GTP-binding proteins
- Downstream effector of EGFR
- Its pathways controls cell growth, differentiation, and apoptosis
9
Q
KRAS Cancer Mutations
A
- Functional effect: downstream activation of signaling pathways and confers resistance to inhibition of cell surface receptor tyrosine kinases such as EGFR
- Prevalence: 27-43% of colorectal cancer patients
10
Q
Anti-EGFR Efficacy + KRAS
A
- Reduces likelihood of responding to anti-EGFR therapy by ~1/3
- Evaluate for KRAS mutations in all mCRC patients before giving anti-EGFR therapy
11
Q
6MP + TPMT
A
- TPMT inactivates 6 MP
- 6MP is used to treat pediatric leukemias
12
Q
TPMT
A
- Thiopurine S-methyltransferase
- Deficiency is an autosomal recessive inherited trait
- Polymorphisms in its gene/allele results in low activity
- Less TPMT leads to decreased clearance of active 6MP and increased toxicity (myelosuppression, hepatotoxicity)
- Multiple variants but 3 alleles account for 95% of the deficiencies
13
Q
6MP Clinical Applications
A
- Efficacy: no loss of efficacy was observed if reduced in patients with low/absent TPMTs
- Toxicity: Severe hematologic toxicity developed in those given standard doses with one of these variants
14
Q
6MP Clinical Relevance
A
- Dosing/Selection: 80-90% dose reduction in those with variants
- If heterozygous variation, dosing recommendations aren’t as clear
- NUDT15 variants now taken into consideration
15
Q
Irinotecan
A
- Camptosar
- Class of topoisomerase inhibitors
- Activity against variety of malignancies like colorectal and SCLC
- Binds to topoisomerase I and inhibits the cleavable complex resulting in DNA breaks
- Prodrug that is metabolized to SN-38 (active form) by UGT1A1
- Significant SE like diarrhea, neutropenia, and vascular syndromes
