Regenerative medicine and genetic aspects of respiration

Question 1

Possible ways to regenerate lung tissue after injury

Answer 1

• Using MSCs (mesenchymal stem cells): they do not engraft or differentiate into lung cells, but they do have anti-inflammatory and growth-promoting effects
• MSCs are immune privileged and thus do not require immunosuppression
• Endogenous lung progenitor cell (ELPC): are found via labeling by the Cre/lox system, tying lox to GFP and Cre to a protein of interest expressed by ELPCs
• Using ELPCs has the potential to grow new lung, but also has the risk of developing cancer stem cells

Question 2

Advantages and disadvantages for using induced pluripotent stem cells (iPS)

Answer 2

• Advantages: cells generated from iPS have same genetic background as pt (b/c they are from the pt) so rejection not an issue
• Best iPS use may be in modeling diseases in an individual
• Disadvantages: safety concerns about using retroviral transfection of transcription factors to make the iPS, possible malignant transformation, likely cannot do everything embryonic stem cells can

Question 3

DTC genetic testing for smoking behavior

Answer 3

• Looking for SNPs in the CHRNA3 (nicotinic) receptor

- Some SNPs in this gene can lead to a predisposition of people to smoke more/become addicted to cigarettes more easily

Question 4

Mutational landscape of lung CA

Answer 4

• Mutations in nicotinic receptor can lead to increased addiction
• AdenoCA associated w/ mutations in telomeres
• Squamous cell CA associated w/ mutations in cell cycle control and DNA repair
• IMPORTANT: mutations in smokers are usually C->A (for NSCLC) whereas mutations in non smokers are usually C->T (also for NSCLC)
• Important thing is that carcinogens in smoke increase odds of particular mutations, and these may lead to CA
• Also: tumors from smokers had 10x more point mutations than those from non smokers

Question 5

Functionally significant driver mutations in lung CA and how they arise

Answer 5

• LOF mutations: mutations of tumor suppressor genes involving inactivating point mutations, deletions, or epigenetic silencing
• GOF mutations: mutations of oncogenes involving activating point mutations, gene amplifications, or gene translocations

Question 6

Implications of intra-tumor genetic heterogeneity

Answer 6

• One tumor may have different mutations in different areas
• Rx w/ a drug may kill one area, but a different area may become resistant and then spread
• May be a method of inducing drug resistance
• Intratumor heterogeneity could foster tumor adaptation and therapeutic failure through selection

Question 7

Fundamental principles underlying Ab and tyrosine kinase inhibitor Rx

Answer 7

• NSCLC w/ activating mutations in EGFR are senstivite to gefitinib Rx
• All pts eventually develop resistance to TKIs
• Resistance to TKIs may be overcome by using an EGFR Ab along w/ the TKI
• Major mutations that can be Rx w/ TKIs: EGFR, KRAS, ALK

Question 8

Strategies to address drug resistance

Answer 8

• Using Abs to receptors along w/ TKIs for genes like EGFR, KRAS, and ALK
• This may allow for overcoming TKI drug resistance