Chapter 20, Problem 28P

Glioblastoma multiforme (GBM) is the most common and aggressive form of brain cancer in humans. Withoutany treatment, the mean survival rate is about three months. Even with standard treatments such as surgical resection, radiation, and chemotherapy, the mean survival rate is between seven and 14 months. GBM tumors differ in their spectrum of genetic changes, and these changes may influence the effect of particular treatments. Answer the following questions about the relevance of particular mutations to particular treatments and outcomes.

a.	Biopsies of about 20% of GBMs show the expression of a certain mutational variant ofthe EGFR (epidermal growth factor receptor) protein called EGFRvIII. The same cancerous cells of these GBMs also show the expression of normal, wild-type EGFR. Is the gene encoding EGFR a tumor-suppressor gene or a protooncogene?
b.	It is very difficult to induce cells expressing EGFRvIII to undergo apoptosis. If you were a radiologist treating a patient with a GBM that expresses EGFRvIII, would you use a higher or lower dose of X-rays than with patients having GBMs with normal EGFR proteins?
c.	EGFR is a protein that extends through the cell membrane, with an N-terminal extracellular part (amino acids 1–500) that binds epidermal growth factor (EGF) and an intracellular C-terminal kinase part (amino acids 501–1000) that is normally activated when EGF binds to EGFR. The active kinase phosphorylates (adds phosphate groups to) other proteins, setting off a signal transduction cascade that promotes cell growth and division. EGFRvIII is a deletion that removes amino acids 6 through 273 of the EGFR protein. How might this mutant protein contribute to cancer?
d.	IressaTM is a drug that blocks the kinase activity of EGFR. Would you expect IressaTM to be a potential treatment for GBMs expressing EGFRvIII, or would you instead anticipate the drug would make the tumors grow faster?
e.	Cisplatin is a platinum compound that binds to DNA and damages it, eventually leading to cell death. ERCC1 is a gene that encodes a DNA repair protein. GBMs are found that show much higher levels of transcription of ERCC1 than normal. Would you treat patients having such GBMs with higher or lower doses of cisplatin than patients whose tumors have normal amounts of ERCC1 mRNAs?