Hall 26 - Biology & Exploitation of Tumor Hypoxia

Question 1

What does the hypoxia inducible factor do?

Answer 1

HIFs are transcription factors that facilitate oxygen delivery and adaptation to hypoxia

Question 2

How do HIFs bind DNA?

Answer 2

As a heterodimer with oxygen-sensitive alpha-subunit (and a constitutively expressed beta-subunit, aka ARNT)

Question 3

How is HIF regulated under normoxia?

Answer 3

HIF is hydroxylated (using O2 as a substrate) and VHL binds and promotes ubiquitination and proteosomal degradation

Question 4

What can aberrantly increase HIF activity?

Answer 4

Increased PI3K/Akt/mTOR signaling
(loss of PTEN)

Germline or somatic mutations in VHL

Question 5

What are the downstream target genes of HIF?

Answer 5

VEGF-A > angiogenesis

Decreased aerobic respiration > increased glycolytic metabolism (Warburg effect) via increase in PDK1 (that inactivates PDH and GLUT1*)

Changes in MMPs and cell adhesion molecules > metastasis

EPO

Carbonic anhydrase-9 (CA-9) > acidic tumor environment

Question 6

What is the unfolded protein response (UPR)?

Answer 6

Unfolded proteins accumulate in endoplasmic reticulum > inhibits protein translation and induces folding chaperones

IRE1 splices mRNA of XBP1 > XBP1 translation > transcription

PERK activation

*Inhibition of XBP1 or PERK decreases tumor growth

Question 7

How can you increase the radiosensitivity of hypoxic (but not aerated) cells?

Answer 7

High LET radiation
Hyperbaric oxygen, carbogen
Blood transfusions

Chemical radiosensitizers (diffuse to hypoxic cells and fix free radical damage) - nimorazole (dose limiting peripheral neuropathy)

Question 8

How do hypoxic cytotoxins target hypoxic cells?

Answer 8

Reduced intracellularly (by hypoxic environment) > bioreductive drug

Ex) Mitomycin C (MMC), tirapazamine

Question 9

How can you target hypoxic cell metabolism?

Answer 9

Inhibit PDK1 with dichloroacetate
Inhibit mitochondrial electron transport chain