The tumor microenvironment: problems and opportunities for therapy. Nic Denko PhD MD Radiobiology 2013. The tumor microenvironment. Unique architectural, physiologic and cellular environment
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Nic Denko PhD MD
OER can be up to 3
Tannock and Hill BSO 1998
ProteasomeHIF-dependent Gene Induction
Kaufman JCB 2012
Feldman and Koong Mol Can Res 2005
Protein Glycosylation requires glucose
Miso pre XRT
Nimorazole shown to be beneficial in patients with HNC treated with XRT
Drug is only
as a single agent
Supply and demand
Can we modify hypoxia
from the demand side?
0h 2h 4h 6h 24h
to be given
Which of the following agents has NOT been found to be useful for measuring human tumor hypoxia?
A. [18F]- 2-fluoro-2-deoxy-D-glucose (FDG),
C. [18F]AzomycinArabinoside (FAZA)
D. [64Cu]- Copper dithiosemicarbazone (ATSM)
E. [18F]Fluoromisonidazole (FMISO)
Pre-treatment correction of anemia with either blood transfusion or epomay be considered in cancer patients. This is based, in part, on which one of the following observations?
A. In a German/Swiss, multicenter, randomized, clinical trial, advanced head and neck cancer patients receiving epoetinalfa achieved higher hemoglobin concentrations and longer progression-free survival than placebo.
B. Anemia correction has been shown to improve quality of life by reducing fatigue.
C. In the Breast Cancer Erythropoietin Survival Trial (BEST), patients with metastatic breast cancer demonstrated improved overall survival when treated with epoetin alpha compared to placebo.
D. The activation of hypoxic signaling pathways, including HIF-1α, is associated with resistance to therapy and depends critically on hemoglobin levels
Which transfusion statement describing tumor vasculature is correct?
A. Tumor blood vessels are hyper-permeable, tortuous, and feature haphazard patterns of interconnection, resulting in spatial and temporal heterogeneity of tumor blood flow.
B. Tumor blood vessels are hypopermeable, irregular, and densely invested with pericytes resulting in poor diffusion of chemotherapeutics into tumor parenchyma.
C. Tumor blood vessels are indistinguishable from normal blood vessels ultrastructurally, however compression caused by proliferating tumor cells leads to vessel collapse and compromised blood flow.
D. Tumor blood vessels are dilated, tortuous and have uniformly thick basement membranes, resulting in limited accessibility of chemotherapy agents.
E. Tumor blood vessel organization resembles that of normal vessels, however tumor vessels differ ultrastructurally, resulting in poor function and heterogeneous blood flow.
The regulation of hypoxia-inducible factor-1α (HIF-1α transfusion ) by oxygen concentration is best described by which of the following statements?
A. Under hypoxic conditions, HIF-1α transcription and translation are upregulated, causing the protein to translocate from the cytosol to the nucleus.
B. Under aerobic conditions, the HIF-1α heme moiety becomes oxygenated. This drives a conformational change in the protein limiting DNA binding preventing up-regulation of target genes.
C. Under hypoxic conditions, HIF-1α is activated by bioreduction, thereby promoting the up-regulation of target genes.
D. Under hypoxic conditions, the HIF-1α heme moiety becomes
deoxygenated. This causes a conformational change in the protein,
enhancing DNA binding promoting up-regulation of target genes.
E. Under aerobic conditions, HIF-1α is hydroxylated by HIF prolyl
hydroxylases. This targets the protein for ubiquitination and subsequent proteosomaldegradation, thereby preventing the up-regulation of target genes.
Methods currently under investigation to monitor the effectiveness of antiangiogenic
therapy include all of the following, EXCEPT:
A. dynamic MRI/CT and PET imaging
B. serial tumor biopsies
C. plasma levels of bevacizumab
D. VEGF concentration in the urine
E. presence of vascular endothelial cells in the peripheral blood