The tumor microenvironment problems and opportunities for therapy
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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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The tumor microenvironment: problems and opportunities for therapy

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The tumor microenvironment:problems and opportunities for therapy

Nic Denko PhD MD

Radiobiology 2013

The tumor microenvironment

  • Unique architectural, physiologic and cellular environment

  • Poor perfusion leads to decreased oxygen (hypoxia), decreased nutrients (hypoglycemia), and increased waste products (acidosis

  • All these stresses have compensatory adaptive cellular responses

Oxygen is a dose modifying factor

OER can be up to 3

Tannock and Hill BSO 1998

Adaptive Biologic Responses

  • Hypoxia: HIF-1 (HIF1a and HIF2a), UPR, SREBP-1, ATF-3, NF-KB

  • Hypoglycemia: HIF-1, Mondo, UPR

  • Acidosis: Sp1 (renal tubule cells), mRNA stability

  • Increased IFP: ???




Prolyl hydroxylase















HIF-dependent Gene Induction


VHL connects hypoxic gene induction to human tumor formation

  • VHL is a classic “two hit” tumor suppressor

  • Loss of VHL leads to constitutive HIF-1 activity

  • Model tumors suggest that this regulation of HIF is a major activity for tumor suppression

VHL-resistant HIF is tumorigenic in Renal Cell Cancers


CC 2002

Unfolded proteins generate a complex, three prong response

Kaufman JCB 2012

Disulfide bond formation requires molecular oxygen

Feldman and Koong Mol Can Res 2005

Protein Glycosylation requires glucose

How to overcome hypoxia?

  • More oxygen delivery

    • RBC Mass (transfusion, Epo)

    • Inhaled oxygen (100% F1 02)

    • Vasorelaxants (hydralazine)

  • Oxygen mimetics (Misonitozole, etanidozole, nimorazole)

  • Hypoxic cytotoxins (MMC, TPZ, AQ4N, Pr104)

  • Less oxygen utilization ?



hypoxic cells

to XRT

Miso sensitizes model tumors to single dose XRT treatment

1000 mg/kg

Miso pre XRT

Development of oxygen mimetics

Nimorazole shown to be beneficial in patients with HNC treated with XRT

Hypoxic Cytotoxins


Drug is only

Toxic in


TPZ + XRT in vivo

TPZ has

Low activity

as a single agent

Oxygen tension is a function of

Supply and demand

Supply Demand







Can we modify hypoxia

from the demand side?

Hours post DCA


oxygen consumption


Increased hypoxia

post DCA

0h 2h 4h 6h 24h



Metabolic (PDHK) inhibitors can enhance TPZ activity in vivo

DCA has

to be given

before TPZ

Can we decrease oxygen consumptionand decrease hypoxia?

  • Use drugs that decrease mitochondrial function and reduce overall tumor oxygen consumption

  • Measure changes in oxygenation

  • Measure radiosensitization

Oxylite A549 tumor MTF response

Tumor Microenvironment

  • No microenvironment modifying agents have yet been successful in improving XRT (nimorazole in Europe).

  • HIF1 may be a marginal target, XBP1 may have some efficacy, Hgb increases always make the patient feel better.

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),

B. pimonidazole

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 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) 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

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