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

The tumor microenvironment:problems and opportunities for therapy

Nic Denko PhD MD

Radiobiology 2013


The tumor microenvironment

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

Oxygen is a dose modifying factor

OER can be up to 3

Tannock and Hill BSO 1998


Adaptive biologic responses

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: ???


Hif dependent gene induction

PI3K/PTEN/akt

?

?

Prolyl hydroxylase

HIFb

constitutive

Ubi

Transactivation

Elongins

VHL

P564-OH

P402-OH

Hif1a

Inducible

Other

targets?

HRE

Proteasome

HIF-dependent Gene Induction

Hypoxia


Vhl connects hypoxic gene induction to human tumor formation

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

VHL-resistant HIF is tumorigenic in Renal Cell Cancers

Kaelin

CC 2002


Unfolded proteins generate a complex three prong response

Unfolded proteins generate a complex, three prong response

Kaufman JCB 2012


Disulfide bond formation requires molecular oxygen

Disulfide bond formation requires molecular oxygen

Feldman and Koong Mol Can Res 2005

Protein Glycosylation requires glucose


How to overcome hypoxia

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 ?


The tumor microenvironment problems and opportunities for therapy

Misonidozole

sensitizes

hypoxic cells

to XRT


Miso sensitizes model tumors to single dose xrt treatment

Miso sensitizes model tumors to single dose XRT treatment

1000 mg/kg

Miso pre XRT


Development of oxygen mimetics

Development of oxygen mimetics

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


Hypoxic cytotoxins

Hypoxic Cytotoxins

Tirapazamine

Drug is only

Toxic in

hypoxia


Tpz xrt in vivo

TPZ + XRT in vivo

TPZ has

Low activity

as a single agent


The tumor microenvironment problems and opportunities for therapy

Oxygen tension is a function of

Supply and demand

Supply Demand

Tumor

Circulation

Systemic

Circulation

Tumor

Vasculature

Can we modify hypoxia

from the demand side?


The tumor microenvironment problems and opportunities for therapy

Hours post DCA

Increased

oxygen consumption

Causes

Increased hypoxia

post DCA

0h 2h 4h 6h 24h

RKO RKOShHIF

d


Metabolic pdhk inhibitors can enhance tpz activity in vivo

Metabolic (PDHK) inhibitors can enhance TPZ activity in vivo

DCA has

to be given

before TPZ


Can we decrease oxygen consumption and decrease hypoxia

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

Oxylite A549 tumor MTF response


Tumor microenvironment

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.


The tumor microenvironment problems and opportunities for therapy

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)


The tumor microenvironment problems and opportunities for therapy

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


The tumor microenvironment problems and opportunities for therapy

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 tumor microenvironment problems and opportunities for therapy

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.


The tumor microenvironment problems and opportunities for therapy

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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