Magnetic resonance imaging monitors physiological changes with antihedgehog therapy in pancreatic adenocarcinoma xenograft model

Alexander Guimaraes, Elena Rakhlin, Ralph Weissleder, Sarah P. Thayer

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

OBJECTIVES:: The sonic hedgehog (Shh) pathway has an established role in pancreatic cancer (pancreatic adenocarcinoma [PDAC]). We tested whether magnetic resonance imaging measures of vascular volume fraction (VVF) using magnetic iron oxide nanoparticles are sensitive to the antiangiogenic effect of targeted Shh therapies in a PDAC xenograft model. METHODS:: Pancreatic adenocarcinoma xenograft lines were subcutaneously implanted into nude mice (n = 19 samples within 4 groups). Therapies were targeted to 3 loci of the Shh signaling pathway (anti-Shh antibody, cyclopamine, or forskolin). Magnetic resonance imaging (4.7-T Bruker Pharmascan) was performed (after 1 week of intraperitoneal therapy) before and after intravenous injection of MION-47. Vascular volume fraction was quantified as ΔR2 (from multicontrast T2 sequences) and normalized to an assumed VVF in muscle of 3%. Linear regression compared VVF to histological indices including microvessel density (MVD), viable gland density (VGD), and proliferative index (PI). RESULTS:: In response to anti-Hh treatment, tumors showed a decrease in VGD, PI, MVD, and VVF compared with controls (P <0.001). Vascular volume fraction was compared with histological indicators of response: PI (R = 0.88; P <0.05), VGD (R = 0.87; P<0.05), and MVD (R = 0.85; P <0.05). CONCLUSIONS:: Magnetic resonance imaging VVF using magnetic iron oxide nanoparticles may serve as a noninvasive measure of biological response to Shh PDAC therapy with easy translation to the clinic.

Original languageEnglish (US)
Pages (from-to)440-444
Number of pages5
JournalPancreas
Volume37
Issue number4
DOIs
StatePublished - Nov 2008
Externally publishedYes

Fingerprint

Heterografts
Blood Vessels
Hedgehogs
Adenocarcinoma
Magnetic Resonance Imaging
Microvessels
Nanoparticles
Therapeutics
Colforsin
Pancreatic Neoplasms
Nude Mice
Intravenous Injections
Linear Models
Muscles
Antibodies
Neoplasms

Keywords

  • Angiogenesis
  • Magnetic resonance imaging
  • Nanoparticle
  • Pancreatic cancer
  • Sonic hedgehog

ASJC Scopus subject areas

  • Hepatology
  • Internal Medicine
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Magnetic resonance imaging monitors physiological changes with antihedgehog therapy in pancreatic adenocarcinoma xenograft model. / Guimaraes, Alexander; Rakhlin, Elena; Weissleder, Ralph; Thayer, Sarah P.

In: Pancreas, Vol. 37, No. 4, 11.2008, p. 440-444.

Research output: Contribution to journalArticle

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abstract = "OBJECTIVES:: The sonic hedgehog (Shh) pathway has an established role in pancreatic cancer (pancreatic adenocarcinoma [PDAC]). We tested whether magnetic resonance imaging measures of vascular volume fraction (VVF) using magnetic iron oxide nanoparticles are sensitive to the antiangiogenic effect of targeted Shh therapies in a PDAC xenograft model. METHODS:: Pancreatic adenocarcinoma xenograft lines were subcutaneously implanted into nude mice (n = 19 samples within 4 groups). Therapies were targeted to 3 loci of the Shh signaling pathway (anti-Shh antibody, cyclopamine, or forskolin). Magnetic resonance imaging (4.7-T Bruker Pharmascan) was performed (after 1 week of intraperitoneal therapy) before and after intravenous injection of MION-47. Vascular volume fraction was quantified as ΔR2 (from multicontrast T2 sequences) and normalized to an assumed VVF in muscle of 3{\%}. Linear regression compared VVF to histological indices including microvessel density (MVD), viable gland density (VGD), and proliferative index (PI). RESULTS:: In response to anti-Hh treatment, tumors showed a decrease in VGD, PI, MVD, and VVF compared with controls (P <0.001). Vascular volume fraction was compared with histological indicators of response: PI (R = 0.88; P <0.05), VGD (R = 0.87; P<0.05), and MVD (R = 0.85; P <0.05). CONCLUSIONS:: Magnetic resonance imaging VVF using magnetic iron oxide nanoparticles may serve as a noninvasive measure of biological response to Shh PDAC therapy with easy translation to the clinic.",
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AB - OBJECTIVES:: The sonic hedgehog (Shh) pathway has an established role in pancreatic cancer (pancreatic adenocarcinoma [PDAC]). We tested whether magnetic resonance imaging measures of vascular volume fraction (VVF) using magnetic iron oxide nanoparticles are sensitive to the antiangiogenic effect of targeted Shh therapies in a PDAC xenograft model. METHODS:: Pancreatic adenocarcinoma xenograft lines were subcutaneously implanted into nude mice (n = 19 samples within 4 groups). Therapies were targeted to 3 loci of the Shh signaling pathway (anti-Shh antibody, cyclopamine, or forskolin). Magnetic resonance imaging (4.7-T Bruker Pharmascan) was performed (after 1 week of intraperitoneal therapy) before and after intravenous injection of MION-47. Vascular volume fraction was quantified as ΔR2 (from multicontrast T2 sequences) and normalized to an assumed VVF in muscle of 3%. Linear regression compared VVF to histological indices including microvessel density (MVD), viable gland density (VGD), and proliferative index (PI). RESULTS:: In response to anti-Hh treatment, tumors showed a decrease in VGD, PI, MVD, and VVF compared with controls (P <0.001). Vascular volume fraction was compared with histological indicators of response: PI (R = 0.88; P <0.05), VGD (R = 0.87; P<0.05), and MVD (R = 0.85; P <0.05). CONCLUSIONS:: Magnetic resonance imaging VVF using magnetic iron oxide nanoparticles may serve as a noninvasive measure of biological response to Shh PDAC therapy with easy translation to the clinic.

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