Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation

Winkler, Frank; Kozin, Sergey V.; Tong, Ricky T.; Chae, Sung-Suk; Booth, Michael F.; Garkavtsev, Igor; Xu, Lei; Hicklin, Daniel J.; Fukumura, Dai; Tomaso, Emmanuelle di; Munn, Lance L.; Jain, Rakesh K.

doi:10.1016/j.ccr.2004.10.011

Cited by 669 publications

(450 citation statements)

References 37 publications

Supporting

Mentioning

425

Contrasting

Unclassified

Order By: Relevance

“…Alternate sequencing strategies and alterations of the degree of temporal separation between hyperthermia and radiation may be employed to maximize the likelihood that radiation is administered during periods of peak radiosensitivity defined by an optimal tumor oxygenation window or a vascular normalization window. 36,37 Lastly, targeting gold nanoshells to tumor vasculature may further localize and concentrate nanoshells along tumor vasculature to facilitate tumor-directed therapy beyond imageguided physical collimation of the laser beam to the tumor alone. Additional clinical benefit could be realized if substances with a high atomic number (Z) accumulate in tissues leading to greater radiation dose deposition, particularly while utilizing kilovolt radiation therapy where highly Z-dependent photoelectric interactions are the predominant form of interaction.…”

Section: Localization Of Gold Nanoshells Within the Tumor Microenviromentioning

confidence: 99%

Modulation of in Vivo Tumor Radiation Response via Gold Nanoshell-Mediated Vascular-Focused Hyperthermia: Characterizing an Integrated Antihypoxic and Localized Vascular Disrupting Targeting Strategy

et al. 2008

View full text Add to dashboard Cite

We report noninvasive modulation of in vivo tumor radiation response using gold nanoshells. Mild-temperature hyperthermia generated by near-infrared illumination of gold nanoshell-laden tumors, noninvasively quantified by magnetic resonance temperature imaging, causes an early increase in tumor perfusion that reduces the hypoxic fraction of tumors. A subsequent radiation dose induces vascular disruption with extensive tumor necrosis. Gold nanoshells sequestered in the perivascular space mediate these two tumor vasculature-focused effects to improve radiation response of tumors. This novel integrated antihypoxic and localized vascular disrupting therapy can potentially be combined with other conventional antitumor therapies.

show abstract

Section: Localization Of Gold Nanoshells Within the Tumor Microenviromentioning

confidence: 99%

Modulation of in Vivo Tumor Radiation Response via Gold Nanoshell-Mediated Vascular-Focused Hyperthermia: Characterizing an Integrated Antihypoxic and Localized Vascular Disrupting Targeting Strategy

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Aside from inducing similar effects, pharmacological neutralization of VEGF also decreases tumor vessel permeability and interstitial fluid pressure, improves tumor perfusion and restores the hydrostatic pressure gradient across the vascular wall, which leads to a deeper penetration of drugs and chemotherapy [14,15]. The resulting 'normalization window' increases tumor oxygenation and improves radiation therapy in most but not all tumor studies [16,17]. This normalization window is transient, since prolonged VEGF-inhibitor therapy ultimately prunes the large majority of tumor vessels, including the normalized ones.…”

Section: Introductionmentioning

confidence: 97%

Vessel abnormalization: another hallmark of cancer?Molecular mechanisms and therapeutic implications

Bock

Cauwenberghs

Carmeliet

2011

Current Opinion in Genetics & Development

184

144

View full text Add to dashboard Cite

As a result of excessive production of angiogenic molecules, tumor vessels become abnormal in structure and function. By impairing oxygen delivery, abnormal vessels fuel a vicious cycle of non-productive angiogenesis, which creates a hostile microenvironment from where tumor cells escape through leaky vessels and which renders tumors less responsive to chemoradiation. While anti-angiogenic strategies focused on inhibiting new vessel growth and destroying pre-existing vessels, clinical studies showed modest anti-tumor effects. For many solid tumors, anti-VEGF treatment offers greater clinical benefit when combined with chemotherapy. This is partly due to a normalization of the tumor vasculature, which improves cytotoxic drug delivery and efficacy and offers unprecedented opportunities for anti-cancer treatment. Here, we overview key novel molecular players that induce vessel normalization.

show abstract

“…Therapeutic TIL modified the tumor landscape by promoting the loss of DLK1 C and DLK2 C pericytes, effectively pruning immature tumor blood vessels. The normalization/maturation of the vascular network, which allows a switch from the hypoxic to a normoxic TME, 32 also resulted in tumors that were coordinately deficient in CD11b C Gr1 C MDSCs and FoxP3 C Tregs that are typically associated with immunosuppression.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

et al. 2017

View full text Add to dashboard Cite

When compared with vascular cells in normal tissues, pericytes and vascular endothelial cells (VEC) in tumor blood vessels exhibit altered morphology and epigenetic programming that leads to the expression of unique antigens that allow for differential recognition by CD8 C T cells. We have previously shown that the Notch antagonist delta-like homolog 1 (DLK1) is a tumor pericyte-associated antigen expressed in setting of melanoma and a range of carcinomas. In this report, we show that therapeutic vaccination against DLK1 in murine models results in slowed tumor growth, but also to the compensatory expression of the DLK1 homolog, DLK2, by tumor-associated pericytes. Vaccines targeting both DLK1 and DLK2 resulted in superior antitumor benefits in association with improved activation and recruitment of antigen-specific Type 1 CD8 C T cells, reduced presence of myeloid-derived suppressive cells, T regulatory cell and tumor vascular normalization. The antitumor efficacy of vaccines coordinately targeting DLK1 and DLK2 was further improved by inclusion of PD-L1 blockade, thus defining a combination immunotherapy theoretically suitable for the treatment of a broad range of solid (vascularized) cancers.

show abstract

Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation

Cited by 669 publications

References 37 publications

Modulation of in Vivo Tumor Radiation Response via Gold Nanoshell-Mediated Vascular-Focused Hyperthermia: Characterizing an Integrated Antihypoxic and Localized Vascular Disrupting Targeting Strategy

Modulation of in Vivo Tumor Radiation Response via Gold Nanoshell-Mediated Vascular-Focused Hyperthermia: Characterizing an Integrated Antihypoxic and Localized Vascular Disrupting Targeting Strategy

Vessel abnormalization: another hallmark of cancer?Molecular mechanisms and therapeutic implications

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

Contact Info

Product

Resources

About