A Novel Theranostic Strategy for <i>MMP-14</i>–Expressing Glioblastomas Impacts Survival

Mohanty, Suchismita; Chen, Zixin; Li, Kai; Morais, Goreti Ribeiro; Klockow, Jessica; Yerneni, Ketan; Pisani, Laura; Chin, Frederick T.; Mitra, Siddhartha; Cheshier, Samuel; Chang, Edwin; Gambhir, Sanjiv S.; Rao, Jianghong; Loadman, Paul M.; Falconer, Robert A.

doi:10.1158/1535-7163.mct-17-0022

Cited by 37 publications

(38 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to future exploration in terms of abnormal vessel formation, immunoresponse, and other host-tumor interactions, the use of MMPs for targeting and imaging of brain cancers is very encouraging. 208,209 Other areas that lack information are MMP epigenetic and metabolic effector functions (including the epigenetic induction of MMPs). An almost uncharted territory in the brain for MMP enthusiasts are the unique mechanical properties of the brain parenchyma and the complicated changes that take place with the ECM during brain diseases.…”

Section: Resultsmentioning

confidence: 99%

Current insights into matrix metalloproteinases and glioma progression: transcending the degradation boundary

Pullen¹,

Pickford²,

Perry³

et al. 2018

MNM

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) remains one of the most deadly cancers, with modest advances in overall survival despite significant improvements in imaging, surgery, and molecular genomic understanding. The highest-grade glioma, GBM is a primary brain cancer that is molecularly heterogeneous among patients and even within the same patient. Key hallmarks include glioma-cell invasion, angiogenesis, and therapeutic resistance. While once considered a major player in glioma invasion, members of the MMP family are also associated with other key pathological hallmarks of glioma. Investigations into understanding MMP function in GBM were slowed due to the failed MMP-inhibitor trials for GBM in the 2000s. In contrast, the field of MMPs in other brain pathologies has flourished in such areas as traumatic brain injury, multiple sclerosis, and stroke. In the past decade, the increase in publicly available data sets documenting patient-biopsy molecular information has empowered laboratory investigations into the spectrum of genomic, transcriptomic, and proteomic changes associated with glioma, including MMPs. In this review, we selected one of these data sets to illustrate a small sample of information that can be obtained from such analyses. Combined with recent reports on the use of MMP-cleavable peptides for imaging and the multifunctionality of MMPs, including intracellular nonproteolytic actions in various cell types, this paves the way for new avenues of MMP research. Understanding the function of MMPs in host-tumor interactions both spatially and temporally during tumor progression and in response to treatment will be crucial for the advancement of targeting specific MMPs in GBM. The opportunities to explore MMP regulation, expression, and function further in GBM have never been so great with progress in modern bioinformatics and molecular techniques, and it is hoped that advancements will translate in some way to patients diagnosed with GBM.

show abstract

Section: Resultsmentioning

confidence: 99%

Current insights into matrix metalloproteinases and glioma progression: transcending the degradation boundary

Pullen¹,

Pickford²,

Perry³

et al. 2018

MNM

View full text Add to dashboard Cite

show abstract

“…However, a major disadvantage of these methods is their invasive nature and lack of clinical availability. We established ferumoxytol‐MRI as a new imaging biomarker for tumor response to TAM‐modulating therapies in mouse models of breast cancer (Daldrup‐Link et al ., ), brain cancer (Mohanty et al ., ), and osteosarcomas (Mohanty et al ., ). In addition, we recently showed that ferumoxytol‐MRI can quantify TAM quantities in patients with osteosarcoma and lymphoma (Aghighi et al ., ) and brain cancer (Iv et al ., ).…”

Section: Discussionmentioning

confidence: 99%

“…Dluciferin (firefly) potassium salt solution (Biosynth, Itasca, IL, USA; 15 mgÁmL À1 ) was injected intraperitoneally (0.139 g luciferin per kg body weight), and mice were imaged until peak radiance was achieved. Total flux (photons per second) of osteosarcomas was measured by a single operator who was blinded to the experimental groups, using LIVING IMAGE 4.0 software (Mohanty et al, 2017;Zanganeh et al, 2016). Total tumor flux (y-axis) was plotted against different time points (x-axis) to measure tumor growth overtime.…”

Section: Bioluminescent Imagingmentioning

confidence: 99%

“…Decalcification with 10% EDTA was performed as described previously (Belluoccio et al, 2013). For Prussian blue iron staining, tissues sections were deparaffinized with xylene, rehydrated, and stained according to the manufacturer's recommendation with the Sigma-Aldrich Accustain Iron Stain Kit (Sigma-Aldrich, St. Louis, MO, USA) (Mohanty et al, 2017). The DAB-Quanto kit (Thermo Scientific, Waltham, MA, USA) was used to enhance Prussian blue stains.…”

Section: Immunocytochemistrymentioning

confidence: 99%

See 1 more Smart Citation

Improving the efficacy of osteosarcoma therapy: combining drugs that turn cancer cell ‘don't eat me’ signals off and ‘eat me’ signals on

et al. 2019

Self Cite

View full text Add to dashboard Cite

The long‐term survival of osteosarcoma patients with metastatic or recurrent disease remains dismal, and new therapeutic options are urgently needed. The purpose of our study was to compare the efficacy of CD47 mAb plus doxorubicin combination therapy in mouse models of osteosarcoma with CD47 mAb and doxorubicin monotherapy. Forty‐eight NOD scid gamma (NSG) mice with intratibial MNNG/HOS tumors received CD47 mAb, doxorubicin, combination therapy, or control IgG treatment. Twenty‐four mice (n = 6 per group) underwent pre‐ and post‐treatment magnetic resonance imaging (MRI) scans with the macrophage marker ferumoxytol, bioluminescence imaging, and histological analysis. Tumor ferumoxytol enhancement, tumor flux, and tumor‐associated macrophages (TAM) density were compared between different groups using a one‐way ANOVA. Twenty‐four additional NSG mice underwent survival analyses with Kaplan–Meier curves and a log‐rank (Mantel–Cox) test. Intratibial osteosarcomas demonstrated significantly stronger ferumoxytol enhancement and significantly increased TAM quantities after CD47 mAb plus doxorubicin combination therapy compared to CD47 mAb (P = 0.02) and doxorubicin monotherapy (P = 0.001). Tumor‐bearing mice treated with CD47 mAb plus doxorubicin combination therapy demonstrated significantly reduced tumor size and prolonged survival compared to control groups that received CD47 mAb (P = 0.03), doxorubicin monotherapy (P = 0.01), and control IgG (P = 0.001). In conclusion, CD47 mAb plus doxorubicin therapy demonstrates an additive therapeutic effect in mouse models of osteosarcomas, which can be monitored with an immediately clinically applicable MRI technique.

show abstract

“…Our recent article by Mohanty et al in Molecular Cancer Therapeutics 1 reported significant therapeutic efficacies of novel theranostic nanoparticles (TNPs) for the treatment of human brain cancers in mouse models. The concept is based on the specific activation of TNPs by enzymes in the tumor tissue, matrix metalloproteinases (MMP-14), which leads to vascular damage and tumor necrosis.…”

mentioning

confidence: 99%

Rethinking Brain Cancer Therapy: Tumor Enzyme Activatable Theranostic Nanoparticles

Daldrup-Link

2017

Mol Imaging

Self Cite

View full text Add to dashboard Cite

This invited commentary discusses a recent article by Mohanty et al in Molecular Cancer Therapeutics about significant therapeutic efficacies of novel theranostic nanoparticles (TNPs) for the treatment of human brain cancers in mouse models. The TNPs were cleaved by enzymes in the tumor tissue, matrix metalloproteinase (MMP-14), which lead to release of a highly potent therapeutic drug, azademethylcolchicine. Data showed that the TNPs caused selective toxic effects in MMP-14-expressing glioblastoma and not normal brain. In addition, the iron oxide nanoparticle backbone enabled in vivo drug tracking with magnetic resonance imaging (MRI). This commentary discusses previous efforts of MMP-targeted therapeutics as well as opportunities for further refinements of tumor enzyme-activatable TNPs. If successfully translated to clinical applications, the TNPs might hold substantial potential to improving cytotoxic indexes and long-term outcomes of patients with brain cancer compared to standard therapy.

show abstract

A Novel Theranostic Strategy for MMP-14–Expressing Glioblastomas Impacts Survival

Cited by 37 publications

References 48 publications

Current insights into matrix metalloproteinases and glioma progression: transcending the degradation boundary

Current insights into matrix metalloproteinases and glioma progression: transcending the degradation boundary

Improving the efficacy of osteosarcoma therapy: combining drugs that turn cancer cell ‘don't eat me’ signals off and ‘eat me’ signals on

Rethinking Brain Cancer Therapy: Tumor Enzyme Activatable Theranostic Nanoparticles

Contact Info

Product

Resources

About