Inhibiting glioma invasion using targeted nanoparticles High grade gliomas are uniformly lethal, even following surgery, temozolomide chemotherapy and radiotherapy. Tumor recurrence is caused by regrowth of glioma cells which infiltrate large distances throughout the normal brain. Glioma-like stem cells are thought to initiate tumor recurrence as they can remain quiescent for a long time;this allows them to resist cytotoxic agents and therapies that rely on cell division (i.e., chemotherapy, radiotherapy). Examination of neuropathological samples of human glioma tumors (representing advanced symptomatic tumors) suggest that glioma cells migrate along blood vessels, white matter tracts, the extracellular space, and subpially. However, it has been difficult to characterize in molecular and cellular detail the individual migration paths in either human tumors or in experimental gliomas. To understand the cellular basis of initial glioma cell invasion we are characterizing the anatomical, biochemical and molecular basis for glioma growth and invasion. We have recently discovered that many glioma cells and glioma stem cells can grow preferentially along the network provided by the tumoral and peritumoral vasculature. As centrifugal glioma invasion occurs along tumoral and peritumoral vessels we now aim to target the blood vessels that sustain glioma cell invasion throughout the brain. Our preliminary data indicate that F3-targeted hydrogel nanoparticles target the tumoral blood vessels that support glioma cell growth, and glioma cell invasion, as well as glioma cells. In this R21 application we propose to test if biocompatible and bio-degradable, F3-targeted hydrogel nanoparticles loaded with therapeutic drugs (i.e., cisplatin, temozolomide) will kill those vessels that sustain glioma dispersion from the central tumor mass into normal brain parenchyma, as well as the main glioma tumors. The peptide F3 binds to nucleolin, a protein overexpressed by tumor vasculature and by glioma tumors, but not by normal brain. We hypothesize that selective killing of tumor blood vessels (utilizing F3-targeted nanoparticles loaded with cisplatin) will inhibit glioma invasion, in combination with F3-targeted nanoparticles loaded with temozolomide to kill the main glioma mass. This proposal will test the hypothesis that combined F3-nanoparticle mediated killing of tumor blood vessels providing the substrate for glioma invasion, and of glioma cells, will reduce glioma growth and tumor recurrence. Our previous experience in the translation of basic science advances into early phase clinical trials for the treatment of human patients suffering from malignant glioma (FDA IND-14574), supports our assertion that, should experiments support our proposed hypothesis, we will be able to efficiently translate such results into Phase I clinica trials for GBM patients.
High grade gliomas (GBMs) are highly invasive malignant brain tumors. Mechanisms by which GBMs grow throughout the brain are not well understood;we have recently shown that glioma cells migrate along the perivascular space and spread throughout the brain. Using targeted nanoparticles, to the tumor vasculature, we aim to stop these tumors from killing experimental animals. This therapeutic strategy has the potential to be further developed for the treatment of patients with GBM, and its implementation in early phase clinical trials.
|Castro, Maria G; Baker, Gregory J; Lowenstein, Pedro R (2014) Blocking immunosuppressive checkpoints for glioma therapy: the more the Merrier! Clin Cancer Res 20:5147-9|
|Castro, Maria G; Candolfi, Marianela; Wilson, Thomas J et al. (2014) Adenoviral vector-mediated gene therapy for gliomas: coming of age. Expert Opin Biol Ther 14:1241-57|
|Qin, Ming; Zong, Hong; Kopelman, Raoul (2014) Click conjugation of peptide to hydrogel nanoparticles for tumor-targeted drug delivery. Biomacromolecules 15:3728-34|
|Lowenstein, P R; Yadav, Viveka Nand; Chockley, Peter et al. (2014) There must be a way out of here: identifying a safe and efficient combination of promoter, transgene, and vector backbone for gene therapy of neurological disease. Mol Ther 22:246-7|
|VanderVeen, Nathan; Paran, Christopher; Appelhans, Ashley et al. (2014) Marmosets as a preclinical model for testing "off-label" use of doxycycline to turn on Flt3L expression from high-capacity adenovirus vectors. Mol Ther Methods Clin Dev 1:|
|Assi, Hikmat H; Paran, Chris; VanderVeen, Nathan et al. (2014) Preclinical characterization of signal transducer and activator of transcription 3 small molecule inhibitors for primary and metastatic brain cancer therapy. J Pharmacol Exp Ther 349:458-69|
|Assi, Hikmat; Espinosa, Jaclyn; Suprise, Sarah et al. (2014) Assessing the role of STAT3 in DC differentiation and autologous DC immunotherapy in mouse models of GBM. PLoS One 9:e96318|
|Candolfi, Marianela; Yagiz, Kader; Wibowo, Mia et al. (2014) Temozolomide does not impair gene therapy-mediated antitumor immunity in syngeneic brain tumor models. Clin Cancer Res 20:1555-65|