Core Technology

Background:
Tumor Microenvironment (TME) – Hypoxia

The tumor microenvironment (TME) is the environment surrounding and within a tumor. GBM tumors are hypoxic and have necrotic foci surrounded by pseudopalisades of tumor cells and microvascular hyperplasia.

Tumor hypoxia is caused by the unorganized and permeable vasculature which plays a major role in promoting aggressive and therapeutic-resistant cancers cells. This leads to rapid tumor progression and poor patient survival. Hypoxia in GBM drives tumor growth by triggering an onslaught of pathways. These responses include increased angiogenesis (blood vessel formation), tumor cell migration and invasion into the surrounding tissue, reduced apoptosis (cell death), resistance to radiation and chemotherapy, and increased tumor cell proliferation.

A major mediator of these GBM responses to hypoxia is the transcription factor HIF-1α (hypoxia-induced factor-1α). HIF-1α orchestrates GBM cellular adaptation to low oxygen by increasing angiogenesis, tumor cell survival, proliferation, migration, and invasion, and regulating pro-tumor transcription factors.

What is Disufenton sodium and
how does it work to reduce tumor growth?

OKN-007: Nitrone derivative developed by OMRF (Oklahoma Medical Research Foundation)
  • Free radical scavenger → Eliminates reactive oxygen and nitrogen species (RONS)
  • Decreases tumor necrosis/hypoxia, abnormal angiogenesis, cell proliferation, lipid metabolites associated with necrosis, and increases apoptosis. It also increases blood-brain barrier (BBB) permeability.
  • Normalizes the tumor microenvironment that drives glioblastoma growth.

Enhances glioblastoma cell death and regression of tumor growth

OKN-007 Multifunctional Activities

OKN-007 opens the Blood-Brain Barrier (BBB) and increases BBB permeability

  • OKN-007 increases blood-brain barrier (BBB) permeability in normal brain, as measured by the uptake of the MRI contrast agent, Gd-DTPA* resulting in an increased MRI signal intensity.
  • OKN-007 can be used to augment the delivery of anti-cancer agents.

(*Gd-DTPA: Gadolinium-DiethyleneTriamine Penta-Acetic acid)

Mechanisms of action: Pathways associated with OKN-007 anti-glioma activity

OKN-007 has multiple anti-cancer activities associated with its effect in gliomas, including increasing apoptosis of tumor cells and decreasing tumor cell proliferation and angiogenesis. The diagram below illustrates the mechanisms of action/pathways associated with OKN-007 anti-glioma activity.

In both the F98 and U87 glioma models, OKN-007 significantly decreases tumor hypoxia (HIF-1α), angiogenesis (MVD, VEGFR2) and cell proliferation (GLUT-1, MIB-1, and Ki-67), and increases apoptosis (cleaved caspase 3). OKN-007 decreases lipid metabolites directly associated with necrosis. OKN-007 decreases necrotic volumes.

GLUT-1: Glucose transport-1 | MIB-1: Mindbomb E3 ubiquitin protein ligase-1 | HIF-1α: Hypoxia-inducible factor-1α
MVD: Microvessel density | VEGFR2: Vascular endothelial growth factor 2

Presentations

2020 ASCO: Phase 1b clinical trial of OKN-007 in recurrent malignant glioma

American Society of Clinical Oncology

2020 SNO: Phase 1b clinical trial of OKN-007 in recurrent malignant glioma

Society of NeuroOncology

2020 SNO: Feasibility pilot study of OKN-007 in combination with adjuvant Temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma

Society of NeuroOncology

2021 SNO: Feasibility study of OKN-007 in combination with Temozolomide and radiation in newly diagnosed glioblastoma

Society of NeuroOncology

Publications

Related papers demonstrating efficacy and mechanisms of action in animal models of brain cancers

Nitrone compounds have anti-cancer activity in gliomas (C6 rat gliomas)

Doblas S et al. Phenyl-tert-butylnitrone induces tumor regression and decreases angiogenesis in a C6 rat glioma model. Free Radic Biol Med 2008; 44(1): 63-72.

Nitrone therapy restored brain architecture

Asanuma T et al. Visualization of the protective ability of a free radical trapping compound against rat C6 and F98 gliomas with diffusion tensor fiber tractography. J Magn Reson Imaging 2008; 28: 574-587.

OKN-007 increased animal survival and decreased tumor volumes (C6 rat gliomas)

Garteiser P et al. Multiparametric assessment of the anti-glioma properties of OKN007 by magnetic resonance imaging. J Magnetic Imaging 2010; 31: 796-806.

OKN-007 restored brain metabolites to near normal levels (C6 rat gliomas)

He T et al. Effects of PBN and OKN007 in rodent glioma models assessed by 1H MR spectroscopy. Free Radic Biol Med 2011; 51: 490-502.

OKN-007 reduced cell proliferation and angiogenesis and increased apoptosis (rat F98 and human xenograft U87 glioma models)

Towner RA et al. Regression of glioma growth in F98 and U87 rat glioma models by the nitrone OKN-007. Neuro Oncology 2013; 15: 330-400.

OKN-007 decreased tumor necrosis and cell proliferation and increased apoptosis (F98 rat gliomas)

Coutinho de Souza P et al. OKN-007 decreases tumor necrosis and tumor cell proliferation and increases apoptosis in a preclinical F98 rat glioma model. J Magn Reson Imaging 2015; 42: 1582-91.

OKN-007 decreased VEGFR-2 (mouse GL261 gliomas)

Coutinho de Souza P et al. OKN-007 decreases VEGFR-2 levels in a preclinical GL261 mouse glioma model. Am J Nuclear Med Mol Imaging 2015; 5(4): 363-78.

OKN-007 decreased free radicals (rat F98 gliomas)

Coutinho de Souza P et al. OKN-007 decreases free radicals levels in a preclinical F98 rat glioma model.  Free Radical Biol Med 2015; 87: 157-168.

OKN-007 decrease tumor volumes, cell proliferation, tumor microvasculature, increases survival, and restored brain metabolites (pediatric GBM patient-derived xenograft)

Coutinho de Souza P et al. Inhibition of pediatric glioblastoma tumor growth by the anti-cancer agent OKN-007 in orthotopic mouse xenografts. Plos One 2015; 10(8): e0134276.

Combining OKN-007 with TMZ decrease tumor volumes, cell proliferation, tumor microvasculature and cell migration, and increases survival (G55 GBM orthotopic xenograft)

Towner RA et al. OKN-007 Increases temozolomide (TMZ) Sensitivity and Suppresses TMZ-Resistant Glioblastoma (GBM) Tumor Growth. Trans Oncol 2019;12(2): 320-335.