Targeting Activated Akt with GDC-0068, a Novel Selective Akt Inhibitor That Is Efficacious in Multiple Tumor Models

Brain-specific angiogenesis inhibitor 1 (BAI1/ADGRB1) is an adhesion G protein-coupled receptor that has been found to play key roles in phagocytosis, inflammation, synaptogenesis, the inhibition of angiogenesis, and myoblast fusion. As the name suggests, it is primarily expressed in the brain, with a high expression in the normal adult and developing brain. Additionally, its expression is reduced in brain cancers, such as glioblastoma (GBM) and peripheral cancers, suggesting that BAI1 is a tumor suppressor gene. Several investigators have demonstrated that the restoration of BAI1 expression in cancer cells results in reduced tumor growth and angiogenesis. Its expression has also been shown to be inversely correlated with tumor progression, neovascularization, and peri-tumoral brain edema. One method of restoring BAI1 expression is by using oncolytic virus (OV) therapy, a strategy which has been tested in various tumor models. Oncolytic herpes simplex viruses engineered to express the secreted fragment of BAI1, called Vasculostatin (Vstat120), have shown potent anti-tumor and anti-angiogenic effects in multiple tumor models. Combining Vstat120-expressing oHSVs with other chemotherapeutic agents has also shown to increase the overall anti-tumor efficacy in both in vitro and in vivo models. In the current review, we describe the structure and function of BAI1 and summarize its application in the context of cancer treatment.

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Abstract P001: The anti-angiogenic antibody BD0801 demonstrates better anti-tumor activity than bevacizumab and synergize with chemotherapies in multiple tumor models

10.1158/1535-7163.targ-21-p001 ◽

2021 ◽

Author(s):

Liting Xue ◽

Jianxing Tang ◽

Yuyin Ding ◽

Lei Song ◽

Shansen Xu ◽

...

Keyword(s):

Tumor Models ◽

Multiple Tumor ◽

Anti Tumor Activity

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TMIC-50. 3D QUANTIFICATION OF DYNAMIC CYTOKINE GRADIENTS PRODUCED BY PRIMARY TUMOR MODELS

Neuro-Oncology ◽

10.1093/neuonc/noz175.1084 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi258-vi259

Author(s):

Eric McGhee ◽

Juan Uruena ◽

Alex McGhee ◽

Duane Mitchell ◽

Catherine Flores ◽

...

Keyword(s):

Immune Cell ◽

Fluorescent Microscopy ◽

Chemotherapeutic Agents ◽

Integrated System ◽

Fluorescence Measurement ◽

Tumor Models ◽

Multiple Tumor ◽

Wide Range ◽

Confocal Fluorescent Microscopy

Abstract BACKGROUND & SIGNIFICANCE The immune response is a coordinated effort directed by cytokine gradients and concentrations. High sensitivity and spatial resolution are necessary to resolve cytokine gradients in 3-dimensions. This system uses in situ confocal fluorescent microscopy with printed bead-based immunoassays. The combination of 3D printing of the beads and biofabrication of patient derived tumors allows for direct imaging, quantification, and movies of tumor cytokine secretion in response to challenges from immune cells, tumor associated fibroblasts, and chemotherapeutic agents. HYPOTHESIS: Cytokine dynamics can be measured in real-time by balancing concentrations of detection antibodies in solution with stationary immunoassay beads with measured capture and release rates. Favorable balancing of assay kinetics can facilitate measurements of concentrations of cytokines between 50 pg/mL to over 2,000 pg/mL. METHODS In situ confocal fluorescent microscopy identifies position, fluorescence, and type of bead relative to the in vitro tumor. Cytokines including IL2, IL6, IL8, IL11, and IFNg and growth factors such as VEGF and TGFb have been measured for a wide range of solid tumors (brain, sarcoma, and epithelial) under different stresses. RESULTS Dynamic gradients of IL8 were found across multiple tumor models showing local concentrations in excess of 2,000 pg/mL. Production rates were estimated to be over 1 protein per second for each cell, and inclusion of cancer associated support cells showed 10x increases in some cytokines. CD4+ cell production of IL2 was confirmed and quantified and showed strong sensitivity to tumor activity and antigen presentation. Multiplexed beads of CCL2, CCL5, CXCL8, CXCL9, and CXCL10 allow for simultaneous measurement of multiple chemokines. Uncertainties associated with fluorescence measurement and quantification of concentrations will be discussed. CONCLUSIONS This integrated system of 3D assay printing, biofabrication of tumors and immune cell constructs, and in situ confocal microscopy provides the first direct measurements of 3D cytokine gradients in response to tumor stress.

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