Brain Tumors

Penetrating the BBB

α4β1/FAK/STAT3 is clinically relevant in 94% of GBM Tumors

Effective treatment of brain tumors requires a) unfettered access to the brain; and b) a clinically relevant target whose mechanism of action plays an important role in the unrestrained aggressiveness of the tumor. 

Our proprietary drugs are high potency inhibitors of α4β1; a clinically relevant target in aggressive brain cancers where the α4β1/FAK/STAT3 controls of STAT3 activation in these therapy-resistant tumors. 

Unphosphorylated, inactive Stat3 is expressed in all cell types. Although STAT3 activation to p-STAT3 in aggressive tumors is regulated by other signaling pathways, α4β1/FAK/STAT3 is the dominant pathway in glioblastoma multiforme. 

While constitutively activated phosphorylated Stat3 (p-STAT3) is found in 94% of GBM tumors, amplification of the EGFR gene and corresponding EGFR signaling is found in only 45-50% of glioblastoma multiforme tumors.

Drug Access to Brain Tumors is Critical for Effectiveness

Overexpression of P-glycoprotein (P-gp) is one of the best characterized transporter-mediated barriers to successful cancer therapy when tumor cells become resistant. P-gp also plays a major role in restricting access of many newer drugs to overcome the blood-brain-barrier (BBB); creating a critical barrier to successful therapy in patients with brain and neurological tumors. P-gp is expressed in the luminal membrane of brain capillary endothelial cells that form the blood–brain barrier, and effluxes these drugs back into the blood. Phenothiazines have a high affinity toward brain tissue and cross the blood-brain-barrier.

Our proprietary drugs are more hydrophobic than most and they are highly potent inhibitors of the P-glycoprotein efflux pump in the blood-brain-barrier so that they have unfettered access to the brain. 

Metastatic and Pediatric Primary Brain Tumors represent Clinically Unmet Needs

Metastatic brain tumors, occurring in up to 75% of certain types of cancer patients, represent a major problem for most cancer therapeutic agents because of their limited access to the brain through the blood-brain-barrier (BBB). It has been estimated that up to 170,000 new cases of brain metastases are diagnosed in the United States each year. The most common primary cancers metastasizing to the brain are lung cancer, breast cancer, melanoma, and colon cancer. Eighty percent of brain metastases occur in the cerebral hemispheres, 15% occur in the cerebellum, and 5% occur in the brain stem. Although the five-year survival rates for patients with breast cancer are about 90%, melanoma 91% and primary brain cancer 25%, the five-year survival rates for patients with distant metastases are 24% for breast cancer, 16% for stage IV metastatic melanoma, and 2.9% for stage IV glioblastoma multiforme. 

Diffuse Intrinsic Pontine Glioma (DIPG) is a glioblastoma-like tumor in the brain stem and one of the most resistant of all cancers. DIPG primarily affects young children between 5 and 7 years old. No effective treatments exist for DIPG.