β1 Integrins and Brain Tumors

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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. 

The most intractable primary brain tumor (DIPG) occurs in children has one of the shortest life expectancies. 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 and these children survive less than one year after diagnosis. No effective treatments currently exist for DIPG. 

Over the past ten years substantial discovery and clinical development effort has focused on epigenetic targets such as EZH2, HDAC and demethylation inhibitors that address the H3K27 mutations present in DIPG. Although the H3K27 mutations imply treatment with these inhibitors would benefit patients, no significant differences in cell proliferation, viability, apoptosis or in vivo survival occur in H3K27 (positive) tumors compared with H3K27 (negative) tumors.  

Oncorx is developing non-toxic, target-selective EZH2 inhibitors as drug therapy for several types of therapy-resistant tumors, including DIPG.