Metastatic cancer occurs when tumor cells spread from the original (or primary) cancer site to a distant location. Cancer that has spread (or metastasized) to a secondary location organ retains some of the features and characteristics of the primary tumor. Therefore, for example, the metastatic lesions in the brain of breast cancer will resemble breast cancer and not brain cancer.
Cancer can metastasize just about anywhere in the body, and likewise, almost all primary cancer can undergo metastatic spread. Common metastatic sites include the brain, bone, liver, and lung.
Developing effective treatments for patients with cancers metastasizing to the brain remains a challenge due in part to difficulty getting drugs past the blood-brain barrier. In addition, brain metastasis occurs in about 20 – 45% of cancer patients.
A new study published in Neuro-Oncology Advances has found a protein associated with poor prognosis for patients with brain metastases. The researchers evaluated brain metastases for proteins that correspond to prognosis. The 30 brain metastases obtained for the study originated from patients with various primary cancers, including bladder, breast, colon, esophagus, lung, skin, and uterus cancers. Additionally, three brain metastases samples came from patients with a primary tumor of unknown origin.
The study involved a technique called RNA sequencing (RNA-seq) which uncovers the RNA present in a biological sample. RNA-seq allowed the researchers to identify all the genes in each brain metastases evaluated.
An analysis found high levels of a specific gene, UBE2C, in the samples examined. UBE2C has many roles in cellular biology, including facilitating an integral step in the cell cycle known as the metaphase-to-anaphase transition.
The study also included tissue microarray (TMA) analysis from 89 independent patients with brain metastases. The TMAs, which allow analysis of protein expression from tissue samples on a microscope slide, came from patients with primary breast, kidney, colon, lung, and skin cancers. Researchers can use this technique to test samples from very small pieces of tumor.
TMA analysis showed poor prognosis correlated to brain metastases with high expression of UBE2C. On average, the patients with the best prognosis lived seven months longer than those with the worst prognosis. Notably, samples from patients with primary brain cancer did not express UBE2C as often as brain metastases. This finding indicates that UBE2C upregulation is unique to brain metastases and not all malignancies in brain tissue.
The researchers then performed a drug screening of 650 compounds, identifying two candidates with the potential to treat UBE2C-driven BM. Mouse models found one of the identified compounds, a PI3K/mTOR inhibitor (dactolisib), prevented brain metastases associated with UBE2C.
Further validation of the role of UBE2C in brain metastases could guide scientists in developing targeted therapies to help patients with metastatic disease.
Sources: Nat Rev Dis Primers, Neuro-Oncol Adv, J Hematol Oncol, Eur J Biochem, Adv Cancer Res