Pharma Strategy Blog

In simple terms, glioblastoma multiforme (GBM) is the most common form of brain cancer, but also the most deadly.  Part of the reasons behind this lie in several factors:

1. It’s a highly complex disease with multiple things going on
2. It’s heterogeneous – many of the subsets have yet to be identified
3. Crossing the blood brain barrier is a challenge for therapeutics

You only have to read a couple of papers from Vogelstein’s group and others (see references) to grasp how complex the underlying biology of this disease is.  From IDH1 deletions to EGFR.   Other targets have included PDGFR-alpha, ERBB2 and MET, with limited success.

A few definitions first to make things easier for people to follow:

Amplifications: An increase in the copy number of a particular gene, which can be either inherited or somatic.  Amplification of oncogenes is a preeminent event in the pathogenesis of many types of human cancer.

Deletions: The absence of one (heterozygous deletion) or both (homozygous deletion) copies of a gene in a diploid cell.  Heterozygous deletions may or may not disrupt gene or protein function and cell function as a result.

The current research looked at Nuclear factor of κ-light polypeptide gene enhancer in B-cells (NF-κB), which is a transcription factor activated by the EGFR pathway. Constitutive activation of NF-κB has previously been observed in glioblastomas.   NF-κB inhibitor-α (NFKBIA) represses NF-κB and signaling in the NF-κB and EGFR pathways.

In addition, mutations of NFKBIA have been found in a variety of tumour types, including Hodgkin’s lymphoma, colorectal cancer, melanoma, hepatocellular carcinoma, breast cancer, and multiple myeloma, which suggests that NFKBIA is a tumour suppressor. In other words, it can prevent drive tumourigenesis and prevent existing therapies such as EGFR inhibitors from working well.

To test this idea out, they analyzed human glioblastomas (n=790) for deletions, mutations, or expression of NFKBIA and EGFR and studied the tumour-suppressor activity of NFKBIA in cell culture. They then compared the molecular results with the outcome of glioblastoma in 570 people.

What they found was interesting:

“NFKBIA is often deleted but not mutated in glioblastomas; most deletions occur in nonclassical subtypes of the disease. Deletion of NFKBIA and amplification of EGFR show a pattern of mutual exclusivity.”

The emphasis above is mine.  Unsurprisingly, deletion and low expression of NFKBIA were associated with more unfavourable outcomes:

“Patients who had tumors with NFKBIA deletion had outcomes that were similar to those in patients with tumors harboring EGFR amplification.”

The researchers concluded that:

“Deletion of NFKBIA has an effect that is similar to the effect of EGFR amplification in the pathogenesis of glioblastoma and is associated with comparatively short survival.”

What these results mean is that because NFKBIA plays such a big role downstream and essentially induces cross-talk signalling with EGFR, future therapeutic strategies may need to take this tumour suppressor into consideration.

References:

Parsons, D., Jones, S., Zhang, X., Lin, J., Leary, R., Angenendt, P., Mankoo, P., Carter, H., Siu, I., Gallia, G., Olivi, A., McLendon, R., Rasheed, B., Keir, S., Nikolskaya, T., Nikolsky, Y., Busam, D., Tekleab, H., Diaz, L., Hartigan, J., Smith, D., Strausberg, R., Marie, S., Shinjo, S., Yan, H., Riggins, G., Bigner, D., Karchin, R., Papadopoulos, N., Parmigiani, G., Vogelstein, B., Velculescu, V., & Kinzler, K. (2008). An Integrated Genomic Analysis of Human Glioblastoma Multiforme Science, 321 (5897), 1807-1812 DOI: 10.1126/science.1164382

Phillips, H., Kharbanda, S., Chen, R., Forrest, W., Soriano, R., Wu, T., Misra, A., Nigro, J., Colman, H., & Soroceanu, L. (2006). Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis Cancer Cell, 9 (3), 157-173 DOI: 10.1016/j.ccr.2006.02.019

Bredel M, Scholtens DM, Harsh GR, Bredel C, Chandler JP, Renfrow JJ, Yadav AK, Vogel H, Scheck AC, Tibshirani R, & Sikic BI (2009).  A network model of a cooperative genetic landscape in brain tumors. JAMA : the journal of the American Medical Association, 302 (3), 261-75 PMID: 19602686

Bredel, M., Scholtens, D., Yadav, A., Alvarez, A., Renfrow, J., Chandler, J., Yu, I., Carro, M., Dai, F., Tagge, M., Ferrarese, R., Bredel, C., Phillips, H., Lukac, P., Robe, P., Weyerbrock, A., Vogel, H., Dubner, S., Mobley, B., He, X., Scheck, A., Sikic, B., Aldape, K., Chakravarti, A., & Harsh, G. (2011). NFKBIA Deletion in Glioblastomas.  New England Journal of Medicine, 364 (7), 627-637 DOI: 10.1056/NEJMoa1006312