Not all cancers are the same.

Each year, in the USA alone, approximately 10,000 new patients are diagnosed with glioblastoma, a severe form of brain cancer. Despite intense treatment plans and supportive care, the median survival rate remains approximately 12-15 months.

This cancer of the central nervous system is the most common and lethal neoplasm of the central nervous system. Typical symptoms of glioblastoma include headaches, seizures, neurological deficits, memory loss, and personality changes.

What Makes Glioblastoma So Severe?

Despite the unprecedented rate of medical advances, it remains almost impossible to completely remove a glioblastoma tumor mass with surgery. The reason for this is that glioblastoma tumors aggressively infiltrate into surrounding, healthy regions of the brain.

In addition, even in the presence of additional treatments that include ionizing radiation and cytotoxic chemotherapy, tumors typically recur within an average of only 6.9 months. As a result of this devastating scenario, the overall 5-year survival rate of glioblastoma patients remains less than 5 percent, and it’s even lower in older patients.

Why Hasn’t Treatment Improved Meaningfully Over the Years?

One reason might lie in its original name: Glioblastoma multiforme. Glioblastoma displays extreme degrees of genetic and phenotypic variations between tumors recovered from different patients. This important finding suggests that each patient has a different form of the disease, and should therefore be treated according to unique features of their disease, as opposed to the standardized treatment strategies that we currently have.

In addition, recent studies have identified another phenomenon, “intratumor heterogeneity”, that is individual cells/compartments within a single tumor mass are associated with different subgroups or with different molecular characteristics. There is a wide spectrum of transcriptional programs, cell states, and proliferation capacities in individual tumor cells isolated from the same tumor mass. Therefore, intratumor heterogeneity creates additional challenges, as a single tumor mass might be a collection of various tumor behaviors, such as malignancy, infiltration, adaptation to hypoxia, self-renewal/quiescence, resistance/sensitivity to current treatment plans, and metastasis.

In simpler terms, a glioblastoma is like a ‘full-option’ tumor, equipped with all the arsenal needed to survive. The co-existence and cooperation of these subpopulations with different abilities helps provide a greater tumor survival rate.

Can Cancer Treatment Make Things Worse?

Glioblastomas, as shown above, are quite aggressive tumor masses. Similar to the concept of antibiotic resistance in bacteria, selective pressure on glioblastoma cells allows the most adaptive clones to survive and carry on the tumor mass. It is then worth noting that current treatment plans, including chemotherapy and radiotherapy, are themselves selective pressures that can trigger cellular evolution and intratumor heterogeneity. In other words, though the treatment may cause massive tumor death, surviving cells with new alterations can reconstitute a more aggressive and malignant tumor mass.

In support of this idea, it has been found that the mutation rate in low-grade tumors increased from 0.2 – 4.5 mutations/megabase to 31.9 – 90.9 mutations/megabase when they relapsed as malignant glioblastomas. Importantly, >98.7% of these new alterations were associated with chemotherapy, and did not exist in original tumors. Thousands of de novo mutations and novel oncogenic signatures observed in these chemotherapy-resistant tumor cells suggest that tumors branch out into new molecular profiles and evolve into even more malignant states after treatment.

The Future of Cancer Treatment: Funding, Biotech Startups

The future of cancer treatment is promising in terms of funding and biotech startups.

There are biotech startups like Oncorus, which is dedicated to oncolytic viruses, a possible remedy for glioblastoma.

Additional funding toward research, such as the $57 million that Oncorus raised and the national recognition and funding that Vice President Biden has contributed towards battling different types of cancers shows promise, according to CEO of Oncorus, Mitchell Finer said in an interview with MedCity News.

However, there are still enigmas. Either through its genetic nature, or through therapies, Glioblastoma maintains a heterogenic environment in favor of its growth and malignancy. Unless we fully understand this heterogeneity and design comprehensive treatment strategies that can systematically target multiple disease elements to eradicate the whole tumor mass, we might continue facing demoralizing consequences.

References:

Cloughesy, T. F., Cavenee, W. K. & Mischel, P. S. Glioblastoma: from molecular pathology to targeted treatment. Annual review of pathology 9, 1-25, doi:10.1146/annurev-pathol-011110-130324 (2014).

Watkins, S. & Sontheimer, H. Unique biology of gliomas: challenges and opportunities. Trends in neurosciences 35, 546-556, doi:10.1016/j.tins.2012.05.001 (2012).

Almendro, V., Marusyk, A. & Polyak, K. Cellular heterogeneity and molecular evolution in cancer. Annual review of pathology 8, 277-302, doi:10.1146/annurev-pathol-020712-163923 (2013).

Patel, A. P. et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344, 1396-1401, doi:10.1126/science.1254257 (2014).

Johnson, B. E. et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 343, 189-193, doi:10.1126/science.1239947 (2014).

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