Seeking Less Toxic Treatments for Most Common Pediatric Brain Tumor
The number of long-term survivors is proving that treatment for medulloblastoma (MB) has become more effective. However, these outcomes come at the cost of quality of life for many patients with the disease, which is the most common form of brain cancer in children, says Zeng-jie Yang, M.D., Ph.D.
As therapeutic approaches with more efficacy and less toxicity are still highly needed, researchers are currently working to identify new targets in the field.
In an interview with CURE, Yang, assistant professor, Fox Chase Cancer Center, discusses the most significant enhancements in the field, ongoing studies into new targets, and the challenges that still lie ahead.
What are the most significant advancements in the MB field?
Previously, classification in MB was mainly based on histology. This divides MB into several subtypes, including the classic large cells; anaplastic, desmoplastic and tumors with extensive nodularity. Such histological classification has been used before to give patients a stratification and a prognosis estimate. For example, large-cell MB and anaplastic MB normally have a worse prognosis. Recently, MB classification is often determined by molecular subgrouping, which is based on the gene expression pattern of tumor cells. I think this represents the most significant advancement in the field.
According to the current agreement, four subgroups of MB can be distinguished, including wingless (WNT), sonic hedgehog (SHH), group 3 and group 4.
So, in theory, individual subtypes of tumors derive from distinct cells of origin, and are caused by aberrant activation of distinct signaling pathways that differ between the subtypes. This allows us to design treatment accordingly, in a more accurate manner, to explore the therapeutic strategy by targeting these particular pathways.
What challenges still remain in MB?
The current MB treatment has been more and more successful, evidenced by a growing number of long-term survivors. However, such a success is often with the price of impairment of life quality in patients. Children patients are still developing, still growing. Treatment, especially chemotherapy and radiotherapy, can cause lots of side effects, which could significantly impair their life quality.
A very common side effect includes cognitive deficit and an increased incidence of a secondary cancer. I think the side effects of tumor treatment still represents the biggest challenge in the field. Therapeutic approaches with more efficacy and less toxicity are still highly needed.
What are the late effects of treatment in children?
The treatment of children patients is particularly challenging, because the radiation leads to massive cognitive impairments. The current strategy for the children patients include completely avoiding radiation, or sometimes at least applying only focal radiation, even though without radiation the chemotherapy very often can also cause a lot of side effects. Those long-term side effects could significantly impair their life quality.
What studies is your lab currently conducting?
Our current research is based on one subtype of MB, SHH. This type of MB covers about 30 percent of MB. This tumor results from over-activation of a pathway called the hedgehog pathway. The current available SHH pathway inhibitor blocks this pathway in both tumor cells and in normal cells, so this causes a lot of side effects.
As I mentioned, this is a particularly big problem in treating children patients, so we have been trying to identify some targeted proteins, which is critical for SHH pathway activation only in tumor cells, but not in normal cells. By targeting these protein, we can design strategies to repress SHH pathway specifically in tumor cells, which would cause much less toxicity.
Recently, we found a protein called nestin that is highly expressed in tumor cells, but not in normal cells. Nestin plays a critical role in activation of SHH pathways in tumor cells. We now continue to further design and screen compounds to target nestin, by which we will test therapeutic efficacy in our MB mouse model.
What role does 17p deletion play in treatment decisions?
It has been debated for many years whether loss of chromosome 17 is associated with prognosis or not. Some studies claim that a chromosome 17 loss predicts a worse prognosis, while other studies concluded no association at all between chromosome 17 and prognosis, so it is highly debated.
Nevertheless, based on the current molecular classification of MB, as I mentioned earlier, there are four subtypes of MB based on their genetic profile in tumor cells. Based on these classifications, we found that chromosome 17 loss is often found in Group 3 and Group 4 MB, which in general have a poor prognosis. Most oncologists now apply intensified immunotherapy or intensified radiotherapy to treat those patients with chromosome 17 loss.
Are there any other targets being investigated in MB?
For the SHH subtype of MB, I think the most common target protein is Smoothened (SMO), so a lot of effort has been focused on identifying the new inhibitor to target Smoothened. We recently characterized several novel therapeutic targets for MB treatment. We have been working together with several pharmaceutical companies to identify compounds that can effectively target these targets. Other targets that are still being investigated in the field include MYC, GSK3B, PI3K/AKT and STAT3 etc.