Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.

If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.

This week’s study is…

Inhibition of Rag GTPase signaling in mice suppresses B cell responses and lymphomagenesis with minimal detrimental trade-offs

We previously published about this research in a story titled “RagC Pathway Could Be Follicular Lymphoma Therapeutic Target” which can be found here. The study was originally published in the scientific journal Cell Reports. You can view the full text of the study here.

This research team was affiliated with the Spanish National Cancer Research Centre and was led by Alejo Efeyan, who leads the Metabolism and Cell Signaling group at the Centre.

What Happened?

Cancers begin that abnormal growth behavior through the manipulation of a diverse array of cellular signals. In the case of follicular lymphoma, which is a form of non-Hodgkin lymphoma, it exploits signals to make it appear as if the cells have the nutrients they need to multiply. Prior research has revealed that around one of every six patients has disease that carries a mutation in the gene RagC, which plays a role in the nutrient signaling pathway mTOR, and that RagC can cause follicular lymphoma.

With this in mind, a theoretical treatment approach for this group of patients would involve inhibiting Rag GTPases. The goal of the researchers in this study was to put this theoretical approach to the test. The research involved developing a mouse model expressing a hypomorphic RagC mutation. This mutation results in the inhibition of normal B-cell activation. In effect, this would cut off the cancer from its source of growth.

This mutation does not fully halt this activity, which is critical to the function of the cell, but instead causes a partial inhibition of its effect. This is a more effective imitation of what the impact of a potential therapy with a similar mechanism could have. The researchers found that inhibiting Rag GTPases in dialing down their activity has a significant effect that effectively helped delay disease progression. This decrease in activity did not appear to have any other wide-ranging effects on mice aging, coordination, weight, or skin thickness.

A lot of progress has been made in the last decade in terms of understanding the proteins in these pathways and the potential effects that they could have in cancers such as follicular lymphoma. The findings supported the potential development of a therapy that could moderately inhibit this signaling pathway to treat diseased B-cells.

About Follicular Lymphoma

Follicular lymphoma is a type of blood cancer. While generally considered rare, it is the most common type of slow-growing non-Hodgkin’s lymphoma. This cancer affects follicle center B-cells, which are also known as centrocytes. There appears to be a genetic basis for follicular lymphoma, and the cancer has been linked to translocation between chromsomes 14 and 18. This results in the overexpression of a gene called bcl-2. Symptoms for this cancer are similar to other blood cancers, such as night sweats, fever, infections, weight loss, swollen lymph nodes, shortness of breath, and fatigue. Treatment options may include monoclonal antibodies, chemotherapy, radioimmunotherapy, and stem cell transplant. Some patients can survive for decades with follicular lymphoma, with a median survival time of 10 years. The five-year survival rate is 72 to 77 percent. With the newest treatments, survival rates are improving. To learn more about follicular lymphoma, click here.

Why Does it Matter?

While this discovery is only going to affect a limited portion of follicular lymphoma patients, the finding nevertheless demonstrated a possible future method of treatment that could lead to better outcomes for people living with this form of lymphoma. While the full development cycle of a drug that could take advantage of the mechanism that was demonstrated in this study is still far away, there is no doubt that it can serve as a stepping stone in the right direction.

There is also the possibility that this finding could have implications for a number of diseases outside of this cancer, such as certain autoimmune illnesses in which the B-cells are affected. In addition, the fact that the mouse model that was developed did not display major phenotypic changes or systemic trade-offs reinforces the fact that this approach could be not only effective but reasonably safe as well.

“This decrease had no harmful side effects or a negative impact on longevity and life expectancy, which has been linked for years to the mTOR pathway. Mice show weights, glucose levels, neuromuscular coordination, skin thickness and liver damage normal for their age.” – Ana Ortega-Molina, first author

“Now that we know that there is a possible therapeutic window for blocking the RagC pathway, the next step is to develop selective inhibitors that can block these signals in patients.” – Alejo Efeyan