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…

SOX11 inhibitors are cytotoxic in mantle cell lymphoma

We previously published about this research in a story titled “SOX 11 Inhibitors Could Treat MCL” which can be found here. The study was originally published in the science research journal Clinical Cancer Research. You can view the abstract of this study here.

This research team was affiliated with The Mount Sinai Hospital.

What Happened?

Mantle cell lymphoma is a difficult-to-treat, rare form of non-Hodgkin lymphoma. While there are available treatments for the disease, it relapses often and is ultimately fatal. Therefore, there is an urgent need for more effective treatments for this type of lymphoma. In prior research studies, scientists had successfully identified that the SOX11 transcription factor is overexpressed in as much as 90 percent of mantle cell lymphoma cases, indicating a potential therapeutic target. It is known to play a role in the pathogenesis of the cancer.

The goal of this study was to discover a potential small molecule inhibitor of SOX11 and test it in the lab setting on human lymphoma cells. The research team, using experimental validations and in silico predictions, found three structurally related compounds that could serve as inhibitors of SOX11 by interfering with its DNA interactions. In the lab setting, the scientists tested the effects of these compounds on mantle cell lymphoma cells. 

The researchers found that one of the compounds was more effective than the others and could selectively “kill lymphoma cells with remarkable efficiency,” as senior author Dr. Samir Parekh puts it. Additionally, this compound was also found to synergize well with ibrutinib, which is used as a second-line therapy for mantle cell lymphoma. In addition, the compound was found to be effective in cells that had developed resistance to ibrutinib.

In a xenograft mouse model created from one of these subjects, the approach also inhibits BTK phosphorylation. This process is a vital component of the cascade of signaling which is necessary to turn regular old lymphocyte B cells into malignant mantle cell lymphoma cells. These findings indicate that these inhibitors of the SOX11 transcription factor could play an important role in treating mantle cell lymphoma.

About Mantle Cell Lymphoma (MCL)

Mantle cell lymphoma is a rare type of non-Hodgkin’s lymphoma. There are only about 15,000 patients in the US. This blood cancer affects B-cells, a type of white blood cell. The risk factors for mantle cell lymphoma are not particularly well known; however, acquired genetic mutations in the affected cells are what eventually causes them to become malignant. Most patients are diagnosed in their 60s. In many cases, the disease is not diagnosed until it has reached an advanced stage. Symptoms include fever, night sweats, enlarged spleen and lymph nodes, and weight loss. Treatment options include immunotherapy, chemotherapy, and targeted therapies. Mantle cell lymphoma often relapses after treatment with chemotherapy. Prognosis is difficult to predict; the five-year survival rate is 50 percent, but this figure improves to 70 percent with limited-stage disease. To learn more about mantle cell lymphoma, click here.

Why Does it Matter?

With a median survival time of around seven or eight years, there is clearly plenty of room for improvement when it comes to the treatment of mantle cell lymphoma. The discovery of an effective compound that inhibits the SOX11 transcription factor could be a concrete step in improving patient outcomes. Transcription factors are special because they bind to DNA and act as a switch that turns off or on the expression of genes. 

In the past, these transcription factors were regarded by scientists as ‘undruggable’—that is, there were no therapies that could effectively target them. Only through an in-depth process that involved scanning millions of compounds on the SOX11 surface were these compounds found. The findings reveal that SOX11 inhibition could be effective both on its own or while being used with ibrutinib, which is already in use as a treatment for this lymphoma.

The discovery will hopefully spur other researchers to attempt to seek ways to target other transcription factors that play a role in different cancers.

“These small molecule inhibitors could also be useful tools for understanding the pathogenesis of other malignancies that can be traced to SOX 11, including epithelial ovarian tumors, medulloblastoma, gliomas, and basal-like breast cancer…Many transcription factors exist in a variety of tumors that could be targeted by scientists, and what we’ve demonstrated through our work is that there is indeed an effective way to make them druggable.” – Dr. Parekh