New genetic avenues for treatment in diffuse large B-cell lymphoma
Scientists from the NTU School of Biological Sciences (SBS) have revealed new avenues in diffuse large B-cell lymphoma (DLBCL) protein pathways that allow for more targeted treatments, thus paving the way in reducing the relapse or refractory occurrences in DLBCL patients.
Left to right: Vijay Varsheni, Asst Prof Li Yinghui and Peng Chen Chen
The hard fight against cancers
Cancer is a devastating disease that is relentless in its attacks, notoriously hard to fight and, in some cases, just keeps coming back.
One of the many reasons effective cancer treatments are difficult to develop and maintain stems from the very nature of cancer cells. Cells sometimes undergo genetic alterations that cause them to multiply uncontrollably and form tumours. These cells are deemed cancerous when they begin to spread to other parts of the body and start affecting normal bodily functions. The genetic mutations that these cancerous cells undergo as they multiply also means that they can quickly develop resistance to efforts aimed at stopping them, resulting in some cancers being unresponsive to treatments and causing patients to suffer relapses.
Diffuse large B-cell lymphoma (DLBCL) and R-CHOP chemotherapy
One form of cancer is DLBCL, which is a rapid-growing and aggressive form of non-Hodgkin’s lymphoma (NHL). It is a cancer of the lymphatic system, which is a part of the immune system. It ironically derives from white blood cells, specifically B lymphocytes that produce antibodies to fight off infections.
To combat DLBCL, and other forms of NHL, doctors rely on R-CHOP chemotherapy. Chemotherapy is a form of cancer treatment where drugs are used to stop or slow the growth of cancer cells. R-CHOP chemotherapy gets its name from the cocktail of drugs involved, one of which is doxorubicin hydrochloride, a cytotoxic drug that can kill cells, including cancerous ones. It does so by inhibiting topoisomerase II, an enzyme responsible for the breaking and re-joining of DNA structures. Doxorubicin is such a strong cytotoxin that caregivers are advised to take precautions to avoid contact with a patient’s bodily fluids for at least 5 days after treatment.
However, due to the heterogenous nature of cancer cells – where they are so different in genetics and behaviour – as well as an acquired resistance developed during treatment, even with the use of such a strong mixture of drugs, about 30 percent of patients with DLBCL will still suffer relapses while 10 percent do not respond to the treatment at all.
Understanding drug-resistance in DLBCL
Although DLBCL is one of the most common subtypes of NHL, accounting for about 80 percent of cases of NHL worldwide, the mechanisms of R-CHOP-induced resistance in DLBCL are still poorly understood. A team of scientists at SBS, led by Nanyang Assistant Professor Li Yinghui, took on the challenge of delving into this area of research. Their efforts focused on revealing the genetic pathways that are activated in response to drug treatments and how that can affect the DLBCL cells’ abilities to overcome drug-induced cytotoxicity. They found that in doxorubicin-resistant cells, there was a persistent activation of the non-canonical NF-κB pathway, which resulted in a greater expression of glycolytic regulators.
The non-canonical NF-κB pathway
In biology, a pathway refers to a series of actions in a cell’s molecules that results in the formation of a product or a change in the cell. NF-κB, or nuclear factor kappa B, is a family of transcription factors that regulates gene expression and biological functions of the cell, such growth, survival and immune responses.
Using transcriptome profiling – the study of genome-wide gene expression patterns – with multiple cellular models that mimic both natural and acquired cytotoxic drug resistance, the team found that the non-canonical NF-κB pathway was aberrantly activated in cancer cells that had doxorubicin resistance. When faced with a threat to their survival, cancer cells sometimes undergo metabolic reprogramming to survive, with drug resistant cancer cells exhibiting higher than usual energy production levels. In DLBCL doxorubicin resistant cells, the team discovered that these higher levels of glycolysis resulted from the persistent activation of the non-canonical NF-κB pathway. Over time, the prolonged activation of the non-canonical NF-κB pathway can cause the subsequent activation of processes that will cause the cells to adapt to doxorubicin-induced stress.
Possible future treatments for DLBCL relapses
To further confirm the role of non-canonical NF-κB pathway in doxorubicin resistance in vivo, the team treated xenografted resistant DLBCL tumours with inhibitors of the pathway. They found that the tumours became re-sensitised to the presence of doxorubicin, with the tumours becoming reduced. Despite the tumours not being entirely regressed, the results do imply that there is a significant potential in the targeting and inhibition of the non-canonical NF-κB pathway as a future therapeutic strategy to overcome cancer cell chemoresistance in relapsed DLBCL patients.
The discoveries by the team shed new light on the genetic pathways that are involved in doxorubicin resistant DLBCL cells and suggest new areas for treatments to target. Future chemotherapy treatments for DLBCL patients should not only involve cytotoxic drugs in the R-CHOP cocktail but be combined with genetic pathway inhibitors and/or metabolic modulators to enhance the effectiveness of treatments, reducing the chances of relapses or refractoriness. With the added knowledge from the team’s research, doctors in the future can also have an earlier detection of how well patients respond to chemotherapy treatments and adjust for more targeted therapies.
