‘Pincer attack’ on transcription factors offers new possibilities for future blood cancer therapies

The simultaneous inhibition of the transcription factors Myc and JunB could represent a pioneering therapeutic option for the treatment of multiple myeloma (MM), the second most common type of blood cancer.

This is the result of a recent study conducted by a team from the Karl Landsteiner University of Health Sciences (KL Krems) together with Austrian and American colleagues. The study was the first to show that the two regulatory proteins have independent effects in MM cells.

The simultaneous inhibition of both proteins thus resulted in a synergistic anti-tumor effect. The findings are published in the Blood Cancer Journal.

Multiple myeloma (MM) is the second most common hematopoietic malignancy, still considered incurable despite unprecedented therapeutic advances over the last two decades. Novel therapies are therefore needed.

For several years, the team of Prof. Klaus Podar, Head of the Division of Molecular Oncology and Hematology, Division of Internal Medicine 2 at University Hospital Krems (one of the education- and research sites of KL Krems) has focused its research on the role of tumor-associated transcription factors (TFs), proteins that bind to specific DNA sequences and act as regulators, and the derived development of TF inhibitors.

However, TF inhibitors were thought to be “undruggable” until most recently. The team’s previous studies have demonstrated a pathophysiologic role of the TF JunB in MM, tumor cell proliferation and drug resistance in particular. Moreover, they established that JunB also increases the proliferation of tumor-promoting blood vessels in the bone marrow.

Separate pathways

The present study shows for the first time that JUNB and MYC, another crucial TF in MM, orchestrate distinct transcriptional programs. In addition, data emphasize the opportunity to employ JUNB and MYC dual-targeting treatment strategies in MM as another exciting approach to further improve patient outcome.

In detail, the team demonstrated that the expression of the respective target genes of the two TFs is controlled independently of each other in MM cells. “This was our first indication that JunB and Myc could actually control largely independent signaling pathways in MM cells,” explains Prof. Podar.

Caught in the pincers

“Of course, we were immediately interested to see whether simultaneous inhibition of both transcription factors have a mutually reinforcing—i.e., synergistic—effect against MM cells,” says Prof. Podar.

The team then carried out several experiments in which the TFs were inhibited individually or together using therapeutic agents or genetic methods. “And indeed, such a pincer attack on MM cells led to a greater increase in MM cell death in both cell and animal models compared to single inhibition,” explains Prof. Podar.

“Our efforts are now focusing on the identification and development of new substances that can be successfully used in our patients.”

Provided by
Karl Landsteiner University