Combination Therapy Proposed for Multiple Myeloma and Mantle Cell Lymphoma

Researchers in California are now proposing a new combination therapy approach to improve treatments of multiple myeloma and mantle cell lymphoma. Currently, treatment resistance is common but investigators at Stanford University have found a potential new target to prevent resistance. Writing in ACS Central Science, scientists report that resistance could be linked to a protein called Nrf1, which appears to respond to proteasome insufficiency or pharmacological inhibition by upregulating proteasome subunit gene expression.

“We found that one of the resistance mechanisms against proteasome inhibitor cancer drugs, a transcriptional proteasome ‘bounce back’ response, is dependent on the deglycosylating enzyme NGLY1 [N-glycanase 1]. This was a surprise because not much was known about how Nrf1 is biosynthesized and processed,” said study investigator Carolyn Bertozzi, a professor of chemistry at Howard Hughes Medical Institute at Stanford University in Stanford, California.

She and her colleagues started working on this from the view of the rare hereditary disease NGLY1 deficiency, and they were surprised to discover that one of the major deficits in these patients is loss of Nrf1 function. Proteasome inhibitors, including bortezomib and carfilzomib, have been effective in treating certain types of blood cancers. However, the drugs have been limited by treatment resistance. Previous studies have suggested that resistance could be linked to Nrf1.

When proteasome inhibitors go into action, Nrf1 is spurred into overdrive to restore the cells' normal activities and keep them alive. By studying NGLY1 deficiency, a seemingly unrelated condition, Bertozzi and colleagues appear to have found a new way of attacking treatment resistance.

The researchers found that NGLY1 is responsible for activating Nrf1 and they demonstrated that dampening NGLY1 allowed a proteasome inhibitor to continue doing its work.

“When Nrf1 was identified as a possible mediator of proteasome inhibitor resistance, it was with some dismay because transcription factors are notoriously ‘undruggable’, and therefore it was not clear what action could be taken to disable this resistance pathway. But NGLY1 is an enzyme that is quite amenable to drug development,” Bertozzi told OncoTherapy Network.

The team established proof of concept for this notion in this current paper. Bertozzi said it may be possible to disable Nrf1 by inhibiting NGLY1, which is far more tractable than efforts to inhibit Nrf1 directly. It is hoped that this line of investigation could lead to the development of new combination therapeutics for blood cancers.

“We hypothesize based on these findings that co-therapy with an NGLY1 blocker could enhance the potency and/or durability of proteasome inhibitors such as Velcade [bortezomib] and Kyprolis [carfilzomib]. Such co-therapy may also extend the use of proteasome inhibitors to other cancer subtypes that are presently considered refractory to proteasome inhibitor therapy. We are following-up with studies that address this notion directly,” said Bertozzi.