New Human Lymphoma Treatment Target Discovered

Lymphoma

According to a study which appears online in the Journal of Clinical Investigation and will be published in the December 2012 issue, scientists lead by Lori Hart, Ph.D., research associate and Constantinos Koumenis, Ph.D., associate professor,and research division director in the Department of Radiation Oncology, both from the Perelman School of Medicine, University of Pennsylvania, and Davide Ruggero, Ph.D., associate professor, Department of Urology, University of California, San Francisco, discovered a new pathway that helps cancerous cells to escape apoptosis (programmed cell death) during the development of lymphomas. This new pathway, called Unfolded Protein Response or UPR, a cell’s way of responding to unfolded and misfolded proteins, is activated in patients with lymphomas and in mice genetically bread to develop human lymphomas. In the moment when UPR pathway was inactivated, malignant cells undergo apoptosis.

The general implications of our work are that components of this pathway may be attractive anti-tumor targets, especially in lymphomas. Indeed, an enzyme called PERK, a kinase that we found to play a central role in UPR, is already being targeted by several groups, in academia and pharmaceutical companies with specific inhibitors., says Constantinos Koumenis, Ph.D.

c-Myc, a gene that has the potential to cause cancer (oncogene) activates both cell proliferation and death. When a cell becomes malignant, c-Myc gene fails to induce cellular death, instead promoting tumor formation by cancerous cell proliferation. Scientists observed that in the moment when a cell is overexpressing c-Myc gene, an increased protein synthesis appears which is essential for c-Myc to cause cancer. To promote malignant cell proliferation, c-Myc gene use this aberrant production of proteins in order to block programmed cell death and to activate the UPR pathway. In conclusion, this malignant cells in order to survive need an increased protein synthesis induced by c-Myc gene. Researchers believe that targeting aberrant protein synthesis by inhibiting c-Myc gene activity may represent a promising therapeutic option for cancer treatment.

Malignant Cell

Increased synthesis of proteins induced by c-Myc gene leads to an accumulation of unfolded proteins in the endoplasmic reticulum (organelle that is involved in the synthesis of proteins) where this proteins must be folded to be used in metabolic processes. The accumulation of this unfolded protein initiates a stress in endoplasmic reticulum which activates UPR and lead to the promotion of malignant cells proliferation. Normally, UPR is activated when in endoplasmic reticulum exists an imbalance between the number of unfolded proteins that need to be folded and chaperones, specialized proteins that have the function to fold them.  By analyzing lymphoma cells, researchers observed that this abnormal cells express higher levels of UPR activation, compared with normal cells and c-Myc gene activates only one arm of the UPR pathway, which increase cells survival by autophagy.

Autophagy is a catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components through the lysosomes, which can ensure cellular survival during starvation or stress by maintaining cellular energy levels. Scientists believe that malignant cells might be addicted to this mechanism, because cancerous cells can survive and proliferate if are deprived of nutrients and oxygen.

It was observed that inhibition of a protein called PERK, which has a very important role in UPR pathway reduced autophagy induced by c-Myc expression and tumor formation. It was also noted that drug and genetic inhibition of autophagy increased cellular death mediated by c-Myc genes.

Our findings establish a role for UPR as an enhancer of c-Myc“induced lymphomas and suggest that inhibiting UPR may be particularly effective against cancers characterized by c-Myc overexpression. In this context the UPR essentially acts as one of the cell's rheostats to counterbalance Myc's runaway cell replication nature and its pro-cell-death tendencies., says Koumenis.

However, researchers indicate that further studies are needed in order to explore the potential effects of PERK inhibition on normal tissues, because data from their labs suggest that PERK inhibition in lymphomas grown in animals is feasible, while other studies suggest that PERK has an important role in the function of secretory tissues such as the pancreas.