Switching off a gene called NF-κB1 caused spontaneous development of stomach (gastric) cancers, driven by chronic inflammation, research have discovered. The study also revealed that immunotherapy may prove to be a significant tool for treating stomach cancers that are driven by runaway inflammation, warranting further investigation.

The findings have ramifications for the understanding and treatment of human cancers.

Dr Lorraine O’Reilly, Dr Tracy Putoczki and Professor Andreas Strasser from the Walter and Eliza Hall Institute, with Professor Steve Gerondakis from Monash University, led the research.

Odd One Out Of The Family

Dr O’Reilly said the finding was unexpected because previous research had shown that high - not low - levels of activity of other NF-κB family members were drivers of stomach and other cancers:

“Until now, it was thought that abnormally increased activity and levels of any of the members of the NF-kB family was linked to cancer. Now, for the first time, we’ve identified NF-kB1 is the ‘odd one out’ in the family because abnormally low expression - or ‘loss’ - of this family member actually causes the development of spontaneous stomach cancers.

We found that defects that led to lower than normal levels of NF-kB1 kick-started uncontrolled inflammation in the stomach and, over the long-term, led to invasive stomach cancers. It is well established that long-term inflammation can lead to stomach cancer in humans. The cellular processes that we have identified in this study as being important for the development of stomach cancer provide new targets for therapy that have not been explored before."

Stomach cancers are relatively common in Australia, with around 2000 cases diagnosed each year. Twice as many men are affected as women and the disease is often not diagnosed until an advanced stage.

Many stomach cancers develop as a result of uncontrolled inflammation over many years.

Anti-PDL1 Immunotherapy

Dr Putoczki noted that the preclinical model would be very useful for testing new treatment options, such as immunotherapy.

“Stomach cancer is a disease where immunotherapy is still in its infancy. This is the first preclinical model of stomach cancer that repeats the pattern of human stomach cancer development, that involves progression from chronic stomach inflammation through to fully invasive cancer.

We showed that there are markers on these stomach tumour cells that indicate they would be responsive to a type of immunotherapy called immune checkpoint inhibitors, in particular anti-PDL1 immunotherapy, which is already used with great success in the treatment of melanoma and certain other cancers. Not only does this research provide compelling evidence for further investigation of immunotherapy for treating stomach cancer, it also provides the first model for preclinical testing of these treatments,"

Dr Putoczki said.

The research was principally supported by Cancer Australia and Cancer Council New South Wales. further support cam from fellowships and grants from the NHMRC, WEHI Dyson Bequest Centenary Fellowship, Victorian Cancer Agency Fellowship, Worldwide Cancer Research, Operational Infrastructure Support Program (Hudson Institute), Cancer Therapeutics CRC (Australia), the Victorian State Government, the Leukemia and Lymphoma Society, and Monash University Faculty of Medicine.

O’Reilly, Lorraine A. et al. Loss of NF-κB1 Causes Gastric Cancer with Aberrant Inflammation and Expression of Immune Checkpoint Regulators in a STAT-1-Dependent Manner Immunity, Volume 48 , Issue 3 , 570 - 583.e8

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