Newly identified drug targets could open door for oesophageal cancer therapeutics

The results of the study, published in Gastroenterology point to two signalling pathways as contributing to EAC tumours.

A new research has found that blocking two molecular pathways that send signals inside cancer cells could stave off oesophageal adenocarcinoma (EAC), the most common oesophageal malignancy in the United States.

National Cancer Institute estimates, only 20% of patients diagnosed with EAC survive five years.(Unsplash)

The study was conducted at the Case Western Reserve University School of Medicine. Researchers identified the pathways using advanced computational and genetic analyses of tumour biopsies from EAC patients. They found 80% of tumours had unusually active genes related to two specific pathways, and that exposing the cells to pathway inhibitors stymied EAC tumour growth in mice.The results of the study, published in Gastroenterology point to two signaling pathways (controlled by JNK and TGF-beta proteins, respectively) as contributing to EAC tumours.

The pathways represent molecular chain reactions that were overactive in patient tumour cells, but not in biopsies from patients with non-cancerous oesophageal conditions, including Barrett’s Oesophagus.

Harmful effects of these pathways could be reduced by turning down JNK or TGF-beta activity. “These findings suggest a rationale for testing JNK/TGF-beta-targeted therapies as a new treatment approach in this increasingly prevalent and lethal cancer,” said senior author Kishore Guda.

National Cancer Institute estimates, only 20% of patients diagnosed with EAC survive five years. Patients struggle to swallow as tumours and cancer cells narrow their oesophagus. Some require nasogastric feeding tubes in end stages of disease. Limited available treatments to shrink tumours include surgery, radiation, or chemotherapy, but the majority of EAC tumours are resistant.

“Targeted therapies are virtually non-existent,” Guda said, adding, “Treatment advancements are also slowed because we don’t know exactly what molecular signals drive EAC pathogenesis.”

In the new study, Guda and colleagues collected 397 biopsy specimens to find common mechanisms that underlie EAC tumour progression. They integrated computational and genetic analyses to identify signaling pathways highly active in EAC. They compared EAC biopsies to those collected from patients with conditions that often precede EAC, but who did not develop the cancer.

After finding JNK and TGF-beta pathways to be overactive only in EAC biopsies, they then incubated EAC tumour cells with therapeutic small molecules designed to block the pathways.

Exposure to JNK or TGF-beta inhibitors reduced the ability of EAC cells to proliferate, migrate, or form tumours when transplanted into mice. Several mice had near total regression of tumour growth following treatment.

Combining JNK and TGF-beta pathway inhibitor treatments further prevented cancer cell growth, but more studies are needed to understand synergy between the pathways during EAC progression.

EAC tumour cells’ reliance on the TGF-beta pathway was unexpected given its widely recognised role as a cancer suppressor, said Guda’s co-senior author on the study. The difference, Varadan said, potentially lies in different roles for TGF-beta in different stages of EAC development.

Varadan added, “In normal esophageal cells, TGF-beta acts as a gatekeeper by inhibiting uncontrolled cell growth.”

“As EAC develops, TGF-beta switches from a growth suppressor to a growth promoter. This is unlike its function in other cancers such as those arising in the colon.” Varadan said, adding, “Our unique application of advanced mathematical modelling that we developed allowed us to tease out these intricate mechanisms, which would have otherwise been missed.”

The results open a new targeted therapeutic avenue for EAC, and lay the foundation for studies in humans.

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