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Combo Therapy Effective in Blocking Lung Cancer’s “Escape Pathway”

Although aberrant Epidermal Growth Factor Receptor (EGFR) signaling is widespread in cancer, EGFR inhibition is effective only in a subset of NSCLC (non-small cell lung cancer) with EGFR activating mutations. A majority of NSCLCs express EGFR wild type (EGFRwt) and do not respond to EGFR inhibition. Tumor necrosis factor (TNF) is a major mediator of inflammation-induced cancer.

Now, researchers at UT Southwestern’s Simmons Cancer Center have found that a combination of drugs – one targeting epidermal growth factor receptor (EGFR) and one targeting tumor necrosis factor (TNF) – effectively blocks the cancer from using TNF as an escape route.

“There has been a tremendous effort over the past several years to block EGFR as a treatment for lung cancer, but this therapy only works in a small subset of patients. The cancer fights back with a bypass pathway,” said senior author Dr. Amyn Habib with the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

Blocking both of these proteins could be a treatment that is beneficial for the majority of lung cancer patients,” said Dr. Habib, Associate Professor of Neurology and Neurotherapeutics with UT Southwestern’s Peter O’Donnell Jr. Brain Institute.

As demonstrated in a mouse

model, the combination of drugs which target both TNF and epidermal growth factor receptor (EGFR) prevent a tumour from being able to use this escape route, and while TNF is blocked the tumour also becomes more sensitive to EGFR treatment. As the combination only includes targeted drugs, it also offers far less side-effects when compared to traditional treatments such as chemotherapy.

A new study demonstrated that using two currently available drugs could be an effective treatment for the majority of lung cancers. The bottom row shows tumors treated with the drug combo, compared with tumors without treatment or with single treatments in the rows above.

The latest findings build on previous work by Dr. Habib’s lab showing that the same combination of drugs was successful in a mouse model of glioblastoma, a deadly type of brain cancer.

Researchers are now planning a phase 2 clinical trial of the two-drug strategy, and because the two drugs are already FDA-approved, they hope to be able to launch the trial within a year, said oncologist Dr. David Gerber with the Simmons Cancer Center, who will lead the trial.

If this strategy is effective, then it might be broadly applicable not only against lung cancer but also against other cancers that express EGFR, which include brain, colon, and head and neck cancers,” said Dr. Gerber, Associate Professor of Internal Medicine and Clinical Sciences.

Another advantage of the anti-EGFR/TNF strategy is that the drugs are well-tolerated. Both the EGFR inhibitors and TNF inhibitors fall into the category of targeted drugs, meaning they affect specific molecules within cancer cells, and therefore have fewer side effects.

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