Previously Funded Research

with lung cancer may have genetic alterations (mutations) in the epidermal

growth factor receptor (EGFR) gene. These mutations are much more common in

never-smoker patients, women, Asians and patients with lung adenocarcinoma

subtype. The presence of these mutations renders the tumor sensitive to EGFR

inhibitors, which are now the preferred treatment of patients with advanced

EGFR-mutated adenocarcinoma of the lung instead of chemotherapy. Although

EGFR inhibitors are able to shrink the tumors in the majority of patients, a

significant number of patients do not have a major benefit from these

treatments and all patients develop resistance after an initial benefit. We

have identified a protein, called Cripto-1, that when it is at high level in lung

cancer cells, determines insensitivity of the tumor to EGFR inhibitors

(intrinsic resistance). The Cripto-1 protein, besides being present on the

membrane of the tumor cells, is also released by the tumor cells into the

blood circulation. We have preliminary evidence that Cripto-1 protein can

cause cancer cell resistance to EGFR inhibitors when it is present at high

levels in several EGFR-mutated cancer cell lines. In this project we will

investigate whether different Cripto-1 forms, that have been genetically

engineered to be secreted or not from cancer cells, will be able to cause

resistance to EGFR inhibitors in lung cancer cell lines and in animal

experiments. We will also study Cripto-1 levels in plasma of patients with

EGFR mutant lung adenocarcinoma, treated with EGFR inhibitors, to see whether

the presence of Cripto-1 in the blood correlates with the level of Cripto-1

in the tumor. We will also investigate in this group of patients whether the

levels of Cripto-1 in plasma is correlated with response to the EGFR

inhibitors. If this is the case, Cripto-1 levels could in the future be used

to stratify patients with EGFR mutant lung adenocarcinoma for EGFR inhibitor

treatment.