Thursday, November 21, 2024
11/21/2024
In the United States, lung cancer is the most common cause of cancer-related deaths, with only 20.5% of the 5-year overall survival rate. Low lung cancer survival rates reflect the large proportion of patients (57%) diagnosed with distant metastases, for which the 5-year relative survival rate is 5%. Non-small cell lung cancer (NSCLCs) is the most common type, representing 85% of lung cancer cases. Twenty to forty percent of NSCLC patients develop brain metastasis at or within a short period of primary tumor diagnosis. The glycan Sialyl Lewis X (SLeX) expression is increased in cancer cells compared to normal epithelial cells due to tumor hypoxia. Clinical studies have shown that patients with tumors expressing high levels of SLeX have a significantly higher risk of developing invasion and metastasis than patients with tumors expressing low levels of this antigen. We show for the first time that SSL11 mediates cell motility arrest by inducing adhesion via binding to SLeX. The properties of binding glycan SLeX and inhibiting cell motility of SSL11 make it an appealing delivery platform against cancers that overexpress SLeX. Pseudomonas exotoxin A (PE) is an ADP-ribosylating AB toxin used to construct immunotoxins targeting cancers with antibodies replacement of the receptor-binding domain of PE. A 24 kDa truncated form of PE (PE24) was fused to a variety of immunotoxins to inactivate eEF-2 in cancer cells, which has shown promising results against multiple cancers. We hypothesize that a fusion protein SSL11-PE24 composed of SSL11 and PE24 will provide a novel therapy against cancers overexpressing SLeX. For proof of principle, we will test whether the SSL11-PE24 exhibits anticancer activities in human lung cancers. We will engineer the fusion protein SSL11-PE24 and characterize its glycan-binding specificity (aim 1). We will explore the in vitro anticancer effects of SSL11-PE24 in human lung cancer cells overexpressing SLeX (aim 2). The outcome of this study will provide a potential novel therapeutic approach based on bacterial toxins against cancers, especially cancers prone to metastasis.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
