Taming two bacterial toxins into an anticancer agent with "sweets"

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.

Grant Number: 1R21CA290139-01
NIH Institute/Center: NIH
Principal Investigator: Chen Chen