BACKGROUND:  Epithelial-mesenchymal transition (EMT) is typically associated with developmental processes, such as tissue remodeling and cellular migration. Recent studies, however, have focused on EMT's role in pathogenesis, where it is suspected to be associated with invasive and motile behavior in cancerous cells. Prior to EMT, epithelial cells possess structural uniformity and rigidity with restricted mobility. In contrast, the mesenchymal cells that appear after EMT are adapted for motion, which is thought to be the underlying mechanism of metastasis in cancer. Recent publications on EMT depicts the overall transformation process as a series of coordinated molecular signaling events, signifying potential for developing therapeutic agents targeted against metastasis of epithelial cancers, such as bladder and prostate cancer.

INNOVATION:  Emerging evidence in a number of epithelial cancers demonstrates that tumor cells acquire invasive and metastatic properties by undergoing EMT, as characterized by the down-regulation of specific group of genes and the up-regulation of others. UCLA researchers have demonstrated in invasive bladder and prostate cancer specimens that the expressions of two cell-surface receptors are involved in acquiring the metastatic phenotype. One of these receptors up-regulates while the other down-regulates in the invasive forms of both cancers. The researchers postulated that this up-regulated receptor is a potential therapeutic target for both cancers and other epithelial cancers as well. The researchers had successfully shown that a neutralizing antibody targeting this receptor blocks bladder cancer cell invasion by reducing phosphorylated Akt expression and further up-regulates the expression of the second down-regulated receptor. These results suggest that this neutralizing antibody can act as an antagonist to the cell-surface receptor target and inhibit the metastatic process. The investigators are observing the effect of the antibody in invasive prostate cancer.

POTENTIAL APPLICATIONS 

• Antibody therapy for invasive prostate and bladder cancers.
• Research reagent for the two receptors.

ADVANTAGES

• Potential application to other metastatic epithelial cancers besides bladder and prostate.
• Antibody therapy can be used alone or in combination with other small molecule inhibitors of mTOR and EGFR.
• The researchers have experience in developing therapeutic antibodies for previously identified targets. One of these targets is the prostate stem cell antigen (PSCA) which had been successfully licensed and is being commercialized.

DEVELOPMENT-TO-DATE: The overexpression of one of the cell surface receptors has been confirmed in both prostate and bladder cancers. A neutralizing antibody for this receptor has been shown to block bladder cancer invasion in vitro and can decrease Akt phosphorylation. The second receptor has been shown to be upregulated in LAPC 9 androgen independent tumors, but the antibody for it has not yet been developed.

Reference: UCLA Case No. 2005-098

PCT Application: PCT/US07/07083