Despite numerous advances in drug development approaches as well as understanding of biology of cancers, no perfect drug is developed to date. Nonspecific chemotherapies carry side effects and targeted therapies are expensive in addition to failures on larger patient populations. This is mainly because, most of the targets of these conventional drugs are 'protein' biomarkers and their expression levels are highly heterogeneous from patient to patient. This suggests that effective cancer treatments need to be either personalized or target universally expressing biomarkers beyond proteins. In addition, paucity of economical and biologically amenable molecular classes as drugs further worsens the problem. We are exploring peptoids as alternative class of economical and bio-compatible molecules. Peptoids are serum stable, non-immunogenic, cell permeable, easy to synthesize and can be optimized at will, and the cost of peptoid development is significantly lower than for small organic molecules, peptides and antibodies. Our approach is to develop variety of large and complex on-bead polypeptoid combinatorial libraries and screen them to identify potential lead compounds. We developed a unique on-bead two-color (OBTC) cell screen to directly identify most specific compounds targeting biomarkers on cancer cells. OBTC assay was used on two approaches: First we identified peptoids targeting protein biomarkers such as VEGR2, EGFR, Fibln-5 broadly found on tumor microenvironment and validated those as antagonists both in vitro and in vivo. As an approach to overcome the protein biomarker heterogeneity, we applied our OBTC assay at an 'unabised' fashion and uniquely identified a lipid- phosphatidylserine (PS) binding peptoid. PS is universally found on the outer layer of tumor endothelium and on many cancer cells as opposed to normal cells. This peptoid also found to be cytotoxic on various tumor types such as lung, breast and prostate and not on normal cells, indicating a wider but tumor specific treatment method.

Novel polypeptoid-combinatorial strategies to target protein and non-protein biomarkers in the tumor microenvironment

248th National Meeting (2014)

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