New drugs that target cancer cells promise to revolutionize cancer medicine. Because they are cancer-specific, they spare the rest of the body from toxic side effects. Unfortunately, suitable protein targets are not available for many types o cancer and there is heterogeneity in marker expression even in tumors for which protein markers are available. This limits the usefulness of targeted drugs to selected groups of patients. Thus, there is a pressing need for a global marker of cancer. The lipid phosphatidylserine (PS) is universally present on the tumor vascular endothelium and absent from healthy normal tissues. PS is also expressed on the surface of many types of cancer cells. To target PS specifically, a peptide-like molecule, called a peptoid, was selected from a large library. The dimeric version of the peptoid potently killed cancer cells by lysing their plasma membrane and disrupted tumor blood vessels inside tumors in an animal tumor model. The peptoid had no effect on normal cells. The overall goal of this proposal is to develop different versions of this peptoid to identify even more effective compounds. The molecular structure of the peptoid will be modified in 2 ways: (i) The active peptoid will be assembled into multimeric forms (e.g. dimers, trimers, tetramers etc.) to enhance the activity and (ii) The active sequence will be modified to improve PS-recognition. These derivatives will be tested for specific lytic activity in many different cancer models;breast, prostate, leukemia, glioma and lung. Next, the mechanism of action of the PS-targeting peptoids will be investigated. The peptoids are expected to act by destroying the tumor's blood vessels, resulting in death of tumor cells through starvation of oxygen and nutrients, and by lysing PS-positive tumor cells. Animal studies will comprehensively evaluate these activities. Peptoids are inexpensive to prepare, stable and can be rapidly refined structurally for optimal efficacy. Thus, the peptoids identified n this study could constitute a new class of drugs with the potential to make a major impact on the treatment of multiple types of cancer.
Our goal is to develop and validate new classes of potential and economical drug leads (e.g. peptoids) that can target multiple types of cancer. While conventional protein targeted drugs are effective on only a small percentage of patient populations, our biological target, lipid phosphatidylserine, is universally present in the tumor microenvironment and absent from healthy normal tissues. The cost of peptoid development is also significantly lower than that for current conventional drug classes such as small organic molecules, antibodies and peptides, and therefore a new class of drugs could be created making a major impact on universal cancer treatment.
|Desai, Tanvi J; Toombs, Jason E; Minna, John D et al. (2016) Identification of lipid-phosphatidylserine (PS) as the target of unbiasedly selected cancer specific peptide-peptoid hybrid PPS1. Oncotarget 7:30678-90|
|Singh, Jaspal; Shukla, Satya Prakash; Desai, Tanvi J et al. (2016) Identification of the minimum pharmacophore of lipid-phosphatidylserine (PS) binding peptide-peptoid hybrid PPS1D1. Bioorg Med Chem 24:4470-7|
|Matharage, Jaya M; Minna, John D; Brekken, Rolf A et al. (2015) Unbiased Selection of Peptide-Peptoid Hybrids Specific for Lung Cancer Compared to Normal Lung Epithelial Cells. ACS Chem Biol 10:2891-9|