A new generation of anti-androgen drugs such as Pfizer and Astellas’ Xtandi and Johnson & Johnson’s Zytiga have increased survival rates in metastatic castration-resistant prostate cancer (mCRPC). But a multidisciplinary research team from New York University wanted to improve the prospects for patients even more. So the scientists designed an entirely new type of drug compound, and they have produced some encouraging early study results.
The experimental drugs tread the middle ground between small molecules and large biologics. Called peptoids, these protein-like compounds have a structure that's similar to that of peptides but they differ significantly in function.
Using computational tools, the team synthesized compounds that reduced the growth of prostate cancer in cell cultures by 95% compared to untreated cells. The drugs also blocked a key cancer cell growth signaling pathway in live zebrafish, the researchers reported in Nature Communications.
Scientists have been exploring new ways to tackle prostate cancer, including focusing on the Wnt signaling pathway, which is found to be mutated in about 20% of mCRPC cases. But drug discovery targeting Wnt remains elusive.
Wnt activation can cause the buildup of the protein beta catenin, which binds to T-Cell Factor (TCF) transcription factors and triggers genes that promote cell proliferation. Activation of these genes are critical for the early development of prostate tissue but it can also lead to cancer in adulthood.
For their study, the NYU team also targeted Wnt and the interaction between beta catenin and TCF. But small molecules aren't adequate for protein-protein binding surfaces, which are typically broad and flat. Thus peptoids emerged as the best choice, because they’re large enough, and they're structured to resist proteolysis—the breakdown of proteins in the body that can cause drug loss during absorption.
The researchers folded a linear peptoid molecule into a 3D, cyclic structure, and “stapled” it, which stiffened it just enough so that it could block the docking site that TCFs normally use, they explained in a press release. When they tested the cyclic peptoids in cancer cell lines for 22 days, they found that the compounds not only reduced mCRPC cell growth, they also performed far better than the unstapled version of the peptoids, and they reduced androgen hormonal signaling.
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The researchers also examined their lead compound in zebrafish with rare Wnt-activating mutations that can lead to beta-catenin buildup, which in turn prevents eyes from forming. When the researchers paired a cyclic peptoid with an inhibitor for another beta-catenin factor, the fish developed eyes.
The NYU researchers are so encouraged by the results they plan to test their lead compound in mouse models of prostate cancer to further examine its therapeutic potential. Meanwhile, they suggest the beta catenin/TCF interaction could also be a good target in treating other forms of cancer, such as colon and breast cancers.