Compound targets ‘undruggable’ prostate cancer cells

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A new type of molecule blocks the action of genes that drive the growth of therapy-resistant prostate cancer, according to a new study.

“Rather than continue making compounds that are just like older drugs, the focus of our work has been to rethink the definition of what a drug-like molecule can be,” says corresponding author Susan K. Logan, associate professor in New York University Langone’s urology department.

New “cyclic peptoids” reduced the growth of prostate cancer cells in cultures by 95 percent compared to untreated cells. The experimental drugs also blocked a key related growth signal in live animal tests.

“We designed our peptoids specifically to hit targets that are currently ‘undruggable,’ such as those causing treatment-resistant prostate cancer,” adds co-senior author Kent Kirshenbaum, a professor in NYU’s chemistry department.

Wnt proteins

The compounds blocked growth by interfering with the interaction between the protein beta-catenin and T-cell factor (TCF) transcription factors—proteins that turn on genes that make cells multiply, according to the study, which appears in Nature Communications.

Although the genes are critical for early development of prostate tissue, this gene activity is normally dialed down in adulthood, unless changes re-activate it, which can lead to cancer.

Unlike many existing drugs, the new compounds don’t target androgen hormonal signals known to encourage prostate cancer. Most patients treated with anti-androgen drugs see their cancer growth resume within months, so the field has sought additional therapeutic strategies.

Many efforts have focused on abnormal Wnt protein signals that occur in 20 percent of the most treatment-resistant prostate tumors, but none have made it to the clinic.

Docking block

Wnts can cause the buildup of the protein beta-catenin in cell nuclei, where it turns on genes. Leading up to the new study, the researchers spent years designing a new class of rugged, adjustable, protein-like compounds called peptoids that are just large enough to engage with the broad, flat surfaces beta-catenin uses to interact with TCFs.

Further, the researchers knew they must engineer their compound not just to include the right chemical components, but also to fold into a desired three-dimensional form. They “stapled” together the ends of a linear peptoid molecule to form a loop-like, or cyclic, structure.

This form resembled the protein hairpins that TCFs depend on to interact with beta-catenin. The stapling stiffened the peptoid such that it could occupy and block the docking site that TCFs would otherwise use.

No toxicity

A new generation of computer simulation tools enabled the team to see early on how drug candidates might fit into their protein target. After this virtual testing, the team then synthesized the compounds for experiments in nutrient-filled, artificial environments called spheroids, where cancer cells grow in three dimensions. Spheroids are more lifelike than in two-dimensional petri dish cultures.

In these experiments, cyclic peptoids reduced treatment-resistant prostate cancer cell growth by roughly 95 percent when compared to untreated cancer cells over 22 days, which compared to just 40 percent growth reduction in cells treated with the unstapled version of the peptoid. The compounds also decreased androgen hormonal signaling, suggesting a dual anti-cancer effect, say the authors.

The researchers also wanted to show that their lead compound could block beta-catenin signals in a live animal. They chose zebrafish, in which rare genetic changes (mutations) that let beta-catenin build up are known to keep eyes from forming. In repeated experiments in fish with such mutations, the team found that that their looping peptoids—by blocking overactive beta-catenin, a TCF interaction similar to those affecting human prostate cancer—rescued eye development.

Further, the treatment showed no toxicity in zebrafish at the rough equivalent of a dose that may work clinically in humans. Moving forward, the team will soon test their peptoids on human prostate cancer cells grown in mice. In addition, tests are planned to see if the compound can block the beta-catenin, a TCF interaction known to encourage growth in colon and breast cancers.

Jeffrey Schneider, a student in Logan’s lab who did much of the experimental work on the project, is the study’s first author. Tim Craven, a student in the lab of Richard A. Bonneau, at the NYU Center for Genomics and Systems Biology, is a co-first author. The National Institutes of Health, the National Science Foundation, and NYU funded the work.

Source: NYU