12:23pm Friday 28 February 2020

Researchers Make Key Discovery Toward Stopping Colorectal Cancer

New molecule targets WNT-driven tumors without associated toxicity

Researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine and other institutions have shown that a molecule developed by Stemsynergy Therapeutics (SSTC3) controls the progression of colorectal cancer in several cell lines and human tumor xenografts. SSTC3 modulates the WNT pathway but does not show the on-target toxicity normally associated with WNT inhibitors. The study was published June 27 in Science Signaling.

“There’s always been a need for WNT inhibitors, and people have been trying for years,” said senior author David J. Robbins, Ph.D., professor of surgery, biochemistry and molecular biology at the University of Miami Miller School of Medicine. “The biggest surprise was that we could get such great efficacy with such minimal on-target toxicity. People had argued the WNT pathway was undruggable.”

Identifying an effective WNT inhibitor could be great news for colorectal cancer (CRC) patients. As many as 90 percent of these tumors are driven by WNT pathway mutations, but there are no approved WNT inhibitors, and the majority of the WNT drugs in the pipeline would be ineffective against CRC.

The stumbling point has been on-target toxicity. WNT inhibitors damage intestinal stem cells, which constantly regenerate new tissue, causing prohibitive toxicity, weight loss and other issues. Robbins and colleagues had to find a way to finesse the problem – identifying an agent that targets WNT signaling in cancer but leaves the pathway relatively untouched in normal intestinal cells.

The answer may lie with the SSTC3 target itself, CK1α, which is a negative regulator of WNT activity. Because CK1α is found at low levels in WNT-driven CRC tumors, an activator might preferentially target tumors, leaving healthy intestinal cells relatively unscathed.

Previous research had shown that pyrvinium – a drug used in the 1960s to treat pinworm – is an effective CK1α activator. Unfortunately, pyrvinium won’t work in colorectal cancer patients.

“It’s great for pinworm,” said Robbins. “When you take it, it goes to your gut and stays in your gut – no bioavailability. Not really useful for colorectal cancer.”

Stemsynergy Therapeutics, a company cofounded by three of the authors (Robbins, Anthony Capobianco, Ph.D., and Ethan Lee, Ph.D.), identified SSTC3 as a bioavailable, effective CK1α activator. In the study, SSTC3 inhibited WNT-driven CRC cells without harming normal intestinal cells. Mice receiving the drug did not experience the weight loss often associated with WNT inhibitors.

The drug’s most significant feat may be inhibiting metastatic human CRC tumor xenografts with KRAS mutations. These tumors are highly aggressive: Only 13 percent of patients live five years after diagnosis.

“There are not a lot of therapeutic options for colorectal cancer,” said Bin Li, Ph.D., first author on the paper and a researcher in the Robbins lab. “For example, EGFR (a targeted cancer therapy) can’t be used on KRAS-mutant CRCs. There’s an urgent need.”

In the big picture, an effective, minimally toxic WNT inhibitor could potentially target treatment-resistant cancer stem cells, which are strongly influenced by WNT signaling in a variety of cancers. Also, because WNT signaling may inhibit immunotherapies, the drug could be used to boost checkpoint inhibitors and other immuno-oncology agents.

“The WNT pathway is also activated in pancreatic, breast, non-small cell lung and some brain cancers,” said Robbins. “Having a safe, effective therapeutic agent for WNT-dependent cancers could be a game changer.”

Miller School of Medicine

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