The team used a small interfering RNA (siRNA) approach to disrupt overactive TAZ-YAPactivity in tumor Schwann cells lacking Lats1/2. They also achieved pharmacological inhibition of TAZ-YAP using the compounds verteporfin and dobutamine. Moreover, suppressing TAZ-YAP function in mice bred to lack Lats1/2 reduced tumor numbers.
These efforts also blocked signaling from platelet-derived growth factor receptor (PDGF), which supports tissue growth. Combined, these steps reduced the size and number of MPNSTs in the mice.
Further study revealed that human MPNSTs also exhibit elevated HIPPO-TAZ-YAPexpression. A similar siRNA knockdown approach also inhibited MPNST growth in human cells and caused tumor cell death.
This suggested that several known medications may be useful as therapies against nerve sheath tumors.
Search continues for best combination therapy
However, the team learned that monotherapies aimed at suppressing TAZ-YAP activity or PDGF signaling alone were not effective.
The team explored two TAZ-YAP blockers, verteporfin and dobutamine, and two PDGF receptor inhibitors, imatinib and sorafenib. While some of the drugs showed tumor-reducing effects in vitro, none of them reversed disease in vivo.
After trying various drug combinations at various dosages, the team reported the strongest in vivo reductions in tumor size and weight from a combination of verteporfin and sorafenib.
“However, in our in vivo treatment studies, we observed a delay of tumor growth rather than tumor regression, suggesting that the drugs tested exerted cytostatic instead of cytotoxic effects,” Lu says. “Further investigation into more druggable targets and combination therapeutic options is warranted for effective inhibition of tumor growth.”
Since publishing this paper, Lu and his colleagues have presented their findings at a neurofibromatosis conference in Paris, and at the Cold Spring Harbor Mechanisms and Models of Cancer meeting in New York. They also have performed a small molecule compound screen using the tumor cell lines derived from their animal models. Results of that work will be published in an upcoming paper.
“We are testing the efficacy of HIPPO-TAZ-YAP inhibitors in combination with other oncogenic pathway inhibitors,” Lu says. “If successful, this could lead to a better treatment of MPNSTs.”