On Sept. 1, 1980, as he approached the city of Thunder Bay in Ontario, a strange pain took hold of Terry Fox’s chest. The 22-year-old had been coughing for days, but it wasn’t until that pain set in that he decided it was finally time to go see a doctor.
That evening, Terry would receive a devastating diagnosis: the osteosarcoma that had taken his right leg three years earlier had not only returned, it had spread to his lungs. Terry was forced to put his Marathon of Hope on hold, and less than a year later, he would pass away from his disease.
Four decades later, little has changed when it comes to the prevention and treatment of metastatic sarcomas. To this day, they are still incurable, which is precisely why an exciting new finding by a group of TFRI-funded scientists at BC Cancer is garnering great interest among clinicians in North America and Europe.
Published in EMBO Reports (October 2019), their ground-breaking discovery could change how osteosarcoma and Ewing sarcoma, the two most common bone sarcomas of children and young adults, are treated, giving doctors a potential new tool in their fight against metastatic disease.
“It’s fairly well understood that in order for tumour cells to leave their primary location, survive in the blood and colonize a distant organ, they must be able to overcome a number of stresses and thus be extremely adaptable,” explains lead study author and BC Cancer pathologist Dr. Poul Sorensen, whose team set out to understand the mechanism of metastasis in sarcomas. “What we have found is that if we use a type of drug known as a Class I HDAC inhibitor, we can hinder a cancer cell’s ability to adapt to these different stressors and therefore block metastasis.”
The team ran a drug screen that tested a library of drugs that are already in clinical trials or approved for other indications, to see which could block adaptive responses in sarcoma cells. Surprisingly, the screen identified Class 1 HDAC inhibitors as potential candidates for this role, and the team then tested them using a variety of mouse models. The results showed that sarcoma cells were unable to adapt to common metastatic stressors such as oxidative stress and hypoxia and could not invade distant organs.
The mechanism through which this occurs appears to be different than what has previously been known about HDAC inhibitors. While prior to the study it was thought that these drugs act solely in the cell nucleus though a process called chromatin remodelling, the study found is that HDAC inhibitors actually also change key stress proteins in the cytoplasm of tumour cells, namely a group of stress adaptive proteins called RNA binding proteins.
By inhibiting the functions of these proteins, the drugs blocked the ability of sarcoma cells to metastasize.
These extremely positive results have pushed the team to quickly begin conversations on how to move these drugs into clinical trials with childhood sarcoma patients, where they hope to test them as anti-metastatic agents administered after patients undergo surgery and/or chemotherapy. Because these drugs have already been approved for other diseases and have favourable toxicity profiles, the team is hoping that they will be able to test this extremely promising treatment in the clinic relatively soon.
“We’re still in the very early stages, but I would like to think that within a year we will have a solid plan for how these agents will move into clinical trials,” says Dr. Sorensen. While their focus is on childhood bone sarcomas, the team believes there is broad applicability to other types of cancers.
Class I HDAC inhibitors enhance YB-1 acetylation and oxidative stress to block sarcoma metastasis
Amal M El-Naggar, Syam Prakash Somasekharan, Yemin Wang, Hongwei Cheng, Gian Luca Negri, Melvin Pan, Xue Qi Wang, Alberto Delaidelli, Bo Rafn, Jordan Cran, Fan Zhang, Haifeng Zhang, Shane Colborne, Martin Gleave , Anna Mandinova, Nancy Kedersha, Christopher S Hughes, Didier Surdez, Olivier Delattre, Yuzhuo Wang, David G Huntsman, Gregg B Morin & Poul H Sorensen
This study was partially funded by The Terry Fox New Frontiers Program Project Grant in New vistas on cancer biology and treatment: conceptual advancements from the forme fruste project
and The Terry Fox New Frontiers Program Project Grant in Targeting the adaptive molecular landscape in castrate-resistant prostate cancer