Toward the first drug to treat a rare, lethal liver cancer

Treatment options for a deadly liver cancer, fibrolamellar carcinoma, are severely lacking. Drugs that work on other liver cancers are ineffective, and while progress has been made in identifying the specific genes involved in driving the growth of fibrolamellar tumors, these findings have yet to translate into treatment. For now, surgery is the only option for those affected — mostly children and young adults with no previous liver disease.

Sanford M. Simon and his group understood that patients who died of fibrolamellar could not afford to wait. “There are people who need therapy now,” he says. So his group threw the sink into the problem and tested more than 5,000 compounds, either already approved for other clinical uses or in clinical trials, to see if any of the compounds could be reused to treat fibrolamellar. The team eventually discovered a few types of therapies that destroy fibrolamellar tumor cells that grow in mice. Their findings are published in Cancer Discovery.

“We decided to be completely agnostic about what we thought would work — we tried everything,” said Simon, head of the Laboratory of Cellular Biophysics. “To our surprise, we found a few compounds that work really well.”

Faster drug discovery

In an ideal world, scientists would conduct extensive experiments to identify the perfect therapeutic target for a disease, then test a range of drugs in model systems to pinpoint promising treatment options to reach the chosen target. The Simon lab is undergoing such experiments, but this process could take years, and the children and young adults now sick with fibrolamellar will likely never see the fruits of such work.

So Simon took a parallel, accelerated approach. After testing an extensive library of drugs on fibrolamellar tumor cells grown in mice over the course of several months, his team identified a few new classes of therapies that seem to effectively kill fibrolamellar tumor cells, and further experiments provided some molecular explanations. on why these drugs are so effective against a disease that has so far baffled doctors treating liver cancer.

“Until now, I’ve had to tell patients that we don’t have drugs that are proven to work,” said Michael V. Ortiz, a pediatric oncologist at Memorial Sloan Kettering Cancer Center and a research associate. “It’s really exciting that we finally have some promising drugs to track in clinical trials. And since every individual responds differently, it’s really exciting that we had multiple hits, which we can now test in conjunction with each other.”

Customized treatment for one

Building on these initial findings, Simon and his colleagues tested the compounds on human cells taken directly from patients’ tumors. They were able to test the cells against their lineup of drug candidates after culturing them for just a few days, yielding results similar to those seen in cells that took months to grow.

“Within three days, we can have therapeutically informative data, which is much faster than previous methods allowed,” said Gadi Lalazar, a clinical research instructor in the Simon lab and lead author of the study. “While there are some logistical hurdles and additional verification is needed, this could potentially be transformative for the treatment of certain cancers.”

The findings suggest it may not be necessary to screen new cancer drug candidates in cells grown in mice before testing on human cells — an additional step that could take cancer researchers many months. Given these results, doctors may soon be able to biopsy cells from a patient’s tumor, subject those cells to a bevy of drug candidates until they find the most effective compound for that particular patient, and develop a treatment plan within days. to have finished. -potentially transform the landscape of precision medicine.

Advances in Precision Medicine

Simon’s recent work is inspired by the 2015 Precision Medicine Initiative, which began in the Obama administration, and which promised to change the face of medicine with a targeted approach tailored to a patient’s unique genetic makeup, lifestyle and environment.

“You don’t want to give everyone who limps the same treatment — you want it to be ‘just targeted’ based on whether they twisted their ankle, broke a bone, or just had a splinter,” Simon says.

Over the past six years, Simon has developed a series of model systems to help identify molecules known to cause cancer, known as oncogenes. But the key to applying precision medicine to cancer, Simon realized, isn’t blindly testing drugs against mutations or abnormally expressed genes — it’s performing functional screenings that ask which drugs actually affect the tumor in matter.

The results of Simon’s approach have now provided the first therapies shown to eliminate fibrolamellar tumor cells, and new hope for those suffering from a deadly disease.


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