Towards the first drug to treat rare and deadly liver cancer

Treatment options for deadly liver cancer, fibrolamellar carcinoma, are sorely lacking. Drugs that work on other liver cancers are not effective, and although progress has been made in identifying the specific genes involved in the growth of fibrolamellar tumors, these findings have yet to be translated into treatment. For now, surgery is the only option for those affected – primarily children and young adults without previous liver problems.

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

“We decided to be completely agnostic about what we thought we could work – we tried everything,” says Simon, director of the Cell Biophysics Laboratory. “To our surprise, we have found a few compounds that work really well. “

Faster drug discovery

In an ideal world, scientists perform in-depth experiments to identify the perfect therapeutic target for a disease, then test a suite of drugs in model systems to identify promising treatment options to reach the chosen target. The Simon Lab undergoes such experiments, but the process can take years, and children and young adults who are now ill with fibrolamellar will likely never see the fruits of such labors.

Simon therefore adopted a parallel and accelerated approach. After testing a large 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 appear to effectively kill fibrolamellar tumor cells, and other experiments have provided some explanation. molecules why these drugs are so effective against a disease that has so far baffled doctors treating liver cancer.

“Until now, I have had to tell patients that we don’t have any medicine that was proven to work,” says Michael V. Ortiz, pediatric oncologist at Memorial Sloan Kettering Cancer Center and study collaborator. “It’s really exciting that we finally have some promising drugs to look for in clinical trials. And, since each individual responds differently, it’s especially exciting that we’ve had multiple hits, which we can now test in combination with each other. others. “

Tailor-made treatment for one person

Building on these early 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 line of drug candidates after growing them for just a few days, getting results similar to those seen in cells that took months to grow.

“In three days, we can have informative therapeutic data, which is much faster than previous methods allowed,” explains Gadi Lalazar, instructor in clinical investigation at the Simon laboratory and first author of the study. “While there are some logistical hurdles and further verification is needed, this could potentially be transformative for the treatment of some cancers.”

The results suggest that it may be unnecessary to screen for new cancer drug candidates in cells grown in mice before testing them in human cells – an extra step that can cost cancer researchers many months. Based on these results, doctors may soon be able to biopsy cells from a patient’s tumor, subjecting those cells to a host of drug candidates until they find the most effective compound for it. specific patient, and have a treatment plan ready within days. -Potentially transform the landscape of precision medicine.

Advances in precision medicine

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

“You don’t want to give everyone who limps the same treatment – you want it to be ‘precisely targeted’ whether they’ve twisted their ankle, broken a bone, or just have a splinter,” says Simon. .

Over the past six years, Simon has developed a series of model systems to help identify molecules known to cause cancer, called oncogenes. But the key to applying precision medicine to cancer, Simon realized, is not to blindly test drugs for mutations or abnormally expressed genes – it’s to perform functional screenings that ask which drugs actually have an impact on the tumor in question.

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


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About Hector Hedgepeth

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