Finding hope for ovarian cancer with a new perspective on ‘undruggable’ targets

Each year, about 20,000 women in the U.S. are diagnosed with ovarian cancer. Since most treatment options don’t work very well, more than 12,000 women a year die from this cancer.

Liron Bar-Peled, PhD, from Mass General Hospital is working to give these women hope. The new technology he is developing can reveal completely new targets for cancer therapies.

With V Foundation funding, he’s been able to focus this technology on ovarian cancer, and the work is already producing some exciting results. “We felt that we had to do something to help ovarian cancer patients,” said Bar-Peled. “With the technology we’re using, we hope to not only be able to tell others what we think could be targetable with drugs but to also develop some lead compounds that pharmaceutical companies could develop into a clinically useful therapy.”

Finding druggable targets

Thanks to the advances in cancer genomics over the past 20 years, scientists know quite a bit about the specific genes involved in a variety of cancers, including ovarian cancer. However, most of the genes that have been identified for ovarian cancer are conventionally considered not druggable, meaning it’s not possible to make a drug that counteracts their effects.

“We’re using a new technology for identifying potential drug targets called chemical proteomics,” said Bar-Peled. “Unlike most existing methods, which simply measure the levels of a macromolecule like DNA, RNA or protein RNA, our approach maps all the druggable targets within a particular cancer specimen — whether it is a cell line or a tumor from a patient.”

This new approach has revealed a whole new class of targets that the broader biotechnology and pharmaceutical communities have previously considered undruggable. It works by mapping how protodrugs — molecules that could eventually be turned into drugs — interact with the amino acid cysteine, a building block for most proteins.

The chemical proteomics approach identifies which cysteines are druggable while also providing some insights into the function of the protein containing the cysteine. This information can be used to develop small molecules that target cysteines located on proteins that can interfere with cancer in some way.

With V Foundation funding, Bar-Peled and his team have used their technology to identify a promising ovarian cancer target that has a druggable cysteine. Using genetic approaches to lower the concentrations of this target, they showed that 60% of ovarian cancer cell lines stop growing. They are now working to develop a drug that can produce this same effect.

Capturing cancer’s diversity

The researchers also worked to modify the chemical proteomics technology so that the mapping can be performed in tumor samples from patients, rather than just cell models of cancer. This helps capture the full diversity of the disease, which can be masked if only cancer cell lines are studied.

“We want to get a portrait of what is druggable for each patient sample, and then feed this information into our drug discovery pipeline,” said Bar-Peled. “Getting the technology to work in the samples wasn’t easy, but thanks, in part, to the V Foundation, we were able to spend some time on developing the right methods.”

Now that they’ve developed methods for patient-specific chemical proteomics, the process can be used to find new druggable targets for any cancer, including ones that can’t be modeled in cells. They are already working with researchers to do this for melanoma and lung cancer, including some rare forms of these cancers.

Collaborations with clinicians have been instrumental in this work, Bar-Peled said. “They provide us with incredibly rare specimens and give us insights in terms of what they think will be the most important targets to pursue. They are really in tune with what patients need,” he said. “Here at Mass General, we are able to combine our fundamental research with input from the clinicians, to make sure our work can really help the most patients.”

Like father, like son Like father, like son
Bar-Peled has been around science labs ever since he was a preschooler. “My dad is also a researcher, and I have really fond memories of doing science in his lab when he was a PhD student,” he said. “I now have a six-year-old son, and I try to get him into the lab as much as possible to expose him to the science that we're doing here.”

In graduate school, Bar-Peled discovered a new tumor suppressor gene that was mutated in some types of ovarian cancers. “As a doctoral student I was hyper-focused on the mechanism involved in this tumor suppressor gene,” he said. But his perspective has shifted over the course of his career. “It was only recently, especially after coming back to Boston to start my lab, that I began to feel the importance of translating fundamental biological discoveries into cures for patients. I believe it is really important to not only increase biomedical knowledge but to also use that knowledge to help people.”
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