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Novel Technology Finds New Targets Among So-Called 'Undruggable' Cancer Targets

In This Article

  • Researchers in Massachusetts General Hospital's Bar-Peled Laboratory are using chemical proteomics to discover new cancer targets that could lead to new anti-cancer drugs
  • Investigator Liron Bar-Peled, PhD, and his team have developed a new technology that quickly maps cancer specimens and their proteins to generate lists of druggable targets within two or three days
  • This novel technology is one of just a few capable of mapping both cellular cancer models and patient tumor samples to target undruggable proteins
  • Dr. Bar-Peled and his team are applying the technology to a wide array of cancers and have notably found several new promising melanoma and ovarian cancer targets among those previously considered undruggable

Researchers in Massachusetts General Hospital's Bar-Peled Laboratory have developed and employed a novel technology to quickly find potential new drug targets among cancer proteins previously considered as undruggable.

While advances in cancer genomics over the last two decades have identified abnormal proteins driving cancer growth, "the majority, roughly 80%, are conventionally considered undruggable," says Liron Bar-Peled, PhD, an investigator in Mass General's Krantz Family Center for Cancer Research. "But to me, there is no such thing as undruggable. It is just yet to be drugged. As a result, we have developed a revolutionary technology that allows us to access these so-called undruggable cancer targets, which should lead to the development of new chemical tools, or small molecule inhibitors, against the worst of the worst in cancer."

Bringing Chemical Proteomics From Bench to Bedside

The technology known as chemical proteomics, scans cancer cells and identifies potential proteins that are druggable which will then enter the lab's drug discovery pipeline.

"This technology has been traditionally siloed to chemistry departments. Half of our group are chemists. But chemists and chemistry departments traditionally do not interact with clinicians," explains Dr. Bar-Peled.

"At Mass General, we have been incredibly lucky to work with our clinical colleagues to understand better the types of clinical problems that need solutions," he continues. "One is that we do not have models for some of the tumors we need to understand better to develop better drugs. We do not have the corresponding cell lines that have enabled so much cancer research to happen. It is also incredibly difficult to model some of these chemo-resistant states."

To overcome this challenge, Dr. Bar-Peled's team spent several years modifying the technology to analyze actual patient samples. The Bar-Peled Lab is now one of just a few labs able to apply this technology to both cellular models of cancer and patient tumor samples.

"It has been an incredibly heavy lift. We have gone through so much optimization, but it has been well worth it."

Utilizing Cysteine Druggability Mapping to Identify Targets

To map targets within a cancer specimen, Dr. Bar-Peled's team gently grinds the sample, ensuring the preservation of the proteins' native state. Then after adding covalent cysteine-reactive drug-like molecules to the sample, they use proteomics to scan the samples to see if and where these small molecules bind on the protein.

"We have discovered that when the drug-like fragments bind to the protein, it is an excellent predictor whether that the protein is druggable or not," he says. Their technology can map a cancer specimen's landscape and generate a list of druggable targets within two or three days.

Dr. Bar-Peled and his team then build out detailed cellular assays of the most promising targets to analyze. They screen the lab's library of covalent inhibitors to determine which ones bind to the proteins.

"Their ability to latch on and not let go gives them unique properties that allow us to target many difficult types of proteins," he says. "From there, we do more chemistry to develop potent and specific inhibitors."

Machine learning is key to this process, and so far, the team has collected over 100 million data points on protein-small molecule interactions.

"We are incorporating a large amount of structural analysis to learn what makes a particular protein druggable because we hope it will save time. Why perform a wet lab experiment when you can do an experiment on a computer that would be faster and may yield higher results? We're not there yet, but this is where we are heading," Dr. Bar-Peled says.

Targeting 'Undruggable' Proteins in Ovarian Cancer

While the lab looks at a wide array of cancers, including skin, breast, and lung, they have uncovered several promising new ovarian cancer targets.

"After talking to my gynecological malignancy colleagues, we were compelled to start where there is a great need," Dr. Bar-Peled says. "There is nothing out there for ovarian cancer. Some targeted inhibitors have worked for a very small percentage of women, but the vast majority do not benefit from them. They go on chemo and gain resistance within a couple of months."

Dr. Bar-Peled's team focused on transcription factors to find new druggable ovarian cancer targets, previously considered undruggable due to their lack of defined binding pockets.

"If you go back 30 to 35 years, people thought targeting kinases was impossible. But now we know that they are very targetable," he explains. "It is the same with transcription factors, which are like the brains of the entire cancer, sitting at the top and orchestrating a lot of gene expression. Looking at our internal data sets, we see hundreds of these targets we think we can go after."

One such target stopped growth in 60% of their ovarian cancer cell lines. Dr. Bar-Peled's team hopes to create a drug that can mimic these results.

"We have made a lot of progress and are excited to show the world what we can do with it," he says.

Providing Hope

A major research focus of the Bar-Peled Lab is advancing the understanding of the rules that govern protein druggability. As a result, Dr. Bar-Peled's team is profiling patient tumor samples to look for commonalities among proteins and patient subsets.

"A lot of drug discovery is trial by fire or by error. We are at the first step of identifying what targets we can go after, and from there, can we learn the fundamental rules? Then, we want to be able to translate them to make inhibitors and protodrugs that we can work on with industry collaborators to help patients."

Dr. Bar-Peled says as the world of small molecule drug discovery rapidly advances, his technology will be just one piece of the puzzle.

"Not only does this technology provide a fundamental understanding of how proteins and small molecules function, but it also provides hope. This technology can make inroads in this devastating set of diseases."

Learn more about Mass General's Bar-Peled Lab

Learn more about the Mass General Cancer Center


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