Proteins called transcription factors are like molecular traffic cops that tell genes when to stop and go. If they malfunction — what scientists refer to as dysregulation — transcription factors stop orchestrating healthy gene expression and instead become a driving force for diseases like cancer.
Unsurprisingly, dysregulated transcription factors have garnered a lot of attention from researchers hoping to create new treatments for disease. But transcription factors have proven hard to drug, in part because they work in the context of various interdependent signaling molecules in the cell.
The MIT spinout Kronos Bio is studying those larger signaling networks to find new ways to disrupt transcription factor activity. By viewing transcription factors in their natural cellular context, the company believes it can develop more effective treatments to the many diseases that are driven by out-of-control transcription.
A key enabling technology for Kronos is a screening tool that allows scientists to study how transcription factors interact with other molecules. Kronos founder and MIT associate professor of biological engineering Angela Koehler has made important contributions to the tool over nearly two decades, and she continues to use it to study transcription factors in her lab today.
“Transcription factors never work in isolation,” Kronos Bio CEO Norbert Bischofberger says. “They work through multiple complex protein complexes. Angela spearheaded screening compounds in the cellular context they work in, and we’re building on that work.”
Kronos is already targeting the mother of all disease-associated transcription factors, known as MYC, in clinical trials. MYC is in every cell, but certain tumor cells overexpress MYC dramatically, relying on its constant transcription to drive cancer growth. Kronos is currently running a phase 1/2 study with patients who have relapsed or resistant MYC-dependent tumors, including patients with ovarian cancer and triple-negative breast cancer. The company’s other drug in clinical trials targets a molecule associated with dysregulated transcription in acute myeloid leukemia.
If the trials are successful, Kronos believes its approach will allow it to develop treatments for a number of other cancers associated with transcription dysfunction.
“If you look at the Tumor Genome Atlas, roughly half of all tumors have amplified MYC, and if you look at triple negative breast and ovarian cancer, it’s 80 percent,” Bischofberger explains. “If you could find drugs that essentially reduce amplified MYC levels, you could take out a broad swath of human tumors for which MYC is a driver of the malignant phenotype. It’s a huge opportunity to improve patient lives.”
From platform to product
Koehler’s interest in transcription factors dates back to the early 2000s. As an investigator at the Broad Institute of MIT and Harvard, where she is still a member, she was part of a group that developed a low-cost way to screen molecules for different binding properties. The approach could be used to find molecules that modulate transcription factors, and it garnered interest from pharmaceutical companies.
“What industry really liked was we didn’t need to purify a protein to run a screen,” Koehler explains. “We could come in with large protein complexes from cells, or potentially even patient cells, and look for our target of interest in a protein complex, which reflected a more native state to evaluate molecules.”
When Koehler started her lab at MIT, she used the approach to find molecules that bind to MYC. Many attempts to target MYC have failed over decades of drug development because it’s a difficult protein for molecules to latch on to.
“The problem is MYC is in this bucket of targets many call undruggable,” Koehler says. “It’s a transcription factor and it’s super floppy. It lacks shape and it’s highly disordered, so it’s difficult for molecules to find a binding pocket.”
Koehler and her collaborators presented their early work on the MYC-binding molecule at a conference, sparking interest from investors.
“The next two or three months, my office was like a revolving door for venture capitalists wanting to talk not just about the molecule, but to understand the platform we used to discover the molecule — that’s actually where there was more interest,” Koehler recalls.
She started Kronos Bio later that year, working with MIT’s Technology Licensing Office to license the screening platform and a few specific molecules for the company. The Deshpande Center for Technological Innovation funded some of Koehler’s early work, and Koehler, who became faculty director of the center this summer, also says it helped connect her to investors and others in the biotech industry.
Two members of Koehler’s lab became the first two employees of the company. Then Koehler met Bischofberger, who had spent 27 years as the head of research and development at Gilead Sciences and was looking to move into a startup.
Since then, Kronos has taken a winding path to developing the final molecules currently being studied in its clinical trials. (That initial molecule she presented at the conference didn’t pan out.) Some of Kronos’ preclinical work was done in conjunction with the Broad Institute, where Koehler is an Institute Member. Koehler, who is also the associate director of the Koch Institute for Integrative Cancer Research and the founder of the MIT Center for Precision Cancer Medicine, sits on the Kronos Bio scientific advisory board and says she’s following along with the company’s clinical progress like everyone else.
“What you’re looking for as a founder is the right group of people who you trust to make the right decisions,” Koehler says. “I’m a mom of four, and I often say it’s like you’re looking for the right college to send your kids to, but then you’ve got to step back and let them live their own life. That’s how I view it.”
Drugging the undruggable
Kronos Bio’s drug candidates are taken orally once a day, which allows patients to skip frequent trips to hospitals for IV infusions. In addition to targeting MYC-dependent tumors, Kronos’ drug is also being tested in humans to address other transcriptionally addicted cancers like sarcomas.
“Sarcomas are not widely mutated like other tumors; it’s often just a simple transcription factor fusion,” Bischofberger says. “The best example is Ewing’s sarcoma. That exists with two transcription factors fused together. Those are driven by aberrant transcription, and that’s something we’re excited to be going after.”
The company plans to present safety data from its trials by the end of this year, and by the middle of 2024 to present data showing whether its lead candidate can shrink MYC-dependent tumors.
“What you want to see is tumor shrinkage because none of these tumors shrink by themselves,” Bischofberger says.
Regardless of those drug candidate’s success, Bischofberger believes Kronos is making important contributions to an understudied area of therapeutics.
“There are about 1,500 transcription factors, and about 200 of those are known to be involved in cancers, but very few have been drugged,” Bischofberger says. “The transcription factors that have been drugged have been widely successful — in multiple myeloma, for instance. This is a huge, open field to be working in.”
de MIT News https://ift.tt/L6QpOVB
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