Ludwig’s cancer research study shows just how bad the news

image: Anthony Letai, Ludwig Harvard researcher and Veerle Daniels, former postdoctoral researcher
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Credit: Ludwig Cancer Research

JUNE 8, 2021, NEW YORK – A study by researchers at the Ludwig Center at Harvard demonstrated how a drug screening method known as dynamic BH3 profiling can be used to quickly identify potentially effective combinations of existing drugs for a personalized cancer therapy.

“We know that cancer cells and healthy cells have different metabolisms,” said Anthony Letai, researcher at Ludwig Harvard, who, along with former postdoctoral researcher Veerle Daniels, led the study published in the current issue of Scientific signage. “Using BH3 profiling, we found a specific metabolic dependence in triple negative breast cancer cells obtained from a patient that we could target with an existing drug, making the cells more susceptible to death and preparing them for. a second targeted drug that could then trigger their death. “

Daniels, Letai and their colleagues also showed that the strategy suppresses the growth of triple negative breast cancer (TNBC) in mice bearing patient-derived tumors.

Although tumors often have unique metabolic adaptations on which they depend, it has proven difficult to specifically target these vulnerabilities with drugs. These drugs have often failed in clinical trials because they were poorly targeted or too toxic at the doses required to kill cancer cells when used alone.

“We wanted to see which of the drugs known to disrupt metabolism would bring TNBC cells closer to death, but leave normal cells unchanged,” Daniels said. The researchers felt that these cells could then be selectively targeted by existing therapies known as BH3 mimetics to push them over the edge. Since the initial initiation treatment requires low doses of the drug, this strategy could reduce the risk of toxicities that have disrupted the development of drugs targeting cancer metabolism.

Therapy often induces a type of programmed death in cancer cells known as apoptosis, which is orchestrated by elaborate protein machinery. However, cells also produce anti-death proteins that inhibit key parts of this machinery. The death or survival of a stressed cell depends on the balance of pro-death and anti-death proteins, and cancer cells tend to produce large amounts of the latter to escape apoptosis and resist treatment.

BH3 mimetics inhibit anti-death proteins, tilting the balance in favor of cell suicide. Notably, a BH3 mimetic has already been approved for the treatment of certain blood cancers, and other such drugs are in various stages of development.

Dynamic BH3 Profiling (DBP), developed in Letai’s lab, measures this same balance of pro-death and anti-death proteins to assess how well a patient’s tumor cells are prepared for apoptosis after exposure. to a drug. It is therefore a potentially fast and unbiased method of screening hundreds of drugs at once to find which ones are most likely to treat a given patient’s tumors.

Daniels, Letai and their colleagues used DBP to examine a “library” of 192 metabolism-disrupting compounds – developed in the lab of Ludwig Harvard co-director Joan Brugge – for their effects on normal cells and TNBC. Eight disrupted the metabolism of cancer cells but did not disrupt normal cells.

Two of these drugs target an enzyme known as NAMPT, which participates in one of the three biochemical pathways that produce NAD +, a molecule of critical importance for metabolism. Some sensitive TNBC cell lines, the researchers showed, depended on the pathway involving NAMPT. They also performed a DBP screen to find out which specific anti-death proteins TNBC cells depended on for survival after inhibition of NAMPT. They used this information to identify the most effective BH3 mimetic drug to use in combination with NAMPT inhibitors.

Using two patient-derived TNBC tumor murine models developed in the Bruges lab, the researchers showed that only mice with NAMPT-dependent tumors responded to a combination of the NAMPT inhibitor and the BH3 mimetic. They propose that the NAMPT inhibitor, which was found to be too toxic as a single agent, could be reused as a combination therapy given at lower doses with BH3 mimetics.

“What we’ve shown overall is that we can use DBP to find metabolic regulators of apoptotic priming and specific anti-apoptotic dependencies in tumors – and thus identify potent combinations of metabolic compounds. and BH3 mimetics for therapy, ”Daniels said.

Letai’s lab uses DBP to methodically identify other drug combinations for the treatment of various cancers. Because it is functional drug screening – examining only whether a given drug is preparing cancer cells for death – DBP does not require prior knowledge of the inner workings of cancer or genetic aberrations.

“We should not limit ourselves to drug targets identifiable only by genetic mutations, which are only a tiny fraction of the true targets in the cancer world,” Letai said.

He and his colleagues are also planning a clinical trial using DBP to identify tailored therapies for individual patients diagnosed with myeloid leukemia.

Letai and Daniels note that the regular inter-laboratory meetings and the collaborative model of the Ludwig Harvard Center were essential in the conception, design and conduct of the study.

“It was a way of combining a unique set of expertise,” Letai said. “I’m good for cell death, not good for metabolism. Veerle is good for metabolism and cell death, but lacked key tools to do his initial screening, so we turned to other members of the Ludwig. Harvard Center that had these tools. We wouldn’t have known about that expertise if we weren’t at the Center, because Harvard is a very big place. “

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Anthony Letai is Professor of Medicine at Harvard Medical School and the Dana Farber Cancer Institute.

Veerle Daniels is now a researcher at Flamingo Therapeutics in Leuven, Belgium.

This study was supported by Ludwig Cancer Research, the United States National Institutes of Health, the Terri Brodeur Breast Cancer Foundation, the Alex’s Lemonade Stand Foundation, Tap Cancer Out, the Brazilian National Council for Scientific and Technological Development, the Breast Cancer Research Foundation, the Breast Cancer Coalition. de Rochester and the American Association for Cancer Research.

About Ludwig Cancer Research

Ludwig Cancer Research is an international collaborative network of renowned scientists who have been at the forefront of cancer research and breakthrough discoveries for 50 years. Ludwig combines basic science with the ability to translate his findings and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested nearly $ 3 billion in life-changing science through the nonprofit Ludwig Institute for Cancer Research and six US-based Ludwig Centers. To learn more, visit http://www.ludwigcancerresearch.org.

For more information, please contact Rachel Reinhardt, [email protected] or + 1-212-450-1582.


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