Metabolic

Study shows how innovative drug screening can individualize cancer therapy



ANI |
Updated:
06/09/2021 8:50 AM IS

Washington [US], June 9th (ANI): A study by researchers at the Ludwig Center in Harvard has shown how, with the help of a so-called dynamic BH3 profiling method for screening, potentially effective combinations of existing drugs for personalized cancer therapy can be quickly identified.
“We know that cancer cells and healthy cells have a different metabolism,” said Anthony Letai, a researcher at Ludwig Harvard who co-led the study published in the journal Science Signaling with former postdoc Veerle Daniels. “Using the BH3 profile, we identified a specific metabolic dependency in triple-negative breast cancer cells in a patient that we could attack with an existing drug, making the cells more susceptible to death and priming them for a second targeted drug, which then could trigger their death. “
Daniels, Letai, and colleagues also showed that the strategy suppressed the growth of triple negative breast cancer (TNBC) in mice with patient-derived tumors.
Although tumors often have unique metabolic adaptations on which they depend, targeting these vulnerabilities with drugs has proven difficult. Such drugs have often failed in clinical trials because they were poorly targeted or too toxic as a single agent at the doses required to kill cancer cells.
“We wanted to see which of the drugs that are known to interfere with metabolism were bringing TNBC cells closer to death, but leaving normal cells untouched,” Daniels said. The researchers argued that such cells could then be selectively attacked by existing therapies known as BH3 mimetics to push them over the edge. Since the initial priming treatment requires low doses of the drug, this strategy could lower the risk of toxicities that have hampered cancer metabolism drug development.
The therapy often induces a form of programmed death known as apoptosis in cancer cells, orchestrated by an elaborate protein machinery. However, cells also produce anti-death proteins that inhibit key elements of this machinery. Whether a stressed cell dies or survives depends on the balance of pro-death and anti-death proteins, and cancer cells tend to produce large amounts of it in order to evade apoptosis and resist therapy.
BH3 mimetics inhibit anti-death proteins and tip the balance in favor of cell suicide. In particular, a BH3 mimetic has already been approved for the treatment of certain types of blood cancers, and other such drugs are in various stages of development.
Dynamic BH3 Profiling (DBP), developed in Letai’s laboratory, measures the same balance of pro-death and anti-death proteins to measure how a patient’s tumor cells are prepared for apoptosis after exposure to a drug . It thus represents a potentially quick and unbiased way to study hundreds of drugs at once to find those most likely to treat a particular patient’s tumors.

Daniels, Letai, and colleagues used DBP to study a “library” of 192 metabolic disruptive compounds – developed in the laboratory of Ludwig Harvard co-director Joan Brugge – for their effects on normal and TNBC cells. Eight interrupted the metabolism of cancer cells but left normal cells untouched.
Two of these drugs target an enzyme called NAMPT, which is involved in one of three biochemical pathways that produce NAD +, a molecule vital to metabolism. The researchers showed that some sensitive TNBC cell lines were dependent on the NAMPT pathway. They also performed a DBP screen to find out which specific anti-death proteins the TNBC cells depended on for survival after NAMPT inhibition. They used this information to identify the most potent BH3 mimic to use in combination with NAMPT inhibitors.
Using two mouse models of patient-derived TNBC tumors developed in the Bruges laboratory, the researchers showed that only the mice with NAMPT-dependent tumors responded to a combination of the NAMPT inhibitor and the BH3 mimic. They suggest that the NAMPT inhibitor, which has been shown to be too toxic as a single agent, could be used as combination therapy at lower doses with BH3 mimetics.
“What we have shown overall is that we can use DBP to find metabolic regulators of apoptotic priming and specific anti-apoptotic dependencies in tumors – and thus to identify powerful combinations of metabolic compounds and BH3 mimetics for therapy”, said Daniels.
Letai’s lab uses DBP to methodically identify other drug combinations for the treatment of a wide variety of cancers. Because it is functional drug screening, which only examines whether a particular drug is preparing cancer cells to die, DBP does not require any prior knowledge of the internal workings of cancer or genetic aberrations.
“We don’t need to limit ourselves to drug targets that can only be identified by genetic mutations that 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 with DBP to find tailored therapies for individual patients diagnosed with myeloid leukemia.
Letai and Daniels point out that the regular inter-laboratory meetings and the cooperation model of the Ludwig Harvard Center were decisive for the conception, design and implementation of the study.
“It was an opportunity to combine unique expertise. I’m good at cell death, not good at metabolism. Veerle is good at metabolism and cell death, but it lacked some key tools for its initial screening, so we reached out to other members of the Ludwig Harvard Center who actually had those tools. We wouldn’t have been aware of this expertise if we hadn’t been at the center because Harvard is a very big place, “said Letai. (ANI)

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