A study of cancer research shows how the new drug screen can individualize cancer therapy


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A study by researchers at Harvard’s Ludwig Center has shown how a drug detection method known as dynamic BH3 profiling can be used to quickly identify potentially effective combinations of existing drugs for personalized cancer therapy.

“It simply came to our notice then cells i they have different metabolisms, ”said Anthony Letai, a Ludwig Harvard researcher who, with former postdoctoral researcher Veerle Daniels, led the study published in the current issue of Scientific signage. “Using the BH3 profile, we found a specific metabolic dependence on 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 by a second targeted drug that could then cause death. “

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

Although tumors often have unique metabolic adaptations on which they depend, specifically targeting these drug vulnerabilities has proven to be a challenge. These drugs have often failed because they were poorly targeted or too toxic at the doses needed to kill cancer cells when used as individual agents.

“We wanted to see which of the known drugs that disrupt metabolism would bring TNBC cells to death, but they were leaving. The researchers reasoned that these cells could be selectively targeted by existing therapies known as BH3 mimetics to push them above the limit. Because initial preparation treatment requires low doses of the drug, this strategy could reduce the risk of toxicities that have affected the development of drugs aimed at cancer metabolism.

Therapy often induces in cancer cells a type of programmed death known as apoptosis, which is 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 often produce large amounts of the latter to escape apoptosis and resist therapy.

BH3 mimetics inhibit anti-death proteins, tipping the balance in favor of cell suicide. It should be noted that a BH3 mimetic has already been approved for the treatment of certain blood cancers and other drugs of this type are in various stages of development.

Dynamic BH3 (DBP) profiling, developed in the Letai laboratory, measures the same balance of pro-death and anti-death proteins to assess the degree of readiness of a patient’s tumor cells for apoptosis after exposure to a drug. Therefore, it represents a potentially fast and unbiased method for detecting hundreds of drugs at once to find those most likely to treat tumors in a given patient.

Daniels, Letai, and colleagues used DBP to examine a “library” of 192 metabolically disrupting compounds, developed in the lab by Ludwig Harvard co-director Joan Brugge, for its effects on normal cells and TNBC. Eight altered the metabolism of cancer cells, but left normal cells undisturbed.

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

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

“What we have shown in general is that we can use DBP to find metabolic regulators of apoptotic preparation and tumor-specific anti-apoptotic dependencies, 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 types of cancer. Because it’s a functional drug screen, which only examines whether a particular drug is primary by death: DBP does not require prior knowledge of the internal workings of cancer or genetic aberrations.

“We must not limit ourselves to targets that can only be identified by genetic mutations, which are only a small fraction of the true targets that exist in the world of cancer, ”Letai said.

He and colleagues are also planning a clinical trial with DBP to identify tailor-made therapies for individual patients diagnosed with myelogenous leukemia.

Letai and Daniels point out that regular meetings between laboratories and the collaborative model of the Ludwig Harvard Center were central to the conception, design, and conduct of the study.

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

Gene research discovers promising combination therapy for triple-negative breast cancer

More information:
Veerle W. Daniels et al, Metabolic disturbances sensitize triple-negative breast cancers to apoptosis induced by BH3 mimetics, Scientific signage (2021). DOI: 10.1126 / scisignal.abc7405

Citation: A Cancer Research Study Shows How the New Drug Screen Can Individualize Cancer Therapy (2021, June 8) Retrieved June 9, 2021 at https://medicalxpress.com/news/2021-06 -cancer-drug-screen-individualize-therapy.html

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