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Drug: metformin

Magazine: Nature and its publications

Highlights:

1) Metformin + heme inhibits tumor growth in triple negative breast cancer

2) Metformin + BCL-2 inhibitor + PD-1 antibody can significantly prolong the survival of breast cancer mice

 

Metformin was discovered in 1922 and began clinical application in 1957. It is currently the most widely used type 2 diabetes drug. However, several studies have shown that it can also inhibit the proliferation of tumor cells, and is expected to open up new horizons in the field of cancer prevention.

This week, this “God Medicine” once again appeared in Nature magazine. Scientists from the University of Chicago have confirmed that mouse studies have shown that metformin combined with another listed drug hemoglobin is expected to be used to treat triple-negative breast cancer (TNBC).

Heme or panhematin was first crystallized by the researchers in 1853 and is now used to treat hemoglobin synthesis defects. In the study, scientists discovered the first anticancer target of heme, BACH1.

 

BACH1 is a transcription factor, called BTBand CNC homology1, which is highly expressed in TNBC and is a protein required for cancer metastasis. High levels of BACH1 usually result in poor treatment outcomes.

 

BACH1 targets mitochondrial metabolism. It controls the transcription of gene information (from DNA to messenger RNA) by combining a specific DNA sequence, which inhibits transcription of the mitochondrial electron transport chain gene. When BACH1 is highly expressed, the cell’s energy source is turned off. Since this protein is not a “essential”, it may have almost no side effects by inhibiting it.

A Cell paper published in 2016 confirmed that the anticancer effect of metformin is related to inhibition of mitochondrial activity.

 

In this study, when scientists treated cancer cells with heme, the level of BACH1 was reduced, making cancer cells lacking BACH1 altered the metabolic pathway. Based on previous studies, the authors speculate that cancer cells with altered metabolic pathways are susceptible to inhibition of mitochondrial respiration by metformin.

Combination therapy map; PDH: pyruvate dehydrogenase; PDK: pyruvate dehydrogenase kinase; ETC: electron transport chain

 

Further research confirms that a novel combination of heme and metformin inhibits tumor growth in a mouse tumor model.

Combination therapy

 

The researchers speculate that patients with low BACH1 expression and high mitochondrial gene expression are more likely to respond to metformin monotherapy; patients with high BACH1 expression and low mitochondrial gene expression are predictive of resistance to metformin, but the addition of heme is expected to make this possible. Patients with TNBC-like are sensitive to metformin.

 

The authors believe that this study suggests that BACH1 is a key regulator of mitochondrial metabolism and one of the determinants of TMS response in response to metformin. In addition, they point out that these findings may extend beyond breast cancer. Because BACH1 is not only highly expressed in TNBC, it is expressed in many cancers including lung cancer, kidney cancer, uterine cancer, prostate cancer, and acute myeloid leukemia.

 

“As far as we know, this is the first study to combine metformin with heme,” concluded Dr. Marsha Rich Rosner, who led the study.

In fact, in addition to combining heme to fight breast cancer, a study published in Nature Communications in February this year confirmed that a triple therapy based on metformin and PD-1 antibodies has also achieved gratifying therapeutic effects.

 

MYC is a gene that is overexpressed in more than 40% of breast cancers and can cause metabolic vulnerability by making breast cancer cells more sensitive to apoptosis. A team led by Dr. Juha Klefström of the University of Helsinki in Finland found that breast cancer cells can be “attacked” by the combination of metformin + BCL-2 inhibitor venetoclax due to this “weakness”.

 

Venetoclax is a drug that induces apoptosis in cancer cells and has been approved by the FDA for the treatment of certain types of leukemia, but has not yet been approved for the treatment of breast cancer. Scientists have discovered metformin when looking for drugs that promote the induction of apoptosis in venetoclax.

 

Studies have shown that the combination of metformin + venetoclax utilizes high-level MYC metabolic defects created in tumor cells, kills cultured breast tumor cells, and blocks tumor growth in animal models of breast cancer. In addition, this combination therapy can effectively kill real breast cancer tissue donated by breast cancer patients.

Untreated patients with breast cancer tissue (left); cancerous tissue treated with metformin + venetoclax. Green indicates cancer cells and red is a marker of apoptosis.

However, the researchers quickly found that although mice transplanted with breast tumors were able to control the tumor when treated with metformin + venetoclax, the tumor “grows back” once treatment is stopped.

 

Analysis showed that at the beginning, the tumor was filled with lymphocytes that killed the tumor, but after treatment with metformin + venetoclax, most of these cells “disappeared”, while the rest expressed PD-1 molecules that inhibited cell killing activity. Therefore, scientists naturally thought of adding PD-1 antibody to the combination therapy.

 

After the primary tumor was surgically removed, the mice received triple therapy: metformin + venetoclax + PD-1 antibody. The role of metformin + venetoclax in inducing apoptosis is to reduce tumor volume and awaken killing lymphocytes; the role of PD-1 antibody is to maintain the activity of killing lymphocytes for a longer period of time. This triple therapy significantly prolongs the survival of mice implanted with tumors compared to monotherapy or dual therapy.

 

Dr. Juha Klefström, who led the study, said: “We finally have a combination of drugs that can make effective use of MYC’s apoptotic function; most importantly, these (all available) drugs can be tested on real patients. , we will conduct relevant clinical trials.”

 

Progress tracking

TNBC accounts for about 15-20% of all breast cancers, and is more common in young women; high mortality, easy recurrence and metastasis; most patients can only receive standard chemotherapy, but soon develop resistance, and the prognosis is not good.

 

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