Why is the "synthetic lethal" effect so aggresive in cancer treatment?

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Why is the “synthetic lethal” effect so aggresive in cancer treatment?

Why is the “synthetic lethal” effect so aggresive in cancer treatment? Have heard of the “starvation therapy” for cancer treatment, did you know that there is a more agressive treatment: “synthetic lethal” effect?

At present, our understanding of PARP inhibitors is only the tip of the iceberg. We look forward to more excavations from the academic community on the efficacy, mechanism, and applicable population of PARP inhibitors!

As early as 1971, Professor Folkman of Harvard University put forward the idea that by inhibiting tumor angiogenesis through antibodies, the blood and nutrient supply of tumor cells can be cut off, and the purpose of “starving” tumor cells can be achieved. This is vividly called “starvation”. therapy”.

This therapy was once mistaken as: if you have cancer, you don’t eat nutritious foods, and you rely on “hungry” to fight it. It attracted public opinion for a while and attracted everyone’s attention.

However, now there is another therapy that is bolder: the tumor cells are made of normal cell gene mutations, which is an abnormal behavior. Simply let the abnormality come more violently. It is commonly known as the “breaking jar and breaking method.”

So, what exactly is this treatment?

The Past and Present

In 1922, geneticist Bridges, who worked in Morgan’s laboratory at Columbia University, discovered an interesting phenomenon in Drosophila melanogaster: when two specific genes are mutated and inactivated at the same time, it will cause fruit flies. The inactivation of either of these two genes alone will not cause fatal damage to fruit flies.

In 1946, the famous geneticist Dobzhansky gave this phenomenon a name, which is today’s famous “synthetic lethal” effect.

However, the proposal of this concept did not arouse the attention of the academic community at that time. Until 51 years later, experts at the Fred Hutchinson Cancer Research Center keenly realized that this “synthetic lethal” concept may be applied to cancer. In treatment.

Isn’t there a certain gene mutation in tumor cells, the corresponding specific gene can be inactivated by drugs, and according to the “synthetic lethal” effect, it can cause fatal damage to tumor cells.

In fact, most cells go from normal to cancer, not because their genes are inherently bad, but because during the growth process, the cell’s DNA will continue to suffer from various internal and surrounding unfavorable factors, such as radiation. , Chemical poisons, harmful metabolites of the cell itself, DNA replication errors, etc., lead to mutations in cancer-related genes, and ultimately lead to cancer.

Why is the "synthetic lethal" effect so aggresive in cancer treatment?

In the human body, the BRCA1/2 gene is a tumor suppressor gene, which is mainly responsible for the repair of DNA double-strand damage. When the BRCA gene is mutated, the damaged DNA cannot be repaired normally, causing the gene to mutate and eventually become cancerous. PARP is mainly responsible for the repair of DNA single-strand breaks through the base excision repair pathway.

In BRCA-mutated tumor cells, the damaged DNA double-strand cannot be repaired. If PARP inhibitors are given to block DNA single-strand repair at the same time, a “synthetic lethal” effect can be formed, leading to the death of tumor cells.

Why is the treatment so ggressive?

This is mainly due to the target of therapy!

It is estimated that the number of single-stranded DNA damages produced by each cell of the human body per day is about 10,000. If other damages are also included, this data will be increased by 10 times to 100,000.

Compared with the damage suffered by DNA, the risk of cancer is insignificant. This is mainly due to the human body’s sophisticated, complex and efficient DNA repair system.

Among DNA damages, the most serious damages are single-strand breaks and double-strand breaks, but single-strand breaks are more common. If these breaks cannot be repaired in time and accurately, the genome will become unstable, which will cause cancer and even directly lead to cell death.

In order to maintain normal physiological functions, cells must have a variety of DNA damage discovery and repair mechanisms, so that damaged DNA can be repaired in time and accurately.

For single-strand breaks, its repair mainly relies on PARP. There are 17 kinds of this enzyme in the human body. Although they look a bit similar, they have different functions.

For double-strand breaks, although they are rare, the situation is more serious. If they cannot be repaired in time, the cell’s DNA will become unstable and the cell will eventually die.

In view of the fact that cancer cells also need to maintain the stability of their own genomes, as a “rational” cancer cell, they will certainly not paralyze all the above-mentioned DNA damage repair mechanisms. However, in order to maintain the vitality of evolution, it is possible that part of the repair method loses its function.

This also gives scientists an opportunity. Taking DNA repair as the target, completely destroy the “broken jar” of cancer cells, where a large number of mutations have appeared in their DNA.

In 2005, the dawn of the “broken jar” of “breaking” cancer cells emerged.

Two independent research teams published important research results back to back in the top journal “Nature”, confirming for the first time that there is a “synthetic lethal” interaction between PARP inhibitors and BRCA1 or BRCA2 mutations, opening the door for synthetic lethal treatment of cancer.

Magical trapping effect

The above are all synergistic lethal effects between PARP inhibitors and BRCA mutations. For cancer cells without BRCA gene mutations, are PARP inhibitors also effective?

In fact, research in 2005 has shown that PARP inhibitors are also lethal to cancer cells without BRCA mutations.

But compared with cancer cells with BRCA mutations, cancer cells without BRCA mutations are nearly 1,000 times less sensitive to PARP inhibitors.

So, how do PARP inhibitors work for cancer cells without BRCA gene mutations? It is due to the “trapping” effect of PARP inhibitors on PARP.

The so-called “trapping” effect means that after the PARP inhibitor competitively binds to the PARP enzyme, it will cause PARP-1 and PARP-2 that bind to the damaged DNA to be trapped in the DNA, and directly cause other DNA. The repair protein can’t bind either. The consequence is that DNA breaks not only cannot be repaired, but they also change from single-strand breaks to double-strand breaks, eventually leading to cell death.

In fact, scientists have realized that “trapping” PARP and “nailing” it to DNA is the biggest killer of PARP inhibitors to destroy cancer cells. Therefore, when comparing the anticancer activity of a single PARP inhibitor, it must be based on its capture efficacy.

Therefore, scientists are now committed to promoting the applicable population of PARP, not just limited to patients with BRCA gene mutations.

Adverse reactions of PARP inhibitors

Experts recommend that patients taking PARP inhibitors have monthly blood routine checks and weekly blood routine checks during the first month of medication. Anemia is the most common hematological adverse reaction of PARP inhibitors, with an overall incidence of about 37%-50%.

Experts hope that every patient with ovarian cancer who uses PARP inhibitors can understand the key indicators that need to be monitored in the blood routine report:

The first is hemoglobin. If the hemoglobin drops to 80-100g/L, you can continue to take the medicine, but you need to follow up blood routine closely every week and pay attention to hemoglobin changes.

If it drops below 80g/L, stop taking PARP inhibitors, and blood transfusions can be done when conditions permit. After the hemoglobin rises to 90g/L, the dose can be reduced. The specific reduction is recommended for outpatient visits. After the medication is resumed, the hemoglobin level will be monitored weekly to smooth.

If the hemoglobin still fails to return to the medication level 28 days after the drug is stopped, or if the hemoglobin is reduced to the lowest dose and the hemoglobin is as low as 80g/L again, the medication should be stopped.

Platelets are another indicator that needs to be monitored. If the platelet count is less than 100*109/L, stop taking PARP inhibitors, and wait for the platelet to rise to above 100*109/L, and decide to resume the dosage according to the lowest platelet count. The specific reduction standard recommends outpatient visits.

Neutropenia is the third common hematological adverse reaction. For example, the neutrophil count drops to (1.5-2.0)*109/L. Continue to use PARP inhibitors under the condition of blood routine monitoring; such as neutral If the granulocyte count is less than 1.5*109/L, the PARP inhibitor should be suspended, and the dose will be reduced after the symptomatic treatment is restored to 1.5*109/L. The specific reduction standard is recommended for outpatient visits.

In addition, taking PARP inhibitors may have gastrointestinal adverse reactions. Nausea is the most common. Others such as constipation, vomiting, diarrhea, etc., can be treated symptomatically with oral antiemetic drugs if they cannot be tolerated. In addition, taking PARP inhibitors before going to bed is helpful To reduce the occurrence of nausea.

More than half of the patients will experience fatigue during the course of taking it; in addition, a small number of patients will experience headaches, insomnia, dyspnea, rhinitis, cough, high blood pressure, tachycardia, etc.

At present, the main indications for PARP inhibitors are ovarian cancer, breast cancer and peritoneal cancer. Especially for ovarian cancer, in the past 30 years, the treatment options for ovarian cancer were mainly surgery and chemotherapy, with few breakthroughs.

Among gynecological malignancies, ovarian cancer has the lowest 3-year survival rate, only 39%, and the 5-year recurrence rate is as high as 70%. Due to the lack of obvious early symptoms and mature diagnosis methods in the onset of ovarian cancer, more than 70% of patients are already at an advanced stage when they are diagnosed.

For patients with ovarian cancer with BRCA mutations, PARP inhibitor maintenance therapy can delay the recurrence of patients for at least 3 years, which is a very remarkable progress.

Of course, our current understanding of PARP inhibitors is only the tip of the iceberg, and we look forward to more excavations from the academic community on the efficacy, mechanism, and applicable population of PARP inhibitors!

(source:internet, reference only)

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