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What you should know about PARP inhibitors in ovarian cancer

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What you should know about PARP inhibitors in ovarian cancer

Ovarian cancer is one of the most common cancers in women with more than 220,000 newly diagnosed cases each year. Ranked as one of the top killers, the high death rate explains why ovarian cancer has received much attention, and the overall 5-year survival rate of ovarian cancer is only 45%, much lower than that of breast cancer with a 5-year survival rate of 89%.

Poor prognosis in ovarian cancer 

There are three major reasons why ovarian cancer has a poor prognosis. 

Difficult to detect early: Early ovarian cancer has no obvious symptoms and it is very easy to be ignored or misdiagnosed. When discovered, it has already progressed into the middle and late stages.

Lack of new drugs:  For many years, the treatment of advanced ovarian cancer has been dominated by surgery and chemotherapy, and no effective targeted drugs or immunological drugs were developed.

Easy to relapse: Although some advanced ovarian cancers are initially sensitive to chemotherapy and shrink after treatment, many of them will relapse and require a second chemotherapy.

Given existing conditions, how to detect ovarian cancer earlier and effectively prevent recurrence has always been a major clinical challenge.

The emerging targeted drug: PARP inhibitors

Many patients with ovarian cancer feel cured after the first surgery plus chemotherapy since no cancer cells are detected. However, Due to the easy recurrence, a second chemotherapy is warranted when ovarian cancer come back again, so there is a period of remission before another chemotherapy is done.

The emergence of PARP-targeted drugs brings huge hopes for patients with ovarian cancer. The data from a published clinical trial of the PARP inhibitor Lynparza showed that patients carrying BRCA1/2 gene mutation can reduce the risk of tumor progression by 70% when using Lynparza during the period of remission.

In the clinical trial, the median progression-free survival rate was 5.5 months in the control group, while the Lynparza treatment group reached 19 months, more than one year longer than the control group. There is no doubt that PARP inhibitors are the biggest breakthrough among the existing standard treatment regimen in the past 30 years.

PARP inhibitors

The emergence of PARP-targeted drugs brings huge hopes for patients with ovarian cancer. As its name implies, PARP inhibitors are PARP-targeted drugs. Like other targeted drugs, PARP inhibitors don’t work against all cancers, and they only target subtype-specific gene mutation, and cancer cells with BRCA1 or BRCA2 mutations are sensitive to PARP inhibitors. 

Since BRCA1 or BRCA1 mutations mainly occur in ovarian cancer, breast cancer and prostate cancer, PARP inhibitors are experimented to treat these three tumors, and they show the best performance in ovarian cancer and have been approved by FDA to treat ovarian cancer.

Mechanism of action of PARP inhibitors

How do PARP inhibitors work, and why are they particularly effective against BRCA1/2 mutant cancer cells? In a nutshell, the mechanism of action for PARP inhibitors is that cancer cells cannot simultaneously loss PARP and BRCA functions. 

PARP and BRCA1/2 are the two major classes of proteins responsible for repairing DNA damage. Under certain circumstances,  BRCA1 or BRCA 2 gene is mutated, and when subjected to enough damage at one time, the altered gene can cause the death of the cells.

BRCA1/2 mutation is a double-edged sword for cancer cells. On the one hand, it weakens the ability to repair DNA breaks and allows cancer cells to accumulate DNA mutations more quickly, which helps tumor cells to evolve faster to resistance drugs. On the other hand, it leaves a deadly weakness for cancer cells. Once cancer cells loss BRCA, they will reply mainly on PARP, and If they further loss PARP, they will completely lose the ability to repair DNA damage, which will lead to death.

Therefore, when BRCA1/2 and PARP dysfunction at the same time, cancer cells would die immediately, which is why scientists develop PARP inhibitors.

Testing for BRCA1/2 mutations

PARP inhibitors are directed against BRCA1/2 mutations, and genetic testing is required before deciding whether PARP inhibitors are used. 

A tumor sample obtained by surgery or puncture is needed to receive targeted testing by a gene sequencing company for targeted testing. 

Theoretically, all patients with ovarian cancer, familial hereditary breast cancer, ovarian cancer syndrome, and hormone receptor-positive breast cancer shall receive the test for BRCA1/2 mutations.

 Hereditary BRCA1/2 mutations

The average cumulative risk of ovarian cancer is about 1.5%. This figure reaches 59% in BRCA1 carriers and 16.5% in BRCA2 carriers. Noticeably, BRCA1/2 mutations are heritable. People have multiple relatives with breast or ovarian cancer, especially if they are diagnosed with breast or ovarian cancer before the age of 50, they may get genetic mutations. 

If detected with BRCA1/2 genetic mutations, people can also choose to remove ovaries. A good case is from Angelina Jolie, the American actress who received a preventive oophorectomy after learning she had a defective BRCA1 gene.

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