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Synthetic lethality: from proof of concept to the listing of PARP inhibitors

Lianyungang Klinechem Co.,Ltd | Updated: Jul 17, 2018

WHAT? Synthetic death

 

Currently, targeted therapies for malignant tumors are often directed at "oncogene addiction." The most typical example is that about 90% of patients with chronic myeloid leukemia (CML) have a BCR/ABL fusion gene, and tumor cells rely on the protein produced by this gene to survive. For normal cells, they are not dependent on it. gene. Therefore, imatinib targeting BCR/ABL can significantly prolong the survival of patients with CML, while being less toxic to normal cells.

[Noun explanation "oncogene addiction" refers to the survival of tumor cells depending on an activated oncogene]

 

Another therapeutic concept of tumors is synthetic lethality, which is expected to achieve the goal of killing only tumor cells without significant effects on normal cells. This concept has been successfully used in the treatment of BRCA 1/2 mutant ovarian cancer with PARP inhibitors.

[The term "synthesis-killing" refers to the cell-dependent gene B survival when the function of gene A is absent, that is, the inhibition of gene B and the loss of function of gene A lead to cell death, but only the loss of gene A function or the inhibition of gene B alone. In no case does it affect cell survival. ]


▲ Oncogene addiction and synthesis lethal


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Synthetic lethality in DDR: familial hereditary BRCA mutations and PARP inhibitors

 

Various endogenous and exogenous factors can cause DNA damage in cells, and cells recognize DNA damage through a series of molecular pathways: DNA damage response (DDR) >>> Prevent cell cycle >>> Mediate DNA repair >>> Keep The integrity and stability of the cellular genome. Among them, poly(ADP-ribose) polymerase (abbreviated as PARP, mainly PARP1 and PARP2) is one of the key proteins in DDR. PARP1 recognizes DNA single-strand break (SSB), and when it binds to a single-strand break site, it activates its catalytic function, synthesizes poly ADP ribose chain (PAR) and assembles it on some proteins (PARylation) to recruit DNA. Damage repair proteins to the injury site to repair damaged DNA. Ultimately, PARP itself will also assemble PAR to dissociate from the repaired DNA.

 

After understanding the function of PARP, PARP inhibitors were gradually developed. Scientists initially developed PARP inhibitors in the hope that they would be able to sensitize traditional DNA damage therapies, including multiple chemotherapy drugs and radiation therapy. This is another synthetic lethal mode of PARP inhibitors, called “PARP trapping”, which will be done later. Detailed introduction. Until 2005, two research groups reported the combined lethality of PARP inhibitors and BRCA1/2 loss-of-function mutations, demonstrating a new therapeutic concept for tumors carrying BRCA mutations.


▲PARP binds to damaged parts of DNA

 

People with a family of hereditary BRCA1 or BRCA2 mutations have a significantly increased risk of malignancy, especially breast and ovarian cancer. Both BRCA1 and BRCA2 are key proteins in DNA double-strand break (DSB) homologous recombination repair (HRR). For family hereditary breast cancer patients, it is usually because of the loss of function on a homologous chromosome in the BRCA1 or BRCA2 gene. Mutation (heterozygous mutation, BRCA+/-), during life, some cells lose the function of BRCA1 or BRCA2 on another homologous chromosome, becoming a homozygous mutation (BRCA-/-), and the loss of BRCA function leads to HRR Loss of function, DNA double-strand break repair is blocked, causing genomic instability, which leads to tumors. However, other BRCA heterozygous mutations (BRCA+/-) still produce BRCA protein normally, which is involved in DNA double-strand break repair.

 

There are about 104 SSBs produced every day in tumor cells. These damages require PARP-mediated repair process. When PARP activity is inhibited, SSB continues to accumulate. During DNA replication, DNA single-strand breaks are converted into DNA double strands. The break, while the DSB produced during the replication process is mainly dependent on HR repair. For tumor patients with BRCA1/2 mutation, tumor cell HRR function is missing, DSB repair cannot be completed, and a large number of DSB accumulation causes DNA replication to collapse and cell death. Compared with BRCA-functioning tumor cells, tumor cells with BRCA function loss are about 1000 times more sensitive to PARP inhibitors than the former. For normal cells of these patients, functional BR BR proteins can be produced by carrying only heterozygous BRCA mutations, and therefore, PARP inhibitors have less effect on them. This is the initial understanding of the scientists' death from the synthesis of PARP inhibitors.

 

In subsequent studies, the scientists found that Talazoparib and Olaparib have comparable inhibition rates on PARP catalytic activity, but Talazoparib is significantly more cytotoxic to BRA mutant tumor cells than Olaparib. In addition, in a cell line with normal BRCA function, a combination of a cytotoxic DNA damaging agent methyl methanesulfonate (MMS) and a PARP inhibitor was also used to produce synthetic lethality. Later studies have found that PARP inhibitors can not only inhibit the catalytic activity of PARP, but also stabilize the complex of PARP protein and DNA, called "PARP trapping". When a DNA single-strand break occurs, the PARP protein binds to the cleavage site. At this time, the PARP inhibitor binds to PARP, which causes the loss of the catalytic function of PARP, affecting the PARP itself's PARylation, and the PARP protein cannot be dissociated from the DNA. Here, PARP is like a lock hanging on DNA, and the PARP inhibitor is like a key broken in the lock cylinder. It is firmly integrated in the lock cylinder, but it can't unlock, and it also prevents other keys from unlocking. Thus, PARP inhibitors form a stable complex of PARP and DNA, while the PARP-DNA complex has strong cytotoxicity and ultimately causes cell death. As mentioned earlier, MMS is a DNA damage reagent that increases the number of DNA single-strand breaks, so that PARP inhibitors can cause more "PARP trapping" and therefore have a synthetic lethal effect on cells with normal BRCA function. Although Talazoparib, Niraparib, Olaparib, and Niraparib have comparable PARP catalytic inhibitory activities, the ability to "PARP trapping" varies greatly. Talazoparib has the strongest "PARP trapping" ability, about 100 times that of Olaparib, followed by Niraparib, and Veliparib. The weakest. This also partly explains why PARP inhibitors with comparable PARP inhibitory activity have different cytotoxic effects on BRCA-mutated tumor cells.


▲The mechanism of action of PARP inhibitors


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Clinical status of PARP inhibitors

 

The main function of PARP is to catalyze the synthesis of PAR, to make a variety of DNA repair proteins PARylation, involved in DNA repair, its substrate for coenzyme I (NAD+), the classic PARP inhibitor is bound to the substrate binding domain of PARP, therefore PARP inhibitors are all substrate analogs. Almost all PARP inhibitors have an aramid moiety to mimic nicotinamide in NAD+, thereby competitively blocking the catalytic activity of PARP. PARP inhibitors initially entered the clinical trial as a combination therapy with the chemotherapy drug temozolimide. Following the study of PARP inhibitor and BRCA mutant tumor synthesis lethal, PARP inhibitors are clinically used to treat BRCA1/2 mutant mammary glands. Cancer and ovarian cancer patients. At present, three PARP inhibitors have been approved by the FDA, and dozens of PARP inhibitors have been clinically tested at various stages, which are described below.


▲PARP inhibitor

 

Olaparib

Olaparib is a PARP inhibitor developed by AstraZeneca. On December 19, 2014, the FDA approved its use in the treatment of advanced ovarian cancer patients who have received more than two treatments and have germline BRCA mutations. The concept of lethality is FDA-approved anti-tumor drugs. In 2015, the Nobel Prize in Chemistry was awarded to scientists who studied DNA damage repair and was also affirmed by this concept of treatment. Clinical studies have found that Olaparib is equally effective for patients with ovarian cancer who are able to benefit from platinum-based chemotherapy drugs, while platinum-insensitive ovarian cancer patients usually do not respond to Olaparib, suggesting that both therapies may be based on the same Mechanism. In a recent large phase III clinical trial, patients with recurrent ovarian cancer with germline BRCA mutations and sensitivity to platinum-based chemotherapy were treated with Olaparib (300 mg tablets twice daily) with no median progression. Survival was as high as 30.2 months, compared with 5.5 months in the placebo group. Common side effects were dizziness, fatigue, vomiting, anemia, neutropenia, and thrombocytopenia, which were consistent with previously reported side effects, indicating Olaparib. As a maintenance therapy, it has the potential to treat recurrent ovarian cancer with BRCA mutations. Currently, Olaparib has several clinical trials for different tumors ongoing.


▲Olaparib

Rucaparib

Clovisarib, the PARP inhibitor of Clovis, was the first PARP inhibitor to be introduced into clinical trials. On December 19, 2016, Rucaparib was approved by the FDA for the treatment of advanced ovarian cancer with a germline or somatic BRCA mutation and at least two treatment regimens. The market was approved based on a phase III of 106 patients. In clinical trials, patients received 600 mg of oral daily treatment with an objective response rate (ORR) of 54%, complete remission (CR) of 9%, and a median duration of remission of 9.2 months. The sensitivity of these ovarian cancer patients to platinum-based chemotherapy drugs and the sensitivity to Rucaparib are highly consistent. Platinum-sensitive patients have an ORR of 66%, platinum-resistant patients with 25%, and platinum-refractory patients with 0%. Common side effects are nausea, fatigue, anemia, and the like. However, Rucaparib may have potential therapeutic risks, including myelodysplastic syndrome, acute myeloid leukemia, and fetal abnormalities. In previous studies, it was found that high concentrations of Rucaparib produced off-target cytotoxic effects compared to Olaparib and Talazoparib, but it is not clear whether these off-target effects are the main cause of toxic side effects.


▲Rucaparib

 

Niraparib

Tesaro's PARP inhibitor Niraparib has been completed in Phase III clinical trials for platinum-sensitive advanced ovarian cancer and was approved by the FDA on March 27, 2017 for complete or partial response but relapse after platinum-based therapy Adult ovarian epithelial cancer, fallopian tube cancer, and primary peritoneal cancer are maintained without the need to detect the BRCA genotype. In a phase III clinical trial, 203 patients who had previously received at least 2 platinum-based therapies and who carried the BRCA mutation received 300 mg of Niraparib daily, with a median progression-free survival compared with the placebo group. Prolonged (21.0 months in the Niraparib group vs 5.5 months in the placebo group). Unlike Olaparib and Rucaparib, Niraparib's clinical trials included not only BRCA-mutated ovarian cancer patients, but also 350 patients who did not carry BRCA mutations. The study found that this group had a median progression-free survival of 9.3. At 3.9 months in the placebo group, patients who did not carry the BRCA mutation but had HRR deficiency had a median progression-free survival of 12.9 months in the Niraparib group, a significant improvement over the placebo group of 3.8 months. This indicates that Niraparib not only has a synthetic lethal effect on BRCA-mutated tumors, but also forms a synthetic lethality with other DNA double-strand repair defects. Common grade 3-4 adverse events are thrombocytopenia, anemia, and neutropenia.


▲Niraparib

 

Talazoparib

Several clinical trials of Talazoparib are underway, including Phase III clinical trials for advanced breast cancer with BRCA mutations. In a previous clinical trial, 13 breast cancer patients with BRCA1/2 mutations received neoadjuvant therapy with Talazoparib. After two months, all patients had tumor shrinkage, and the treatment is currently under 4-6 months. Clinical trials of neoadjuvant therapy. In preclinical studies, Talazoparib has excellent PARP trapping ability, which is 100 times more toxic to BRCA mutant tumor cells than Niraparib. Therefore, in clinical trials, the clinical dose of Talazoparib is very low, only 1 mg per day.


▲Talazoparib's structural formula is undergoing several clinical tests

 

Iniparib

Iniparib was once considered a PARP inhibitor and has a different mechanism of action than traditional PARP inhibitors. In Phase II clinical trials, the combination of Iniparib with gemcitabine and carboplatin for the treatment of triple-negative breast cancer has achieved remarkable results, increasing progression-free survival and overall survival without increasing toxicity. However, Phase III clinical trials of non-small cell lung cancer and platinum-resistant ovarian cancer have failed. Moreover, this molecule does not selectively kill tumor cells that are BRCA-mutated. After detailed research, it was finally found that Iniparib is not a true PARP inhibitor, and its anti-tumor activity is not caused by inhibition of PARP. Iniparib and Olaparib's failure of several large phase III clinical trials reduced the enthusiasm of pharmaceutical companies for PARP inhibitors at the time, AstraZeneca terminated the PARP program, and other large pharmaceutical companies also sold their PARP products at a discount. Later, AstraZeneca found from previous clinical data that PARP inhibitors have excellent efficacy for BRCA-mutated tumors, and restarted Olaparib to treat phase III clinical trials of BRCA-mutant ovarian cancer, bringing people back to these drugs. interest. Iniparib has also become a typical counterexample in drug development.


▲Iniparib was confirmed not to be a PARP inhibitor


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Outlook

? PARP inhibitors for the treatment of BRCA mutant tumors successfully applied the concept of synthetic lethality to the treatment of tumors, but currently PARP inhibition

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