The "anti-cancer miracle drug" that can kill all solid tumors is coming?
Experts say AOH1996 is still far from being effective
◎ Chen Xi, reporter of this newspaper
Recently, the "anti-cancer miracle drug" AOH1996 has aroused heated discussions. It is understood that on August 8, "Cell Chemical Biology" published the scientific research results of the American Cancer Treatment and Research Institute Hope City online. According to the article, scientists have developed an oral small molecule targeted chemotherapy drug, AOH1. In preclinical studies, the drug was able to kill all solid tumors.
At present, there is no pan-solid tumor anti-cancer drug that can kill all tumors clinically, so this research result has attracted great attention. Wang Haitao, chief physician of the oncology department of the Second Hospital of Tianjin Medical University, said that the data that the research drug can inhibit a variety of solid tumors is limited to the cell experimental stage and has not yet entered clinical trials. Generally, 90% of research drugs will fail on the way to clinical trials. Therefore, it is too early to say that AOH1996 is an "anti-cancer miracle drug".
Can interfere with cancer cells self-repair
AOH1996 is a research-stage oral small molecule proliferating cell nuclear antigen (PCNA) inhibitor used to inhibit tumor cell proliferation.
Why can PCNA be an anti-cancer target?
"The rapid proliferation of cancer cells creates a conflict between replication and transcription (TRC) within the cell, where two key cellular machines responsible for gene expression and genome replication collide in the same genomic location, which is the main cause of endogenous DNA double-strand breaks and genomic instability." Wang Haitao introduced that this feature of cancer cells is also used in many anti-cancer strategies, similar to DNA damage repair inhibitors, which are to inhibit the DNA damaged by repairing cancer cells, so as to achieve the purpose of destroying cancer cells. PCNA, a protein found in all eukaryotic cells, plays a key role in DNA synthesis and repair, and is therefore also seen as a potential anti-cancer target.
The researchers tested AOH1996 in multiple cancer cell lines and several normal control cells, and they found that AOH1996 can interfere with cell repair TRC, inducing cancer cells to produce DNA double-strand breaks in a transcription-dependent manner without interrupting the reproductive cycle of healthy stem cells, so the drug is able to selectively kill cancer cells.
"This anti-cancer principle makes AOH1996 act on a wide range of tumors, and at the same time, it has certain targets, which can hit tumors more accurately, rather than 'killing a thousand enemies and self-damaging eight hundred' like traditional chemotherapy." Wang Haitao said.
The real test is still in clinical trials
"Although everyone is looking forward to AOH1996, AOH1996 is still far from clinical application." Wang Haitao pointed out that AOH1996 is still in preclinical research, and it generally takes 8-10 years from after entering the clinic to being approved for marketing.
Preclinical research mainly conducts pharmacokinetic as well as drug safety and drug toxicology studies through model and animal experiments. However, no matter how rigorous medical theories and drug treatment models are, they may not be achievable in reality. "The ecological environment of the human body is very complex, and it is effective for cells and animal models, but it does not mean that it is effective for people." Wang Haitao said that it has passed the preclinical study, which can only be said to have seen the dawn, and the real test is still in clinical trials.
Phase I clinical trials mainly observe the tolerance and pharmacokinetics of new drugs; Phase II clinical trial is to preliminarily study the safety and efficacy of drugs through a small range of sick populations; Once the phase II clinical trial is effective, the phase III clinical trial will expand the trial sample to more widely investigate the efficacy and safety of the new drug on the human body, as well as the combination of drugs during use.
This process is not only long-term, but also has a very high risk of "rollover".
"And the biggest difficulty in the development of pan-solid tumor anti-cancer drugs is that although pan-solid tumor anti-cancer drugs can kill all tumors in theory, their efficacy varies greatly in different cancers." Wang Haitao said.
Although research and development is not small, scientists are still enthusiastic about the research and development of pan-solid tumor anti-cancer drugs. For example, in May 2017, the US Food and Drug Administration (FDA) approved pembrolizumab (K drug) for patients with multiple solid tumors with high microsatellite instability (MSI-H) or mismatch repair defect (dMMR), with an effective rate of nearly 5%; In 40, the FDA announced the approval of entrectinib for the treatment of a variety of tumors with NTRK gene fusion; In 2019, the FDA approved a new indication for K drug "unlimited cancer" for high tumor mutation burden (TMB-H).
Wang Haitao said that although AOH1996 cannot be called an "anti-cancer miracle drug", the PCNA target it targets is an innovation. Because previously, the protein was considered undruggable. At present, the research drug has entered phase I clinical trials, and scientists have verified the unique mechanism of action of the drug, through which the protocol of inhibiting transcriptional and replication conflicts may open up new avenues for selectively killing cancer cells. (Science and Technology Daily)