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Could This New Drug Be The Cancer Treatment We’ve Been Waiting For?

Posted on 4 August 2023

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There’s a good chance you’ve heard about it by now – it’s called AOH1996, and it’s an experimental anticancer molecule that has been reported on by quite a few media outlets over the past week. Even though it hasn’t yet been validated in human clinical trials, many people are hailing it as a major potential breakthrough in cancer therapy. So, what exactly is AOH1996 and why are people excited about it?

How Does It Work?

It all starts with a molecule called PCNA, which stands for proliferating cell nuclear antigen. PCNA is an impressive-looking protein known as a ‘DNA clamp’. It assembles around the DNA strand and acts as a binding site for the many proteins involved in DNA replication, repair, and for the remodelling of DNA-associated proteins that is occurring constantly in all our cells. Needless to say that PCNA is a very important protein for cell division – if anything goes awry with PCNA, the cell’s whole DNA copying machinery can fall apart.

Depiction of the PCNA protein complex surrounding a central DNA double helix.
By Boghog – Own work, Public Domain,

The entirety of the cell’s DNA must be replicated each time a cell divides. Outside of cell division, sections of the DNA are continually copied to serve as templates for protein production in a process called transcription. Because this machinery is so active in cancer cells, conflicts often arise where these two processes run into each other – the cancer cell tries to both replicate and transcribe its DNA at the same time. This situation must be resolved – the transcription machinery must give way and allow DNA replication to proceed.

AOH1996 is a molecule that exploits these conflicts by targeting a specific form of PCNA only found in cancer cells (caPCNA). AOH1996 binds to a specific binding site on the caPCNA protein, which causes caPCNA to interact more strongly with a key component of the transcription machinery called RNA polymerase II. This disrupts the DNA replication process in a major way, causing both DNA strands to break in multiple places. AOH1996 essentially forces transcription and replication into an impasse and breaks them both as a result.

Representation of a transcription-replication conflict (TRC). AOH1996 prevents resolution of the TRC by stabilising the interaction between PCNA and RNA polymerase II. This causes double-stranded breaks in the DNA and leads to degradation of the RNA pol II subunit (RPB1).
Small molecule targeting of transcription-replication conflict for selective chemotherapy

Why Is This Exciting?

AOH1996 has so far only been studied in two species, mice and dogs, which received transplants of cancer cells from human patients. However, the results from these preclinical studies are quite encouraging due to its ability to target a wide range of cancer cells without harming normal cells.

Tumour volume over time in mice treated with 40mg/kg of AOH1996 (grey) or controls (black). From left to right: neuroblastoma; breast cancer; small-cell lung cancer.
Small molecule targeting of transcription-replication conflict for selective chemotherapy

AOH1996 was toxic to over 70 cancer cell lines, was able to significantly shrink tumours in animals, enhance the effectiveness of chemotherapy and improve survival. Even when these species were given six times the effective dose (which is the minimum dose required to produce a biological effect), no toxicity was observed on normal cells, which suggests that AOH1996 is very good at targeting only the cancerous form of PCNA. 

In contrast, typical chemotherapy doesn’t discriminate between cancer cells and normal rapidly-dividing cells, and also tends to damage tissues surrounding the tumour, which makes the cancer more likely to recur later on. Due to the toxic side effects of chemotherapy, you can’t give someone too much at once, and this gives the cancer more opportunity to develop resistance against the treatment by mutation. The hope here is that even if cancers are capable of developing a new resistant form PCNA, they won’t have much of a chance to do so because high doses of AOH1996 in combination with conventional therapies will kill them first. 

Ultimately we’ll have to wait and see, as phase I human clinical trials have only just begun, and the road to the clinic is long and bumpy…

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    Small molecule targeting of transcription-replication conflict for selective chemotherapy

    Title image by National Cancer Institute, Upslash

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