AOH1996 treatment targeting PCNA shows promise for reoccurring solid tumours

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Published: 8 Aug 2023
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Dr Linda Malkas - City of Hope, Duarte, USA

Dr Linda Malkas speaks to ecancer about her talk at AACR 2023 on AOH1996, a cancer medicine, which targets PCNA and shows promise in treating cancer patients with reoccurring solid tumours.

She outlines the background and design of the trial.

Dr Malkas explains they identified a potent PCNA inhibitor (AOH1996). The results showed AOH1996 selectively kills many types of cancer cells at below micromolar concentrations without causing significant toxicity to a broad range of non-malignant cells.

This highlights the potential of AOH1996 as a broad-spectrum therapeutic agent for the treatment of many types of cancer patients with solid tumours.

 

The focus of my talk and research has been about, one, the identity of a very novel target for therapeutic development for cancer. It’s a target called proliferating cell nuclear antigen, or PCNA, and it is uniquely modified in cancer cells versus normal cells. So, we exploited that protein that is uniquely expressed in cancer cells for the development of a small molecule compound that is now in phase I clinical trial. 

A little bit about PCNA, it is a protein that has about 200 interacting partners and the small molecule targets the ability of PCNA to interact with its partners. So, in effect, you’re shutting down a number of critical pathways which PCNA would be a part of. I always liken PCNA to a molecular hub: kind of like an airport. You have an airline terminal and then you have all these jet ways. You could think of the jet ways as planes or protein partners that would bind to the airline terminal, which is PCNA. So we have built a molecule that inhibits the proteins for binding to, or the planes from binding to, the PCNA terminal.

It is in clinical trial now; it is targeting with a drug which is called AOH1996. It is for all solid tumours; it is an oral drug, it is given twice a day. Where we are in accrual, I am happy to say, that the patients thus far have not shown any toxicity to the drug which was one of the original hopes when we were making the potential drug, that because it’s against a protein or a molecular target that is uniquely in cancer cells, that it would leave normal cells alone and that’s what it looks like it’s doing.

The clinical trial is a standard phase I trial. You start at a low dose. The plan is for an accrual of approximately, I believe, 27 patients. The cycle for the trial is 28 days. So, the first patient made it and went through the trial, no toxicity, was observed. That patient then came off the trial after 28 days because of medical issues not related to our drug. The second patient came on and now you double the dose that the first patient had received. That dose that was given to the patient would be aware that the drug could be now entering an effective dose based on our animal tumour studies that we had looked at. That patient came on at double that dose of the first patient; they made it successfully through their 28-day cycle. They have continued on the drug, now they are out more than 100 days and still not exhibiting toxicity issues.

The third patient was accrued, I believe now has passed successfully that 28-day cycle. And, of course, that patient, the third patient, is double the dose that the second patient was receiving. So, we should be where the effective concentration for action for the drug is. Again, that patient now I believe is now beyond the 28-day cycle and is doing well. So they will be now recruiting a fourth patient, again doubling the dose. So that’s where we are and that’s more or less the design of the trial.

The trial is ongoing so we don’t really have results but so far, at least on the three increases of the drug that we have seen, three bounces in dose that the patients have observed, during the cycle of the trial they have not exhibited toxicity.

The future for this study, hopefully we see some potential inklings of response. Again, it’s a phase I trial so you’re really looking at toxicity. What we will also be looking at, collecting samples to look for, the ability of the drug to penetrate the tumour. We have shown it for preclinical studies in animal models that, indeed, the drug does penetrate the cells of a tumour and behave in the manner that we conceptualised. What will happen after this trial, we have been doing a number of preclinical studies looking at how AOH1996 interacts or essentially synergises with therapies that are currently used in the clinic. Since AOH1996 is exhibiting little or no toxicity it could prove to be a very good agent in combination with current therapeutics in potentially allowing us to lower the dose of the current therapeutic in that combination, therefore making the overall treatment for patients less toxic. 

The action of our drug, because it is targeting PCNA which is a protein that functions in a variety of important cellular pathways, including DNA replication, DNA repair, cell cycle regulation, chromatin assembly, a number of very critical cellular functions, we have seen very nice synergy with platinum compounds, topoisomerase inhibitors and other types of currently used drugs. So, we’re excited, we believe, I think, where this drug will find its home as a very strong component of combination therapies. As I like to say, I know it sounds a little hokey, but I think it’s going to be the olive of therapeutic cocktails.