With the tumultuous year we have had looking after my father with his multiple admissions to hospital due to the progression of his cancer followed finally by his death a month ago, my own health has taken a bit of a battering. I’ve now started to take up the rowing I did after all my kids were born as we have an indoor rower already and it’s there, sitting idle and free for me to use.
I’ve also taken to watching movies while I row because it can get kind of boring, the last cohort of movies being the entire series of Harry Potter. In these movies, death is an oft mentioned feature and I can see now how death alters how one sees life, much like one can only see thestrals, those skeletal horse things that are only visible to those that have witnessed death. I can see why things like the Resurrection Stone are enticing; the ability to resurrect a loved one who has died, especially if they are young. I don’t wish my dad to be brought back to life but I do wish that there had been more treatments available.
It was interesting therefore to read of a new cancer drug called AOH1996 which was tested and found to be effective on 70 different cancer cells including melanoma, colon cancer, breast, prostate and brain to name a few.
What is AOH1996?
It was created after a little girl called Anna Olivia Healey who died of a neuroblastoma aged 9y in 1996. The drug is codenamed AOH1996 after her. Dr Linda Malkas, of the team of researchers at City of Hope, one of the largest cancer research and treatment organisations in the USA, had met with Anna’s father just before she died and promised to look for new treatments in her memory. The drug has been in development for the past two decades.
What does AOH1996 do?
It targets a protein called proliferating cell nuclear antigen or PCNA, a protein which is essential for DNA replication.
Isn’t that what most chemotherapy drugs do, target DNA replication?
Yes, cancer cells are constantly replicating so many traditional chemotherapy drugs damage DNA and induce cell death but this causes severe side effects and drug resistance.
So how is AOH1996 different?
AOH1996 targets a novel cancer-associated PCNA isoform (caPCNA) that is expressed in a broad range of cancer cells but is not highly expressed in non-malignant cells.
[Gu L, Hickey RJ, Malkas LH. Therapeutic targeting of DNA replication stress in cancer. Genes (Basel). 2023 Jul;14(7):1346]
The first compound found to inhibit caPCNA was called AOH1160 but it lacked the properties for it to proceed into clinical studies. However a variant of it was found to have remarkable therapeutic properties; it is available in an oral formulation, was found to be effective in inhibiting solid tumours in animal studies or made them more sensitive to other chemotherapy drugs and caused no toxicity ie no side effects at six times the effective dose. This variant is called AOH1996.
[Gu L, Li M, Li CM et al. Small molecule targeting of transcription-replication conflict for selective chemotherapy. Cell Chem Biol 2023; S2451-9456(23)00221-0. doi: 10.1016/j.chembiol.2023.07.001. Online ahead of print.]
The future?
PCNA is a multi-function protein so it seems likely that inhibition of this is not the only way in which AOH1996 is working against cancer cells. Also, the initial studies were of short duration, the treatment was given for eight consecutive days only, and were also of a small size.
Most importantly, positive animal studies do not always translate into positive results in treating cancers in humans. But it’s a start.
And it shows that something positive can come out of death after all…
Kind regards,
Sandy
Dr Sandy Flann, Consultant Dermatologist
