A New Hope for Cancer
Updated Nov 5, 2023 by Dr Jack Kreindler
From hopeless in 1996 to Hope in AOH1996
The inspiring City of Hope Hospital’s own cancer research department has possibly achieved something that no other pharma company has managed since chemotherapy began in the mustard gas days. Its an oral therapy candidate called AOH-1996 (not in humans yet).
In 1996 I first saw cancer patients in the real and quizzed my tutors in medical school as to why we give chemotherapy so widely in solid tumours when it suppresses the very immunological Armed Forces that constantly fight malignancies in our bodies every day. Surely we should enhance our T cells and NK cells and and get more on target with laser guided weapons, and not just blitz everything?
25 years later Immune therapies are now a major force in cancer treatment but alas they only work in a proportion of cancers that have ample tumour antigens that the immune system can "see" and where the immune response can be strong enough. Breakthrough bio techs are engineering modified stem cells and like our friends at Orionis in Boston, are reprogramming the immune systems to get better results and more breakthroughs soon. But still Immunotherapy is often trialled after chemo fails or is withdrawn and so more often than not is given after toxic whole body chemo and localised radiotherapy has failed. A widely held perception by patients is that the chemo is almost as scary as the disease and it usually comes back more aggressively afterwards anyway.
How much solid progress have we made in solid tumor chemotherapy the last 25 years? How much more liquid are the drug companies thanks to chemo. The numbers are not impressive. We’re just ticking along in small incremental improvements. It makes so many patients and even professionals beg an answer for why are we treading water still or arguably still drowning in the chemo industry?
With the exception of a few cancers with profound changes that targeted drugs hit, the main examplesbeing breast cancer, non small cell lung cancer and melanoma, the data do show that even the best targeted therapies are a temporary defence in the battle but they also cause damage to the host and don’t win the war. And we can’t prevent all cancers or treat them all early enough for cure even if we tried. So the effort to find highly effective, affordable, quality of life preserving, oral cancer treatments is still a grand challenge in pharma and medicine. The current holy grail is to turn cancer into a chronic disease, something we live with, not die of, keeping it controlled while we live out the rest of our days with a good quality lifespan.
From 1996 to AOH1996
In 1996, the same year I raised the chemo paradox, Anna Olivia Healey was born, and by all accounts it seemed that she had every hope of a wonderful life ahead of her. Alas just 10 years later, in 2006 she lost her life to Neuroblastoma, a devastating but rare cancer despite every chemo therapy available and, of course, all the toxicity. Her family started a charity and donated to City of Hope department led by Professors Linda Malkas, Long Gu PhD and their brilliant team https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279569/ who has spent 20 years working out how to target cancer at its core - in the modified DNA PCNA splitting pathway called caPCNA in cancer cells.
City of Hope is not a pharma company. It’s a not for profit research hospital in California with a big interest in trying to do better for cancer patients.
The real story here is not just about the drug, it’s about who’s developed it. AOH1996 is the code name for the oral therapy (a small, orally absorbable molecule) City of Hope designed it quite ingeniously,and it may be the first major leap in chemotherapy for a wide range of cancers that we’ve seen in the last quarter century. It’s still early days as it’s only been used in animals but there are some very promising reasons why it’s making even the likes of me and our charity ACTforcancer.org.uk are getting excited about, and only wish our current patients and friends with hard to treat cancers today could one day soon have access to in trials.
How does it work?
It breaks apart DNA in a non-reversible way and does so preferentially in cancer cells more than in normal cells, without interfering with other cellular functions, as it targets something called PCNA that’s needed in DNA replication for all dividing cells, but it can be mutated in cancer and the levels of caPCNA go up inside a wide range of solid cancers much more than in normal cells. Up to 30 times more. But wait. Isn’t that what all targeted drugs do? There’s a mutation causing cell growth in cancer and that offers a potential target that’s found in cancer cells more often than in normal healthy cells. So don't all targeted drugs have the same principle? Don’t we already have a way of only hitting cancer cells mutating for abnormal growth and spread? Isn’t this the same? No, from what I’ve read of the paper just published it looks like, in simple terms, AOH1996 can make DNA breaks and cause them to fail to repair in cancer cells in a much more direct, profound and specific way than the chemotherapyor targetted drugs we currently use. This has so far shown no discernible side effects in doses far in excess of the effective dose in animals. But, and it’s a big but, City of Hope have only tested this in non-human animals so far. Breath hold.
The Complex Bits
In the animal studies it almost completely inhibits the growth of xenograft [grafted from another species, probably human] tumors and sensitizes them to topoisomerase inhibition. In studies that follow the good laboratory practice (GLP) guidelines of the US Food and Drug Administration (FDA), AOH1996 causes no discernible toxicity at 6 or more times the effective dose in mice and dogs. This, especially if reproducible in the real world, is remarkable and a breakthrough. But still we need to see what happens to 50 year old humans before we can stop holding our breath.
Hope
Whatever the human results will show it is exceptional the work and dedication of City of Hope Hospital and the team there to making better treatments across a wide range of cancers that are still cheap and easily deliverable to the masses. Watch this space
https://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(23)00221-0
Jack Kreindler
With special thanks to Peter McDougall (DrugAnalyst.com) and Andy Gaya (Oncologist)