Targeted Therapy Kills All Kinds of Cancer in the Lab
A twice-daily pill is now being tested on humans.
A new targeted therapy that has killed more than 70 types of cancer in preclinical trials without harming healthy cells is now being tested in humans.
The Challenge Targeted therapies for cancer focus on specific genes or proteins that are required for cancer cells to grow, divide, and spread. While these are very effective therapies, cancers often evolve to resist them.
In theory, proteins named PCNAs (proliferating cell nuclear antigens) would be ideal targets for cancer therapy.
Unfortunately, PCNA has long been considered “undruggable.
New Targeted Therapy City of Hope researchers appear to have overcome the challenge of targeting mutant PCNA with a new drug called AOH1996.
City of Hope was able to develop an investigational drug that targets a challenging protein.
The new study details how the drug killed more than 70 types of cancer in laboratory tests and three types (neuroblastoma, breast cancer, and small cell lung cancer) in tests on mice. When administered to mice and dogs, there were no signs of toxicity to healthy cells.
Because PCNA was considered “untreatable,” no one had ever targeted PCNA as a therapeutic agent, but City of Hope was able to develop an investigational drug targeting an apparently difficult protein.
How does it work? When cells divide, the mechanisms that replicate the cell’s DNA and the mechanisms that express genes sometimes collide.
This phenomenon is called “transcription-replication collision” (TRC) and can cause genome instability and DNA damage. To avoid this, our cells have mechanisms to resolve these collisions.
City of Hope’s targeted therapy interferes with this resolution process in cancer cells, which have been shown to experience more TRCs than healthy cells, by enhancing the interaction between mutant PCNA and an enzyme called RPB1.
To our knowledge, our results are the first to show that the interaction between PCNA and RPB1 creates cancer-selective vulnerability.” Future Outlook The Phase 1 clinical trial of AOH1996 was initiated in October 2022. City of Hope’s plan is to enroll eight patients with treatment-resistant solid tumors in the trial, each of whom will receive targeted therapy administered as a pill twice daily for 28 days.
If the disease does not stop progressing at the end of the 28 days, another 28-day cycle will begin with an increased dose. The plan is to repeat the process until the cancer stops growing or the treatment becomes too toxic to continue.
AOH1996 is just such a new treatment,” said study co-author Daniel von Hoff.
Soruce: Targeted Therapy Kills All Kinds of Cancer in the Lab