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New compound molecule S63845b could help kill up to a quarter of all cancer types.

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Still pre-clinical, but promising.

Scientists have developed a new compound that's effective at inhibiting the growth of multiple types of cancer models in the lab – slowing as many as a quarter of all known types of cancer.

The molecule, called S63845, works by blocking the protein MCL1, which many different types of cancer cells rely on to grow. And without access to MCL1, the cancer cells die off.

The discovery could help researchers fight blood cancers such as acute myeloid leukemia, lymphoma, and multiple myeloma. Solid tumours – including melanoma and cancers of the lung and breast – could also see new treatments.

"MCL1 is important for many cancers because it is a pro-survival protein that allows the cancerous cells to evade the process of programmed cell death that normally removes cancer cells from the body," says one of the team, Guillaume Lessene from the Walter and Eliza Hall Institute in Australia.

"Extensive studies performed in a variety of cancer models have shown that S63845 potently targets cancer cells dependent on MCL1 for their survival."

Cancerous cells are difficult for the body's immune system to kill, because they can quickly evolve and spread faster than our defences can keep up, and can also evade what's called apoptosis – a form of programmed cell death.

Blasting them with chemotherapy drugs or radiation can be an effective way to combat cancer cells, but these techniques usually take healthy cells along with them, and cause debilitating side effects.

What makes S63845 so promising is that, in addition to cutting off cancer's life support system, it can be given at doses that don't harm normal cells, the team suggests.

The compound is the latest development in a new class of anti-cancer drugs called BH3 mimetics, which target a family of proteins that cancers rely on to sidestep and resist programmed cell death.


Top Reddit comment:

Some important caveats:

  • This drug is intended to inhibit the activity of MCL1. We know from genetic studies that deleting MCL1 in mice is embryonic lethal. Further, the protein is required for a number of essential processes, including hematopoiesis. So any inhibitor needs to walk a very narrow therapeutic window between killing the cancer cells and killing the human.

  • The authors claimed to have found a molecule that can function in that window. I'm not entirely convinced, based on the data presented here. They show they can kill caner cells with the drug (with a decent IC50 - maybe a bit high, but not bad for a preclinical molecule). Then they try to show that treating mice with the drug doesn't hurt hematopoiesis. Here I have a couple of concerns. First, this is a drug designed to inhibit human MCL1 and shown to inhibit human tumor growth (the proteins differ in amino acid sequence by about 25%). I'd need to see some more data to be convinced that testing hematopoiesis in mice is even a fair proxy for how the drug may affect non-tumor cells in humans. Second, the time point they look at is pretty narrow - at day 9, following five days of treatment, four days recovery. And even at this time point, they are starting to see defects in hematopoiesis. And ultimately, this would have to be considered in the context of a clinical regimen - most chemotherapies and radiation therapy regimens can be quite brutal on the hematopoietic system. 

  • History has made me a bit skeptical. MCL1 has been chased as a target for quite some time now. None, to my knowledge however, have made a dent in the clinic yet. I think this paper would have been much more convincing with some non-human primate toxicology data and a claim that it was progressing to a Phase I trial.

All those critiques aside, though, this is cool science. Just because something hasn't been done before is no reason to give up. And I would never want skepticism to blunt people's optimism about trying to find new ways to kill cancer.