Thread by @sbarnettARK

Besides #immunotherapy, how can #CRISPR be used to treat cancer?

Researchers at @CNIOStopCancer just published an exciting proof-of-concept showing how CRISPR can delete cancer-causing gene fusions, selectively killing cancer cells.

I'll elaborate.

nature.com/articles/s4146…

First, let's discuss what gene fusions are. As shown below, fusions result when two genes crash into each other and fuse together.

The resulting protein product is a hybrid. It has some features of Protein A and some of Protein B.

This usually is very bad.

We know that cancer-causing (#oncogenic) fusions have been found in nearly all cancer types. They're more common in pediatric cancers, but still are present in as many as 15-20% of adult cancers.

If present, fusions often are the main drivers of tumor growth.

I've done another thread on how fusions, especially those involved in cell-signaling pathways, drive tumor growth. I'll link my thread, but also recap with one example (NTRK-fusions).

My thread also describes the challenge in diagnosing fusions.

https://twitter.com/sbarnettARK/status/1273667124322545664

NTRK genes encode proteins that sit on the surface of cells. These proteins can be turned ON or OFF by signals outside of the cell. When ON, these proteins tell the cell to grow and divide.

If fused, NTRK proteins are stuck in the ON position, causing uncontrolled growth.

Therefore, oncogenic NTRK fusions, if left untreated, spur cancer cells to grow uncontrollably. Other fusions behave similarly.

This has given rise to small-molecule drugs (like Vitrakvi) that inhibit NTRK protein pathways.

But, what if we could delete the fusion altogether?

One rationale for attacking gene fusions directly is that they only exist in malignant cells, allowing for highly-specific, targeted treatment.

The @CNIOStopCancer researchers sought to delete fusions in cancer cells while ensuring that healthy genes would be unaffected.

Recall that #CRISPR can be used to break/delete DNA at desired locations in the genome.

As shown below, the researchers chose to break intronic (non-coding) regions of each gene partner in the fusion.

This means that the area between those introns (the fusion), would be deleted only in cancerous cells.

More simply, in repairing itself, a tumor is tricked into deleting its own food source, causing its own death.

Finally, the researchers studied the efficacy of this proof-of-concept in mouse models, demonstrating that in vivo CRISPR-deletion of fusion oncogenes has a) a therapeutic effect and b) has synergy with standard of care chemotherapy (DOX), as shown below:

In closing, fusions are one of the most exciting/emerging diagnostic/therapeutic targets within oncology. It's amazing to see novel detection methods (e.g. AMP Chemistry) proliferating alongside both small molecule agents, and potentially CRISPR-based treatments.

Source(s):

cancer.sanger.ac.uk/cosmic/fusion

researchgate.net/figure/The-ide…

nature.com/articles/s4146…

All drawings are mine.