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.…
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.

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.

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More from @sbarnettARK

24 Sep
Interesting, Exact Sciences ($EXAS) is halted and spiking up ~15%, likely because of what's going on at the Cowen liquid biopsy conference. I will provide updates.
This is the first time, to my knowledge, Exact has seriously discussed multi-cancer liquid biopsy instead of just colorectal cancer screening via Cologuard. They presented preliminary data evaluating a blood-based multi-cancer test.
The cohort was relatively small, but showed sensitivity of ~85% (true-positive rate) and specificity of ~95% (true-negative rate). This is definitely the highest sensitivity I've seen from a test like this, but also the weakest specificity. Granted, this is early data.
Read 4 tweets
24 Sep
Rapid whole genome (🧬) sequencing (rWGS) is one of the most exciting (and benevolent) collisions of #AI and #genomics I can think of.

rWGS can diagnose a critically ill child in minutes where previously it took years.…
A few years ago, Illumina ($ILMN) and Rady Children's Hospital (@RadyGenomics) collaborated to offer sequencing services for diagnosing critically-ill infants and toddlers.

Roughly 70% of rare diseases are genetic and they can take five years to diagnose.
As sequencing costs dropped and #AI got faster, this collaboration became Project Baby Bear: a pilot study for rWGS's diagnostic yield, clinical utility, and health economics in practice.

Several innovative companies joined Rady's in creating a rapid diagnostic pipeline.
Read 14 tweets
22 Sep
Hi, @7MaxxChatsko --

I agree with a lot of what you've laid out above. However, I think I should clarify some parts of my thread and offer counterpoints to a few of yours. I'm always game to trade notes.

I disagree that the DNA sequencing market is worth $10 billion. Today, it’s less than that. Should Illumina (a) drive unit prices lower (w/ super resolution, see below) & (b) help customers up the platform upgrade cycle to realize bleeding-edge OpE...

…that the market could be worth much more. I’ll cede that this position isn’t ideal because, as you point out, the vastest TAM is within clinical genomics. Still, investors could be ‘headed for the exits’ because their time horizons may not be long enough.
Read 18 tweets
21 Sep
Illumina ($ILMN) Acquires GRAIL: Pros, Cons, & Questions

Earlier today, Illumina announced its intent to acquire cancer-screening company GRAIL for $8 billion, marking its most direct foray into clinical #genetics.

Here's what we think:

I'll begin with some positives (✅).

GRAIL's test (Galleri) is being evaluated in some of the largest clinical studies within genomics. Three of these studies are ongoing:

PATHFINDER (n=6,200; Ends Jan 2022)
STRIVE (n=99,481; Ends May 2025)
SUMMIT (n=50,000; Ends Aug 2030)
I'm basing timelines off of the study completion dates (see below). I'm doing this because I believe the secondary outcome measures are more relevant to commercialization and/or reimbursement, as is the case w/ STRIVE, for example.…
Read 37 tweets
21 Sep
It’s now official: Illumina is acquiring GRAIL for $7.1 billion in a cash + stock transaction. I’ll be discussing my take as well as the potential pros and cons in a thread later today.

EDIT: $8B* transaction
After listening to the conference call, I think there's an even greater need for a thread. There were many details/questions that I feel went unaddressed. I plan to post a thread later today. Happy to see questions accumulate below so I can address or respond ad hoc.
Read 4 tweets
18 Sep
Long Reads and Dark Genes (🧵)

Despite common misconception, we’ve never sequenced 100% of the human #genome.

Since the completion of the Human Genome Project in '03, scientists have struggled to fill in numerous small gaps scattered throughout our 23 chromosome pairs. (1/7)
These gaps, sometimes called dark genes, constitute holes in our understanding of #genetics, evolution, and human disease. Dark genes contain long, highly repetitive stretches of DNA that cause short-read sequencers to make errors.

Many of these errors begin during sample preparation, making it difficult or impossible to overcome with software tools. Last week, researchers published a complete copy of chromosome 8—the first non-sex chromosome to be fully sequenced.

Read 7 tweets

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