Full Episode here ! youtu.be/TEhPlF29yl4

I also experiment with a CGM and share opinions on what these devices can tell us and what they can't. #discoverydialogues #diabetes #cgm #podcast #medicalhistory #Type1Diabetes #type2diabetes

From a Holocaust survivor to one of the most prolific innovators in recent times, Heller's story is absolutely incredible.

This project was led by a highly talented grad student Rema Iyer with help from others in the lab esp. Anagha Deshpande, and fantastic collaborators at @sbpdiscovery.bsky.social including Ben Finlay, @ Vuori Lab Gerard Brien (Edinburgh), Hiromi Wetterstein (UCSD) and @alice.soragnilab.com @ (UCLA).

Finally, TAK-981 robustly suppressed tumor growth in xenograft models, reducing tumor growth, decreasing SS18::SSX protein levels, and lower cellularity. This study strongly indicates SUMO2 inhibition as an effective therapeutic strategy against synovial sarcoma in vivo.

Prior studies (McBride et al., Benabdallah N. et al., Boulay G. et al.,) have demonstrated H2AK119ub activation by SS18::SSX fusions. We observed that SUMO2 inhibition substantially reduced H2AK119ub, esp. at fusion target sites corresponding with fusion loss.

These results were borne out by CUT&Tag which showed strongly diminished SS18::SSX fusion protein on chromatin after SUMO2 inhibition using TAK-981.

Surprisingly, SUMO2 inhibition did not just reverse downstream targets, but also SS18::SSX protein levels themselves. Both shRNA and TAK-981 treatments lowered fusion protein levels across different variants (SSX1 and SSX2), establishing SUMO2 as a regulator of the fusion itself.

This was a surprise - reminiscent of candidates that target the fusion protein itself - or immediately proximal targets. Excited by this, we tested whether SUMO2 inhibition targets the fusion protein.

Fusion activated oncogenic targets (e.g., HOXA10, SUZ12, TYMS) were down-regulated, while fusion-repressed genes such (e.g., KLF4, GADD45B) were derepressed upon SUMO2 inhibition.

Surprisingly, transcriptomic studies revealed that SUMO2 inhibition showed a dramatic reversal of the transcriptional program of SS18::SSX fusions described in Jerby-Arnon L, et al. (Regev Lab).

Genetic knockdown of SUMO2 had similar effects

We were also excited about SUMO2 because of the availability of TAK-981, a potent, clinical-stage SUMO2 inhibitor which strongly suppressed growth of synovial sarcoma lines, increased apoptosis, and dramatically reduced colony-forming ability of synovial sarcoma cells at low nM

We then conducted targeted CRISPR screens in vitro and in vivo using synovial sarcoma cells, and SUMO2 emerged as one of the strongest dependencies in both - validating DepMap predictions. Since SUMO2 was also a SS18::SSX fusion target, was prioritized for further studies.

So, we began with the dependency maps dataset (DepMap) to ask: which genes are selectively essential for synovial sarcoma compared to other cancers?

In addition to expected genes (SS18, SSX, BRD9), one pathway jumped out: SUMOylation. And right at the core of this was SUMO2.

A few years ago, we got interested in Synovial Sarcoma - an aggressive, difficult-to-treat cancer. There is a single fusion protein - the SS18::SSX fusion - that drives this malignancy, but there isn’t much known about actionable vulnerabilities in this disease.

In this Episode, Pamela Itkin-Ansari and I explore a chemical reaction that links golden toast and roasted potatoes to chronic disease, and uncover the astonishing story of a breakthrough medical test born in a place no one saw coming. #diabetes #A1C #HbA1c #hemoglobin #glycation #MaillardReaction

Awesome Jordan...when you get a chance listen to this one ;-)

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