Thread by @LeslieCrewsPhD

Our first paper authors.elsevier.com/a/1cRqD6tu0Cbo… is now out @CellStemCell! With @ionispharma & the Jamieson Lab @UCSanDiegoDRM, we found that selective #antisense oligonucleotides inhibiting #IRF4 reduce disease burden & #multiplemyeloma #regeneration in #cancer models. @CellPressNews 1/

IRF4 (interferon regulatory factor 4) is a key plasma cell transcription factor that is known to play a critical role in #myeloma progression. It's been shown to activate networks of #cellcycle and cancer regulators, including the notorious #cancer and #stemcell gene, #MYC. 2/

In this new work, the talented @PhoebeMondala & @AshniVora first dug deeper into the IRF4 networks activated in high-risk forms of #myeloma, including #plasmacellleukemia. IRF4 target genes (SLAMF7, BCMA) were widely induced, especially among genes regulating the #cellcycle. 3/

Using elegant cell-based myeloma models developed by @lazzaelisa and @AshniVora, we found that myeloma #progenitors were enriched in bone marrow-like niches and with IRF4 overexpression. Human stromal cells also protected against cell cycle arrest induced by #lenalidomide. 4/

With such abundant & relatively restricted expression of IRF4 in myeloma cells, many groups have noted its potential as a therapeutic target. BUT, as a #transcription factor, these types of genes are often considered #undruggable. This is where #antisense tech comes in. 5/

We worked with the @ionispharma #Oncology team to test their IRF4-targeted #antisense oligonucleotides, or ASOs, in myeloma models. IRF4 ASOs are small pieces of engineered DNA that bind to & block cellular #RNA (which is produced from the cell's DNA encoding the IRF4 gene). 6/

Using pre-clinical models from diverse mutational backgrounds, our teams found that in myeloma cells grown in a dish, IRF4 ASOs consistently reduced IRF4 RNA & protein expression, blocked myeloma cell survival, & also interfered with downstream target gene expression (#MYC). 7/

In addition, in mice bearing human #myeloma, IRF4 ASO treatment reduced myeloma burden, improved overall animal survival, & cleared myeloma #progenitor cells from the #bonemarrow. We had a hard time finding any IRF4-positive myeloma cells left! 8/

Intriguingly, although normal #Bcells also typically express some - albeit low levels of - IRF4, the abundance of healthy B cell progeny was unaffected by IRF4 ASO treatment in normal human #blood #stemcell-derived in vivo models. 9/

We further explored some of the mechanisms underlying these promising therapeutic effects. Similar to what we observed with #lenalidomide, IRF4 ASOs induced #cellcycle arrest in a dose-dependent manner. They also sensitized myeloma cells to lenalidomide and bortezomib. 10/

Some takeaways: Selective IRF4 antisense inhibition 1) reduces myeloma #regeneration in #preclinical assays, 2) sensitizes myeloma cells to clinical drugs, & 3) spares normal #immune cells. IRF4 target genes like MYC & CXCR4 could provide functional #biomarkers of response. 11/

Perhaps most importantly for the #myeloma community, this industry/academic collaborative research helped identify a lead agent, #ION251, now in clinical trials @UCSDHealth Moores Cancer Center & nationwide. @Ccostello7 12/ clinicaltrials.gov/ct2/show/NCT04…

Congrats to @PhoebeMondala and @AshniVora who spearheaded this work in my lab & the Jamieson Lab @UCSanDiegoDRM. Btw, both of these talented #WomenInSTEM are currently in the grad school market, so if you see their applications at your institution, be sure to snatch them up! 13/

This work was a phenomenal team effort, other key contributions from Luisa Ladel @UCSanDiegoDRM, clinical insights from long-time collaborator @Ccostello7, & of course the industry team led by Rob MacLeod @ionispharma. Thx also @MCC_IR & @lalalaleisa 4 collab. opportunities! 14/

We're also grateful 4 support from @theNCI @NIDDKgov @LLSResearch @CIRMnews @ucsdactri @UCSDHealth Senate, Moores Cancer Center, & @IMFmyeloma for providing vital grant & pilot funding that made this translational research possible. @UCSanDiegoWiHS @UCSanDiego @UCSDMedSchool /END