In Chen's latest grantapplication, only just published, he seems to have identified a new target intreating AML, IGF2BP2. - https://app.dimensions.ai/details/grant/grant.10021118
"Title: The roleand therapeutic potential of IGF2BP2 in MLL-rearranged leukemia. Background:N6-methyladenosine (m6A) modification is the most abundant internalmodification in eukaryotic messenger RNAs (mRNAs) and plays roles in manynormal bioprocesses. Evidence is emerging that the aberration in m6Amodification and the associated machinery also plays important roles in varioustypes of cancers...
...we have developeda potent inhibitor (namely CWI1-2) that targets IGF2BP2 directly and exhibitshigh anti-leukemia efficacy as shown in our preliminary studies. Hypothesis:IGF2BP2 plays an essential role in MLLr AML pathogenesis and LSC/LICself-renewal, and that pharmacological inhibition of IGF2BP2 can lead toeffective treatment of MLLr AML."
Further background onIGFBP2 - https://cancerci.biomedcentral.com/articles/10.1186/s12935-021-01799-x
"The humaninsulin-like growth factor 2 (IGF2) mRNA binding proteins 2 (IGF2BP2/IMP2) isan RNA-binding protein that regulates multiple biological processes.Previously, IGF2BP2 was thought to be a type 2 diabetes (T2D)-associated gene.Indeed IGF2BP2 modulates cellular metabolism in human metabolic diseases suchas diabetes, obesity and fatty liver through post-transcriptional regulation ofnumerous genes in multiple cell types. Emerging evidence shows that IGF2BP2 isan N6-methyladenosine (m6A) reader that participates in the development andprogression of cancers by communicating with different RNAs such as microRNAs(miRNAs), messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs).Additionally, IGF2BP2 is an independent prognostic factor for multiple cancertypes. In this review, we summarize the current knowledge on IGF2BP2 withregard to diverse human metabolic diseases and its potential for cancerprognosis."
FTO and IGFBP2?- https://pubmed.ncbi.nlm.nih.gov/30371117/
"FTO andIGF2BP2 are the genetic loci associated with an increased risk of diabetes type2, as well as being involved in lipid and carbohydrate metabolism... In thisstudy, we examined the association between FTO and IGF2BP2 gene polymorphismsand gestational diabetes mellitus."
Discussion:
Keen to hear somethoughts. Interesting that FTO and IGF2BP2 increase the risk of diabetes andpotentially impact insulin secretion (as identified earlier this year in Lille). Notingalso that there has been no public update to the future work Chen isundertaking on FTO inhibition since this grant was published - https://grantome.com/grant/NIH/R01-CA243386-02
First question thatcomes to mind; does FTO and IGF2BP2 illicit the same response in the body or is inhibiting IGF2BP2 more effacious than inhibiting FTO for thetreatment of cancers?
Is IGF2BP2 and CWI1-2 a consolation prize, considering Chen’spatent on Zantrene (the most potent inhibitor of FTO) was ultimately rejected?
Could IGF2BP2 be a biomarker identified by Race/Sheba and shared with Chen and COH for further investigation?
Finally; it’s 4am, why am I reading this?
(20min delay)