Research Projects

Small Molecule Inhibitors

SBI-756


small molecule we have been developing as inhibitor of the eiF4F complex. SBI-756 binds with eiF4G2 and interfere with eiF4F complex assembly, resulting in the sensitization of tumor cells to targeted therapy and attenuating their resistance to therapy. Ongoing studies set to further characterize the activities of this small molecule inhibitor in effort to improve its in vivo efficacy.




Siah inhibitors


A number of screening campaigns were carried out in our lab to identify small molecule inhibitors, as well as short peptides, to inhibit Siah1/2 ubiquitin ligases. Ongoing studies address Siah1/2 dimerization properties.




SLC1A5 inhibitors


The finding the glutamine levels play an important role in the susceptibility of breast cancer tumors to paclitaxel treatment, allowing to stratify patients to combination therapy based on the level of glutamine carrier proteins, led us to perform a screen to identify novel inhibitors of glutamine uptake.





Ubiquitin Ligases

RNF5


a ubiquitin ligase that is engaged in ERAD, but also define tumor recognition by the immune system. Our recent study established that RNF5 KO mice are more resistant to development of melanoma due to enhanced anti-tumor immunity. Enhanced anti-tumor immunity is mediated by altered gut microbiota composition in RNF5 KO mice. A select subset of 11 bacterial strains is sufficient to turn on anti-tumor immunity and inhibit melanoma growth, when administered to germ free mice, highlighting the role of RNF5 in gut microbiota organization. Underlying these changes is altered UPR signaling, which is largely downregulated in intestinal epithelial cells of RNF5 KO mice, but also in patients that respond to immune checkpoint therapy. Conditional KO RNF5 mice is currently being used to define the relative contribution of select cell types to each of the phenotypes identified in the RNF5 KO mice.

Notably, coupled with the resistance of RNF5 KO mice to develop melanoma, is their sensitivity to develop severe intestinal inflammation when exposed to an inflammatory agent (DSS). Exploring RNF5 contribution to intestinal inflammation we identified S100A8 as RNF5 substrate that is responsible for the acute inflammatory phenotype. Further, we have demonstrated that neutralizing antibodies to S100A8 would abolish IBD like phenotypes, even if administered after DSS (see paper here).




Siah2


A ubiquitin ligase that is implicated in UPR, hypoxia, cell migration and mitochondrial dynamics. We recently identified the role of Siah2 in anti-tumor immunity, given that Siah2 KO mice effectively limit the growth of melanoma. Mechanistically, Siah2 affects the recruitment and proliferation of T regulatory cells, which results in strong anti-tumor immunity. Notably, Siah2 KO mice resemble mice that were subjected to CDK4/6 inhibitors, which are thus able to mount an effective PD1 therapy against tumors that would otherwise be non-responsive to this ICT.




RNF125


The ubiquitin ligase RNF125 has been implicated in the resistance of melanoma to BRAF inhibitor therapy. We study it in pancreatic cancer, where it appears to play an important role in development and therapy response.





Tumor Types

Melanoma


Our studies currently address critical unmet needs in melanoma, from the control of anti-tumor immunity, to the regulation of melanoma metastasis and resistance to therapy. Our studies rely on genetic models for select genes we have identified to play an important role in melanoma, and therefore devote significant effort to understand how they contribute to melanoma development, progression and resistance phenotypes, and further, whether we can identify new means to interfere with their contribution.




AML


The role of RNF5 in AML is being explored given the elevated expression of RNF5 in this tumor type. RNF5 is required for AML development and maintenance and in addition to its effect on protein processing it was found to control gene transcription, which is HDAC dependent.




Pancreatic Cancer


The ubiquitin ligase RNF125 has been implicated in the resistance of melanoma to BRAF inhibitor therapy. We study it in pancreatic cancer, where it appears to play an important role in development and therapy response.





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