Ubiquitin ligases in cancer
The importance of RNF5 in defining key biological processes, through its role in ERAD, has beenexplored using conditional KO mouse models and respective cultures. Ongoing studies explore howRNF5 controls the UPR (Nature Comm 2021) and how RNF5 can affect the gut microbiome composition (Nature comm, 2019), which in turn regulates anti-tumor immunity and susceptibility to intestinalinflammation (Cell Reports 2018).
Having established in the past few years the importance of Siah2 in the control of prostate tumor progression to castration resistance and metastatic (Cancer Cell, 2011, 2013), and the importance of Siah2 in the regulation of T-regulatory cell proliferation and infiltration to tumors (establishing its role in the TME; Nature Comm, 2021) we more recently demonstrated its importance in the control of macrophage differentiation with implication to lung cancer as well as melanoma, using conditional KO mice (BioRxiv). Developing inhibitors to Siah2 has been challenging, and while progress was made with select peptides (Chem & Biol), ongoing studies aim at identifying a novel class of small molecule inhibitors.
Often referred to as the relative of RNF5 (>75% homology), this ubiquitin ligase is similarly anchored in the ER membrane and implicated in ERAD. Deregulation of RNF185 was noted in advanced prostate tumors, which led us to study the importance of RNF185 in the etiology of prostate tumor progression and metastasis.
The possible importance of RNF125 in cancer, with emphasis on pancreatic cancer, is being explored.
Epigenetic regulators impacting tumors and their TME (tumor immunity)
The role of Protein Methyl Transferase 5 in controlling antigen presentation and innate immunity, which together define tumor immune evasion, has been demonstrated in our recent studies (Science Translational Medicine, 2021). Ongoing studies address PRMT5-dependent changes that impact neoantigen presentation with implications for tumor immune recognition.
Asparagine synthase modulators have been used for treating ALL, while failing treatment of solid tumors. In recent studies, we demonstrated the importance of ATF4 and MAPK inhibition in pancreatic and melanoma tumors as a means to achieve effective tumor inhibition in culture and preclinical models (Nature Cell biol. 2019). While paving the road to ongoing clinical trial (NCT XXX), we currently assess the long-term effectiveness of this combination treatment per tumor resistance and propensity to metastasize.
Through a surprising set of discoveries, we mapped the importance of glutaryl-CoA dehydrogenase (GCDH) for melanoma survival. Although a component of the lysine catabolism pathway, melanoma addiction to GCDH relates to its post-translational modification of proteins, namely, glutarylation. GCDH glutarylation of NRF2 was found to confer NRF2 tumor suppressor role, which led to programmed cell death of melanoma via its activation of ATF4, ATF3, and CHOP (Nature Cell Biology, 2022). Dependence of GCDH was confined to melanoma, as it was not observed in liver, breast, or prostate cancer (cells as in patient specimens). Ongoing studies further elaborate on mechanisms underlying GCDH control and effectiveness, as on the development of novel small molecule inhibitors to GCDH, which are expected to offer novel therapeutic modality.
Search for an orphan nuclear receptor that defines tumor response to the immune system led to identifying NR2F6. Through controlling tumor intrinsic pathways, NR2F6 was found to impact antigen presentation and tumor recruitment of immune cells, limiting its growth (BioRxiv). Ongoing studies map the mechanisms for controlling NR2F6 and for small molecule inhibitors that are expected to offer a new therapeutic approach for melanoma immunotherapy.
Targeting components of the translation initiation complex have been attractive for cancer as for neurological disorders, where a surge in eIF4f complex activity confers oncogenic and neuropathological pathologies. Extended studies in our lab have focused on targeting eIF4G1 as one of the eIF4F complex components. This led us to develop distinct means to limit eIF4F activities using small molecule inhibitors (Cancer Research 2015). CRISPR technology advanced our approach and enabled our focus on select domains of eIF4G1 and respective small molecules that target it, offering a new line of small molecules that are currently explored in cancer and beyond.