Targeting SUMO1 degradation for advanced colon cancer therapy

Project Summary/Abstract
The advanced colon cancer with organ invasion and liver metastasis are the most common cause of colon cancer
death in part due to the resistance to current standard therapies. The ultimate goal of this project is to develop
small-molecule degraders of small ubiquitin-related modifier 1 (SUMO1) as the first-in-class anticancer drugs for
treatment of advanced colon cancers. To achieve this goal, we have already identified SUMO1 as a cancer drug
target, developed cancer cell-based drug screen, identified the hit compound, and optimized the more potent
lead compounds through chemical modification of the hit compound. Investigating the drug-targeted pathway,
we have identified the compound binding cytoplasmic activation/proliferation-associated protein-1 (CAPRIN1)
and revealed the CAPRIN1-CUL1 ubiquitin ligase complex. Upon the binding of CAPRIN1, SUMO1 degraders
induce the recruitment of SUMO1 to CAPRIN1-CUL1 ligase for SUMO1 ubiquitination and degradation in cancer
cells. Using genetically characterized human colon cancer cell lines, 3-dimensional (3D) organoids and patient’s
derived xenografts (PDXs), we have provided the proof-of-principle that targeting SUMO1 by its degraders is a
safe and effective therapy for colon cancer. The objective of this project is to investigate the mechanism and
therapeutic efficacy of SUMO1 degraders in treatment of advanced colon cancer, alone and in combination of
the standard chemotherapy. To achieve this, we will first evaluate the therapeutic efficacy of the lead compounds
in treatment of advanced colon cancer in Aim 1. To this end, we will test the in vivo toxicity, target engagement
biomarker and therapeutic efficacy of the lead compounds using genetically characterized advanced colon
cancer PDX models. Next, we will determine how SUMO1 degraders drive metabolic reprograming of glycolysis
and glutaminolysis in advanced colon cancer for the anticancer activity (Aim 2). We will reveal the mechanism
on how the degraders regulate the sumoylation of the transcription of the metabolic StAR-related lipid transfer
domain protein-7 (STARD7) in advanced colon cancer. Finally, we will determine the mechanism and therapeutic
efficacy of the combination of the lead compounds and standard chemotherapy in treatment of advanced colon
cancer in Aim 3. In particular, we will determine whether the metabolic enzyme G6PD (glucose-6-phosphate
dehydrogenase) is conjugated by SUMO1 and thus SUMO1 degraders eliminates its conjugation and functions
and sensitize colon cancers to the standard chemotherapy. Next, we will evaluate the therapeutic efficacy of the
combination of the degraders and chemotherapy in treatment of a large panel of genetically characterized 3D
organoid and PDX models. Upon completion, we expect that this preclinical project will provide solid scientific
foundation for development of SUMO1 degraders as the first-in-class anticancer drugs for treatment of advanced
colon cancer, a deadly human disease.

Grant Number: 5R01CA266699-04
NIH Institute/Center: NIH
Principal Investigator: Anita Bellail