KGCRF Poster Competition Winners 2022

GAVIN KUZIEL | G5
Chemical Biology
Seth Rakoff-Nahoum Lab

Functional diversification of plant small molecules by the gut microbiota drives intestinal homeostasis
Diet is instrumental in driving the composition and dynamics of the gut microbiome and in the development and prevention of human disease. Plants are broadly composed of carbohydrates, macromolecular building blocks, and phytochemicals, bioactive small molecules with roles in plant defense. Broadly metabolized by diverse members of the gut microbiota, carbohydrates have been established as a strong selective pressure on the evolution of glycan utilization systems across organisms. The products of carbohydrate catabolism by the microbiota, short chain fatty acids, have critically been shown to modulate local immune programs in the gut to maintain homeostasis and prevent the development of intestinal diseases such as colitis and colorectal cancer. In contrast to carbohydrate catabolism, there is a dearth of information as to phytochemical-microbe interactions, whether these abundant and chemically diverse molecules are metabolized by enteric organisms and how products of phytochemical catabolism affect host physiology. Here, we show that diverse gut symbionts leverage distinct genetic and enzymatic systems to bioactivate dietary phytochemicals to immunomodulatory metabolites. Our findings provide new insight into the role of the microbiome in the activation of abundant dietary phytochemicals and the effects of these metabolic transformations on the maintenance of intestinal homeostasis and protection from enteric disease.

PATRICK LOI | G5
Biological and Biomedical Sciences
Karen Cichowski Lab

Epigenetic based therapeutic strategies for KRAS mutant colorectal cancers
Polycomb Repressive Complex 2 (PRC2) is a highly conserved developmental regulator that maintains cellular identity by dynamically silencing key genes involved in differentiation. Alterations in PRC2 have been shown to play a driving role in many cancers. EZH2 is the major catalytic methyltransferase of PRC2 and activating mutations in EZH2 have been detected in a subset of cancers, such as melanoma and lymphomas. However, in other solid tumors, EZH2 is more commonly overexpressed rather than mutated. EZH2 expression levels progressively increase in advanced tumors and has been functionally shown to drive prostate cancer metastasis. Nevertheless, the role of EZH2 in other solid tumors, including colorectal cancers (CRC) has not been sufficiently explored. Specifically, EZH2 is overexpressed in 66% of CRC, and its expression appears to inversely correlate with patient survival and advanced disease. This makes EZH2 an attractive therapeutic target, although its role and targets in CRC is unknown. CRC is the is one of the leading causes of cancer deaths worldwide, and advanced metastatic disease is still incurable. Thus, there is a significant unmet clinical need for treatments for CRC, especially those with activating mutations in KRAS. Many drugs that target classic oncogenic kinases are ineffective therapies as single agents, such as MEK inhibitors for KRAS-mutant solid tumors. Therefore, one approach has been to develop more effective combination therapies that might enhance the sensitivity of cells to MEK inhibitors and/or prevent resistance. In a series of studies, our lab has been developing EZH2 inhibitor-based combination therapies with other targeted agents in different solid tumors. Interestingly, we have found that EZH2 inhibitors are frequently effective when combined with agents that target other key oncogenic pathways in each tumor type, such as in breast and prostate cancer. We hypothesize that co-targeting EZH2 along with key oncogenic pathways may lead to cooperative killing of CRC cells by clamping down on crucial oncogenic signals at both the kinase level and the transcriptional level. My preliminary data demonstrates that a combination of EZH2 and MEK inhibitors cooperate to kill KRAS mutant CRC in a variety of in vitro, in vivo xenograft, and organoid models, which reveals a novel approach for treating this advanced disease. Using a combinatorial RNA-seq and ChIP-seq approach, EZH2/MEK inhibitors induce a shift in the differentiation state of the cell by modulating key transcription factors and regulators involved in colonic development. Together, these findings will establish a new paradigm for epigenetic-based combination therapies for advanced diseases that are currently untreatable.

FRANCESCA NARDI | G3
Biological and Biomedical Sciences
Karen Cichowski Lab

Co-targeting translation initiation as a therapeutic strategy for KRAS-mutant lung cancers
 Despite the success of KRASG12C inhibitors in non-small cell lung cancer (NSCLC), improved treatments are still needed. Here we show that agents targeting eIF4A, a component of the eIF4F translation initiation complex, potently synergize with KRASG12C inhibitors. When combined, these drugs kill NSCLCs that are only modestly sensitive to single agent KRASG12C inhibitors and dramatically enhance tumor regression in vivo. We further demonstrate that the synergy is mediated by the suppression of multiple BCL-2 family proteins. Accordingly, KRASG12C/eIF4A inhibitors are broadly efficacious in NSCLCs, irrespective of their relative dependency on MCL1, BCL-xL, or BCL-2, which is known to be heterogeneous. Importantly, eIF4A and MEK inhibitors similarly cooperate in tumors harboring other KRAS mutations. Finally, we show that MYC overexpression confers sensitivity to these combinations, by creating a dependency on eIF4A for BCL-2 family protein expression. Together, these studies identify two promising therapeutic strategies for KRAS-mutant NSCLCs, demonstrate that BCL-2 family proteins are critical mediators of the therapeutic response, and uncover a predictive biomarker of sensitivity. 
 

LISA SITU | G4
Biological and Biomedical Sciences
Karen Cichowski Lab

Combinatorial strategies to target NRAS-mutant melanoma
Although 15–30% of melanomas harbor activating mutations in NRAS, there are currently no approved targeted therapies for this melanoma subtype. When NRAS-mutant melanomas are treated with MEK inhibitors that decrease signaling downstream of RAS, progression-free survival increases by only several months, highlighting the clinical need to uncover additional therapeutic targets that may improve the efficacy of single agent MEK inhibition. To address this, we performed a genome-scale CRISPR negative selection screen in an NRAS-mutant melanoma cell line to identify genes which, when suppressed, confer sensitization to MEK inhibition. This approach has uncovered a novel combinatorial strategy to elicit melanoma cell death, via inhibition of MEK in combination with suppression of USP7, a deubiquitinating enzyme. Combined inhibition led to cell death in vitro and tumor regression in vivo, with evidence supporting that the mechanism of cooperative activity may involve disruption of USP7-mediated chromatin remodeling. This work not only suggests that this combination may have the therapeutic potential to cause regression in human tumors, but may also reveal the functional importance of key adaptation pathways in melanoma.