Volume 5 Issue 1, January 2024

Inhibiting glutamine metabolism has thus far been clinically challenging. Two studies in preclinical mouse models now report that, in contrast to the failure of glutaminase inhibitors, broad suppression of glutamine metabolism with glutamine analogs delivered to tumors results in reduced pancreatic cancer growth, with targetable resistance mechanisms.

In vitro-transcribed RNA is a promising emerging class of therapeutic, but the poor specificity of cargo RNAs so far has limited their application in cancer immunotherapy. A new study reports the delivery of a synthetic circular RNA with inline cis-acting translational elements — encoding an engineered, mitochondrion-specific oncolytic protein — that shows both therapeutic and prophylactic potential against adenocarcinoma.

Genomic features of de novo metastatic prostate cancer can clarify prognosis and direct therapy. Using multi-region profiling of synchronous primary and metastatic patient tissues, we reveal the complex evolutionary histories of this lethal disease and identify strategies to better capture the genomic features of dominant metastatic populations.

Chromosomal instability (CIN) (a hallmark of human cancer) is caused by persistent errors in chromosome segregation during mitosis. Pharmacological inhibition of the mitotic kinesin KIF18A selectively exploits a mitotic vulnerability for which cancer models with CIN are enriched, which leads to robust anti-cancer effects and durable tumor regression in mice.

Imetelstat is a first-in-class telomerase inhibitor with efficacy in a number of blood cancers. Intriguingly, telomere lengths do not predict patient responses to imetelstat. We now show that imetelstat causes cell death by a mechanism that involves two regulators of fatty acid metabolism (FADS2 and ACSL4), driving excessive lipid reactive oxygen species formation and ferroptosis.

Microbiome diversity has been associated with improved outcomes after allogeneic stem-cell transplantation in patients with hematological cancers. Multimodal analysis of intestinal microbiome and metabolome data helped identify immunomodulatory microbial metabolites that were predictive of survival, transplant-related mortality and cancer relapse. These metabolites were products of short-chain-fatty-acid-synthesis pathways, and their associated genes were expressed by both bacterial species and bacteriophages.

Schulze and colleagues discuss the latest advances in understanding the role of lipids in cancer progression and metastasis and reflect on opportunities to target lipid metabolism in tumors.

Feng et al. describe a gasdermin D circRNA-based approach to target mitochondrial inner membrane cardiolipin and demonstrate that this tool can trigger mitochondrial autophagy and affect tumor growth and immunity in EIF4G2⁺ /PTBP1⁺ pan-adenocarcinoma.

Bruedigam et al. explore the mechanism of action and therapeutic benefit of telomerase inhibitor imetelstat in a collection of PDXs from patients with AML and demonstrate that, in combination with chemotherapy, it re-sensitizes treatment-resistant AML cells.

Payton et al. develop small-molecule inhibitors of kinesin KIF18A able to selectively kill cancer cells with high chromosomal instability and demonstrate that the inhibitors are therapeutically beneficial in cancer patient-derived in vivo models.

Kimmelman and colleagues show that inhibition of glutamine (Gln) metabolism using a Gln antagonist decreases pancreatic cancer tumor growth, but is compensated by upregulation of extracellular signal-regulated kinase signaling, which can be co-targeted.

Recouvreux et al. show that inhibiting glutamine metabolism in pancreatic cancer blocks tumor growth and that therapy effectiveness is linked to asparagine metabolism, which can be synergistically targeted.

Warner et al. analyze tumor tissue and ctDNA from patients with de novo metastatic castrate-sensitive prostate cancer and find high intratumoral heterogeneity, suggesting that genomic profiling of multiple samples per patient is needed for accurate outcome prediction.

Simon and colleagues show that liver cancer cells undergo cell cycle arrest and senescence upon deprivation of methionine and identify GSK3 inhibitors as a senolytic to selectively deplete MAT2A inhibited senescent liver cancer cells.

Rich and colleagues identify that lymphatic endothelial-like cells in glioblastoma drive the growth of cancer stem cells via CCL21–CCR7 signaling, inducing KAT5 to acetylate HMGSC1, which enhances its protein stability and cholesterol synthesis.

Ginhoux and colleagues perform multi-omic characterization of hepatocellular carcinoma and identify an onco-fetal niche that includes fibroblasts, macrophages and endothelial cells and influences immunotherapy response and relapse.

Poeck and colleagues identify a microbiome signature in patients receiving allogenic stem cell transplantation, which is associated with protective immune-modulatory metabolites, improved survival and less transplant-related mortality.