An Inhibitor of KrasG12D Shows Efficacy in Pancreatic Cancer Models
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with few therapeutic options. The majority of patients with PDAC harbor a mutation in the KRAS oncogene. Kemp and colleagues utilized a small-molecule inhibitor of KrasG12D, MRTX1133, and identified deep tumor regressions in multiple immune-competent PDAC models. Additionally, inhibition of KrasG12D remodeled the tumor microenvironment from an immune-suppressive to an immune-reactive state with increased infiltration of M1-like macrophages and cytotoxic T cells. These results provide preclinical evidence for the efficacy of KrasG12D inhibition in PDAC and suggest MRTX1133 has the potential for translation to the clinic.
The Mechanism of MMRd Impacts Response to PD-1 Checkpoint Blockade
While tumors with mismatch-repair deficiency (MMRd) all have high mutation burdens, only a fraction of patients respond to PD-1 checkpoint blockade. In a cohort of patients receiving pembrolizumab for MMRd endometrial cancer, Chow, Michaels, and colleagues found that the underlying molecular mechanism of MMRd was associated with treatment response. Patients with mutational MMRd tumors had a 100% response rate (6 of 6) compared to 44% with epigenetic MMRd tumors (8 of 18). Differential responses to pembrolizumab were correlated with distinct features of the circulating immune repertoire. The molecular mechanism of MMRd may represent a useful biomarker for cancer immunotherapy.
Ribosomal RNA Methylation Drives Leukemic Stem Cell Self-renewal
Posttranscriptional RNA modifications are emerging as pathogenetic mechanisms in cancer. Zhou, Aroua, and colleagues showed that human leukemia stem cells express high levels of the rRNA 2'-O-methyltransferase fibrillarin (FBL). FBL overexpression dynamically increases ribosomal RNA (rRNA) methylation in acute myeloid leukemia cells at various novel target sites. Increased rRNA methylation at specific sites reprograms protein translation and increases leukemia stem cell number and function in patient-derived xenografts. Together, these results uncovered a novel molecular mechanism promoting leukemic stem cell transformation and self-renewal.
MinimuMM-seq Genomically Profiles Circulating Tumor Cells in Myeloma
In this study, Dutta, Alberge, and colleagues demonstrate a novel liquid biopsy approach, MinimuMM-seq, that enables enumeration and whole-genome sequencing of circulating tumor cells (CTC) to replace standard molecular cytogenetics performed on bone marrow of patients with multiple myeloma (MM). In precursor and symptomatic MM, CTCs harbored the same hallmark DNA mutations as clinical bone marrow biopsy samples (including translocations, hyperdiploidy, and copy-number abnormalities). These proof-of-concept results demonstrate that genomic biomarker profiling of CTCs could be used clinically for screening, risk classification, and longitudinal monitoring of patients with MM in a minimally invasive manner.
Human Bone Marrow Organoids Support Disease Modeling and Target Validation
A major bottleneck in the development of novel therapies for hematologic cancers is the lack of in vitro systems that adequately model human bone marrow. In this study, Khan and colleagues describe a stepwise differentiation protocol in which human induced pluripotent stem cells generate key stromal, vascular, and hematopoietic bone marrow cell lineages. These 3D cultures self-organize, generating bone marrow organoids with substantial architectural and transcriptional homology to native hematopoietic tissues. The utility of these organoids was also demonstrated for modeling bone marrow fibrosis, screening inhibitors, and supporting survival of lymphoid and myeloid cancer cells from patients, including cells that are typically poorly viable ex vivo.
Oncoloop Is a Precision Platform That Predicts Tumor Drug Sensitivity
OncoLoop prioritizes cancer treatments by predicting drug sensitivity in human tumors and their cognate models. Vasciaveo, Arriaga, Nunes de Almeida, and colleagues applied OncoLoop to prostate cancer (PCa) using an extensive series of mouse tumors as cognate models. Interrogation of human PCa cohorts by Master Regulator (MR) conservation analysis showed that most advanced patients were represented by at least one cognate tumor. Drugs predicted to invert MR activity in patients and cognate tumors were validated in PCa models of tumors and metastasis and enhanced the efficacy of clinically relevant drugs. These results suggest the applicability of OncoLoop to many cancers for which patient data and cognate models are available.
Therapy-Induced Senescence in Cancer Promotes Antitumor T-cell Immunity
Cellular senescence is a nonapoptotic response to severe damage that affects many aspects of cellular biology. Marin and colleagues show that the induction of senescence expands the repertoire of presented antigens, promotes antigen presentation, and renders cells very efficient in activating antigen-presenting cells and antigen-specific CD8+ T cells. Accordingly, immunization of mice with senescent cancer cells elicits strong antitumor protection that is superior to cancer cells undergoing immunogenic cell death. Finally, upon therapy-induced senescence, human primary cancer cells also exhibit augmented activation of autologous antigen-specific tumor-infiltrating CD8 lymphocytes. Together, this study indicates that senescent cancer cells can be exploited to improve CD8-dependent antitumor immunity.
Senescence Amplifies IFNγ Sensing to Ignite Antitumor Immunity
Using an immunocompetent mouse model of liver cancer in which tumor cell senescence reactivates anti-tumor immunity, Chen and colleagues show that, in addition to producing a senescence-associated secretory phenotype (SASP) that alters the tissue environment, senescence drives the remodeling of a cell's tissue sensing capacity by altering their surfaceome and intracellular signaling programs in a manner that can facilitate immune surveillance. One outcome of this altered sensing capacity is a hypersensitivity to extracellular IFNγ, leading to robust upregulation of the antigen presentation machinery and improved senescent cell targeting by cytotoxic T cells. This mechanism provides a framework and rationale for harnessing senescence to improve cancer immunotherapies.
Targeting UGCG Overcomes Resistance to Lysosomal Autophagy Inhibition
Resistance to lysosomal autophagy inhibition (LAI) is common. Jain and colleagues showed that LAI treatment upregulates the glycosphingolipid synthesis enzyme UGCG, which contributes to LAI resistance as upregulated UGCG resists lysosomal membrane permeabilization (LMP) leading to cancer cell survival. These LAI-induced changes were correlated with increased GM1+ membrane microdomain (GMM) formation on plasma membrane and lysosomes. Use of the FDA-approved UGCG inhibitor eliglustat combined with LAI demonstrates durable antitumor activity in multiple animal models of melanoma, including a therapy-resistant patient-derived xenograft. UGCG inhibition abrogates GMM formation and augments LAI-induced LMP, resulting in cancer cell death and supporting future clinical trials combining eliglustat with LAI.
Metastasis Initiation Is Tied to NG2+ Cell-Mediated Bone Remodeling
Bone undergoes constant turnover during physiologic and pathologic processes, but how the dynamics of the bone microenvironment impacts metastatic colonization of disseminated tumor cells remains undetermined. Zhang and colleagues observed a connection between bone remodeling and bone metastasis initiation in mouse models, and a specific subset of bone mesenchymal stromal cells, which express NG2 protein and directly contribute to osteogenesis, was identified that links the process of bone repair and expansion of metastatic tumor cells. Mechanistically, cell–cell interactions between N-cadherin–expressing NG2+ cells and epithelial tumor cells, which was further strengthened upon osteogenic differentiation, promoted cancer cell proliferation and migration.
Targeting Lipids Inhibits the Growth of Cancers with IDH1 Mutations
The genes encoding isocitrate dehydrogenase 1 and 2 (IDH1/2) are mutated in multiple cancers, resulting in high levels of (R)-2-hydroxyglutarate and epigenetically driven oncogenicity. However, their subcellular localization and frequency differ across cancers, suggesting there may be additional underlying metabolic differences. In this study, Thomas and colleagues pinpoint clinically actionable metabolic vulnerabilities by analyzing the lipid metabolome in patient samples and reveal the lipid synthesis enzyme ACC1 as a synthetic lethal target in IDH1-, but not IDH2-, mutant cancers. The findings have implications for precision dietetics and define novel targets for tumors resistant to IDH inhibitors.