Search

The dependency of cancer cells on glucose can be targeted with high-fat low-carbohydrate ketogenic diet (KD). However, hepatic ketogenesis is suppressed in IL-6 producing cancers, which prevents the utilization of this nutrient source as energy for the organism. In two IL-6 associated murine models of cancer cachexia we describe delayed tumor growth but accelerated onset of cancer cachexia and shortened survival when mice are fed KD. Mechanistically, we find this uncoupling is a consequence of the biochemical interaction of two simultaneously occurring NADPH-dependent pathways. Within the tumor, increased production of lipid peroxidation products (LPPs) and, consequently, saturation of the glutathione (GSH) system leads to ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impairs the biosynthesis of corticosterone, the main regulator of metabolic stress, in the adrenal glands. Administration of dexamethasone, a potent glucocorticoid, improves food intake, normalizes glucose homeostasis and utilization of nutritional substrates, delays onset of cancer cachexia and extends survival of tumor-bearing mice fed KD, while preserving reduced tumor growth. Our study highlights that the outcome of systemic interventions cannot necessarily be extrapolated from the effect on the tumor alone, but that they have to be investigated for anti-cancer and host effects. These findings may be relevant to clinical research efforts that investigate nutritional interventions such as KD in patients with cancer.

Background Trigger finger and carpal tunnel syndrome are the two most common non-traumatic connective tissue disorders of the hand. Both of these conditions frequently co-occur, often in patients with rheumatoid arthritis. However, this phenotypic association is poorly understood. Hypothesising that the co-occurrence of trigger finger and carpal tunnel syndrome might be explained by shared germline predisposition, we aimed to identify a specific genetic locus associated with both diseases. Methods In this genome-wide association study (GWAS), we identified 2908 patients with trigger finger and 436 579 controls from the UK Biobank prospective cohort. We conducted a case-control GWAS for trigger finger, followed by co-localisation analyses with carpal tunnel syndrome summary statistics. To identify putative causal variants and establish their biological relevance, we did fine-mapping analyses and expression quantitative trait loci (eQTL) analyses, using fibroblasts from healthy donors (n=79) and tenosynovium samples from patients with carpal tunnel syndrome (n=77). We conducted a Cox regression for time to trigger finger and carpal tunnel syndrome diagnosis against plasma IGF-1 concentrations in the UK Biobank cohort. Findings Phenome-wide analyses confirmed a marked association between carpal tunnel syndrome and trigger finger in the participants from UK Biobank (odds ratio [OR] 11·97, 95% CI 11·1–13·0; p−300). GWAS for trigger finger identified five independent loci, including one locus, DIRC3, that was co-localised with carpal tunnel syndrome and could be fine-mapped to rs62175241 (0·76, 0·68–0·84; p=5·03 × 10−13). eQTL analyses found a fibroblast-specific association between the protective T allele of rs62175241 and increased DIRC3 and IGFBP5 expression. Increased plasma IGF-1 concentrations were associated with both carpal tunnel syndrome and trigger finger in participants from UK Biobank (hazard ratio >1·04, p Interpretation In this GWAS, the DIRC3 locus on chromosome 2 was significantly associated with both carpal tunnel syndrome and trigger finger, possibly explaining their co-occurrence. The disease-protective allele of rs62175241 was associated with increased expression of long non-coding RNA DIRC3 and its transcriptional target, IGBP5, an antagonist of IGF-1 signalling. These findings suggest a model in which IGF-1 is a driver of both carpal tunnel syndrome and trigger finger, and in which the DIRC3-IGFBP5 axis directly antagonises fibroblastic IGF-1 signalling.

T-cell immunotherapy and molecular targeted therapies have become standard-of-care treatments for renal cell carcinoma (RCC). There is a need to develop robust biomarkers that predict patient outcomes to targeted therapies to personalise treatment. In recent years, quantitative analysis of imaging features, termed radiomics, has been used to extract tumour features. This narrative mini review summarises the evidence for radiomics prediction of immunotherapy and molecular targeted therapy outcomes in RCC. Radiomics may predict survival, treatment response, and disease progression in RCC treated with tyrosine kinase inhibitors (eg, sunitinib) and immune checkpoint inhibitors (eg, nivolumab). Further validation is necessary in large-scale studies. PATIENT SUMMARY: We summarise evidence on the ability of features extracted from CT (computed tomography) scans to predict patient outcomes from new treatments for kidney cancer. Although these features can predict treatment outcomes for patients, including survival, treatment response, and cancer progression, further research is necessary before this technology can be applied clinically.

The dependency of cancer cells on glucose can be targeted with high-fat low-carbohydrate ketogenic diet (KD). However, hepatic ketogenesis is suppressed in IL-6 producing cancers, which prevents the utilization of this nutrient source as energy for the organism. In two IL-6 associated murine models of cancer cachexia we describe delayed tumor growth but accelerated onset of cancer cachexia and shortened survival when mice are fed KD. Mechanistically, we find this uncoupling is a consequence of the biochemical interaction of two simultaneously occurring NADPH-dependent pathways. Within the tumor, increased production of lipid peroxidation products (LPPs) and, consequently, saturation of the glutathione (GSH) system leads to ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impairs the biosynthesis of corticosterone, the main regulator of metabolic stress, in the adrenal glands. Administration of dexamethasone, a potent glucocorticoid, improves food intake, normalizes glucose homeostasis and utilization of nutritional substrates, delays onset of cancer cachexia and extends survival of tumor-bearing mice fed KD, while preserving reduced tumor growth. Our study highlights that the outcome of systemic interventions cannot necessarily be extrapolated from the effect on the tumor alone, but that they have to be investigated for anti-cancer and host effects. These findings may be relevant to clinical research efforts that investigate nutritional interventions such as KD in patients with cancer. Citation Format: Miriam Ferrer, Nicholas Mourikis, Emma E. Davidson, Sam O. Kleeman, Marta Zaccaria, Jill Habel, Rachel Rubino, Thomas R. Flint, Claire M. Connell, Michael J. Lukey, Eileen P. White, Anthony P. Coll, Ashok R. Venkitaraman, Tobias Janowitz. Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1162.

Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 and CTLA4 are effective treatments in multiple cancer types, but durable responses are seen only in a minority of patients. Resistance to ICI is likely to reflect a combination of tumor-intrinsic, such as tumor mutational burden, and tumor-extrinsic factors, such as systemic immune suppression and host genetics. With the advent of large-scale germline genotyping studies, there is emerging evidence that host-specific genetic factors can substantially modify both disease risk and responsiveness to therapy. There has been limited characterization to date of the interaction between host genetics and response to ICI. Here, we perform harmonized mutation calling in available normal exome sequencing from 668 metastatic cancer patients treated with ICI (derived from n=7 studies, spanning n=3 cancer types and PD-1/PD-L1/CTLA4-directed therapy) and performed exome-wide association studies in European ancestry patients. For each cancer type (melanoma, renal cell carcinoma, urothelial carcinoma), we conducted exome-wide Cox regression (with PC1-4 and sex as covariates) to identify coding single-nucleotide polymorphisms (SNPs) associated with overall survival (OS). On fixed-effect meta-analysis, we identified a single coding variant (rs140221307, C allele, MAF 0.5% in European populations) that met genome-wide significance (p=1.11 × 10−15, HR=4.86, 95% CI 3.30-7.15). This SNP causes a substitution of Trp to Arg at amino acid 320 at the interface between the transmembrane and extracellular domains of interleukin 17 receptor A (IL17RA). While the secretion mechanism is uncharacterized, soluble IL17RA can be readily detected in plasma and the survival-reducing variant is associated with substantially elevated plasma IL17RA (p=1.90 × 10−9, beta=1.01, Sun et al. 2018) as well as reduced monocyte counts in UK Biobank (p=2.20 × 10−308, beta=-0.60). We have established a prime editing strategy to induce this variant in cultured human monocytes to investigate its biochemical and functional consequences, and are performing validation studies in independent patient cohorts. Soluble IL17RA would be expected to function as a decoy receptor to antagonize IL17/IL17RA signaling, and so these data suggest that activation of IL-17 receptor signaling might improve responsiveness to ICI therapy. Citation Format: Sam O. Kleeman, Michael Chan, Matthew Chvasta, Tobias Janowitz. Exome-wide association study identifies coding variant in IL17RA associated with survival in cancer patients treated with immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5226.

ObjectiveWe assessed whether famotidine improved inflammation and symptomatic recovery in outpatients with mild to moderate COVID-19.DesignRandomised, double-blind, placebo-controlled, fully remote, phase 2 clinical trial (NCT04724720) enrolling symptomatic unvaccinated adult outpatients with confirmed COVID-19 between January 2021 and April 2021 from two US centres. Patients self-administered 80 mg famotidine (n=28) or placebo (n=27) orally three times a day for 14 consecutive days. Endpoints were time to (primary) or rate of (secondary) symptom resolution, and resolution of inflammation (exploratory).ResultsOf 55 patients in the intention-to-treat group (median age 35 years (IQR: 20); 35 women (64%); 18 African American (33%); 14 Hispanic (26%)), 52 (95%) completed the trial, submitting 1358 electronic symptom surveys. Time to symptom resolution was not statistically improved (p=0.4). Rate of symptom resolution was improved for patients taking famotidine (pConclusionsFamotidine was safe and well tolerated in outpatients with mild to moderate COVID-19. Famotidine led to earlier resolution of symptoms and inflammation without reducing anti-SARS-CoV-2 immunity. Additional randomised trials are required.

Trigger finger (TF) and carpal tunnel syndrome (CTS) are two common non-traumatic hand disorders that frequently co-occur. By identifying TF and CTS cases in UK Biobank (UKB), we confirmed a highly significant phenotypic association between the diseases. To investigate the genetic basis for this association we performed a genome-wide association study (GWAS) including 2,908 TF cases and 436,579 European controls in UKB, identifying five independent loci. Colocalization with CTS summary statistics identified a co-localized locus at DIRC3 (lncRNA), which was replicated in FinnGen and fine-mapped to rs62175241. Single-cell and bulk eQTL analysis in fibroblasts from healthy donors (n=79) and tenosynovium samples from CTS patients (n=77) showed that the disease-protective rs62175241 allele was associated with increased DIRC3 and IGFBP5 expression. IGFBP5 is a secreted antagonist of IGF-1 signaling, and elevated IGF-1 levels were associated with CTS and TF in UKB, thereby implicating IGF-1 as a driver of both diseases.

The secreted protein Cystatin C (CyC) is a cysteine protease inhibitor of incompletely characterized biomedical function, used clinically for estimation of glomerular filtration rate. Plasma CyC is elevated in many patients, especially when they receive glucocorticoid (GC) treatment. Here we empirically connect GCs with systemic regulation of CyC. First, we leveraged genome-wide association and structural equation modeling to determine the genetics of the latent trait CyC production in UK Biobank. Using multi-modal genomic, transcriptional, and experimental approaches, we demonstrated that CyC is a direct target of GC receptor, with GC-responsive CyC secretion exhibited by macrophages and cancer cells in vitro. Elevated serum CyC levels were positively correlated with GC levels in a murine model of cancer progression. Consistent with the coupling of CyC levels to GC signaling in a disease relevant manner, CyC predicted elevated all-cause and cancer-specific mortality in humans. These associations were orthogonally confirmed by a polygenic score (PGS) capturing germline predisposition to CyC production. This PGS predicted checkpoint immunotherapy failure in a combined clinical trial cohort of 685 metastatic cancer patients, with available germline exome sequencing. Taken together, our results demonstrate that CyC captures biomedically-relevant variations in endogenous GC activity, raising the possibility that CyC may be a direct effector of GC-induced immunosuppression and therefore a target for combination cancer immunotherapy.

Whether the immune suppressive action of glucocorticoid steroids, such as dexamethasone, might reduce the benefits of cancer immunotherapy has long been a concern. Observations that established tumor regressions in response to immune checkpoint inhibitors (ICIs) often persist, despite the use of steroids to mitigate ICI-related autoimmune breakthrough, are not sufficiently reassuring, because these observations do not address the potential blunting of immune priming at the initiation of ICI therapy. With increasing indications for ICI in combination with chemotherapy, this issue merits reconsideration. Professional society guidance advises that dexamethasone should be used as first-line prophylaxis for nausea and vomiting in patients receiving ICI and highly emetogenic chemotherapy combination regimens. Here, we review the availability of data on this subject and propose an alternative approach focused on the adoption of steroid minimization or sparing for prophylaxis of nausea until the underlying immune biology is better understood.

Simple Summary Colorectal cancer is the third most common cause of cancer-related deaths. The Wnt signaling pathway is activated by genetic mutations in most patients with colorectal cancer. A number of different types of Wnt pathway mutation have been described: some increase the sensitivity of tumor cells to Wnt ligands produced by stromal cells (ligand-dependent), while others drive downstream activation of the pathway (ligand-independent). Ligand-dependent tumors are of particular interest as there are a number of emerging treatment options, such as porcupine inhibitors, that can specifically target these tumors. In this review, we discuss what is known about these different types of Wnt activating mutations. We propose that ligand-dependent tumors should be viewed as a separate subset of colorectal cancer with its own biomarkers, prognosis and targeted therapies. Abstract Wnt signaling is ubiquitously activated in colorectal tumors and driver mutations are identified in genes such as APC, CTNNB1, RNF43 and R-spondin (RSPO2/3). Adenomatous polyposis coli (APC) and CTNNB1 mutations lead to downstream constitutive activation (ligand-independent), while RNF43 and RSPO mutations require exogenous Wnt ligand to activate signaling (ligand-dependent). Here, we present evidence that these mutations are not equivalent and that ligand-dependent and ligand-independent tumors differ in terms of underlying Wnt biology, molecular pathogenesis, morphology and prognosis. These non-overlapping characteristics can be harnessed to develop biomarkers and targeted treatments for ligand-dependent tumors, including porcupine inhibitors, anti-RSPO3 antibodies and asparaginase. There is emerging evidence that these therapies may synergize with immunotherapy in ligand-dependent tumors. In summary, we propose that ligand-dependent tumors are an underappreciated separate disease entity in colorectal cancer.

An elevated neutrophil–lymphocyte ratio negatively predicts the outcome of patients with cancer and is associated with cachexia, the terminal wasting syndrome. Here, using murine model systems of colorectal and pancreatic cancer we show that neutrophilia in the circulation and multiple organs, accompanied by extramedullary hematopoiesis, is an early event during cancer progression. Transcriptomic and metabolic assessment reveals that neutrophils in tumor-bearing animals utilize aerobic glycolysis, similar to cancer cells. Although pharmacological inhibition of aerobic glycolysis slows down tumor growth in C26 tumor-bearing mice, it precipitates cachexia, thereby shortening the overall survival. This negative effect may be explained by our observation that acute depletion of neutrophils in pre-cachectic mice impairs systemic glucose homeostasis secondary to altered hepatic lipid processing. Thus, changes in neutrophil number, distribution, and metabolism play an adaptive role in host metabolic homeostasis during cancer progression. Our findings provide insight into early events during cancer progression to cachexia, with implications for therapy.