A perspective on diet, epigenetics and complex diseases: where is the field headed next?

Dietary factors can regulate epigenetic processes during life, modulating the intracellular pools of metabolites necessary for epigenetic reactions and regulating the activity of epigenetic enzymes. Their effects are strong during the prenatal life, when epigenetic patterns are written, allowing organogenesis. However, interactions between diet and the epigenome continue throughout life and likely contribute to the onset and progression of various complex diseases. Here, we review the contribution of dietary factors to the epigenetic changes observed in complex diseases and suggest future steps to better address this issue, focusing on neurobehavioral, neuropsychiatric and neurodegenerative disorders, cardiovascular diseases, obesity and Type 2 diabetes, cancer and inflammatory skin diseases.

The Role of Cytokinome in the HNSCC Tumor Microenvironment: A Narrative Review and Our Experience.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer. In locally advanced (LA) HNSCC, a multidisciplinary approach consisting of surgery followed by chemoradiation (CRT) or definitive CRT is the mainstay of treatment. In recurrent metastatic (R/M), HNSCC immune checkpoint inhibitors (ICIs) with or without chemotherapy represent the new first-line option. However, cancer will recur in about two out of five patients with LA HNSCC. If progression occurs within six months from platin-radiotherapy treatment, anti-programmed cell death-1 (PD-1) may be prescribed. Otherwise, immunotherapy with or without chemotherapy might be considered if PD-L1 is expressed. Despite several improvements in the outcome of patients with R/M HNSCC, overall survival (OS) remains dismal, equaling a median of 14 months. In-depth knowledge of the tumor microenvironment (TME) would be required to change the course of this complex disease. In recent years, many predictive and prognostic biomarkers have been studied in the HNSCC TME, but none of them alone can select the best candidates for response to ICIs or targeted therapy (e.g., Cetuximab). The presence of cytokines indicates an immune response that might occur, among other things, after tumor antigen recognition, viral and bacterial infection, and physic damage. An immune response against HNSCC results in the production of some cytokines that induce a pro-inflammatory response and attract cells, such as neutrophils, macrophages, and T cell effectors, to enhance the innate and adaptive anti-tumor response. We revised the role of a group of cytokines as biomarkers for treatment response in HNSCC.

Inhibition of the angiotensin II type 2 receptor AT2R is a novel therapeutic strategy for glioblastoma.

Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (AT2R) is a therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through AT2R. We repurposed EMA401, an AT2R antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of AT2R-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity. The crystal structure of AT2R bound to EMA401 was determined and revealed the receptor to be in an active-like conformation with helix-VIII blocking G-protein or ß-arrestin recruitment. The architecture and interactions of EMA401 in AT2R differ drastically from complexes of AT2R with other relevant compounds. To enhance central nervous system (CNS) penetration of EMA401, we exploited the crystal structure to design an angiopep-2-tethered EMA401 derivative, A3E. A3E exhibited enhanced CNS penetration, leading to reduced tumor volume, inhibition of proliferation, and increased levels of apoptosis in an orthotopic xenograft model of GBM.

Circulating Cytokines in Metastatic Breast Cancer Patients Select Different Prognostic Groups and Patients Who Might Benefit from Treatment beyond Progression.

Cancer induces immune suppression to overcome its recognition and eradication by the immune system. Cytokines are messengers able to modulate immune response or suppression. There is great interest in the evaluation of their changes during treatment in order to identify their relationship with clinical outcome. We evaluated 18 cytokines in breast cancer patients treated with eribulin before starting treatment (T0) and after four courses of therapy (T1). Longitudinal modifications were considered and cytokine clusters through PCA and HCPC correlated to patients' outcomes were identified. Forty-one metastatic breast cancer patients and fifteen healthy volunteers were included. After clustering, we identified at T0 six patient clusters with different risk of relapse and death. At T1, only four clusters were identified, and three of them accounted for thirty-eight of forty-one patients, suggesting a possible role of treatment in reducing heterogeneity. The cluster with the best survival at T1 was characterized by low levels of IL-4, IL-6, IL-8, IL-10, CCL-2, CCL-4, and TGF-ß. The cluster showing the worst survival encompassed high levels of IL-4, IL-6, IL-8, IL-10, CCL-2, and IFN-γ. A subgroup of patients with short progression-free survival (PFS) and long overall survival (OS) was comprised in the cluster characterized by low levels of CCL-2, IL-6, IL-8, IL-10, and IL-12 at T0. Our data support the prognostic significance of longitudinal serum cytokine analysis. This approach may help identify patients for whom early treatment stop avoids needless toxicity or might justify treatment beyond early progression. Further investigations are required to validate this hypothesis.

Further Understanding of the Immune Microenvironment in Head and Neck Squamous Cell Carcinoma: Implications for Prognosis.

PURPOSE: We aimed to review the literature on the tumor microenvironment as a key player in tumor growth and anti-cancer treatment responses in head and neck cancer. PATIENTS AND METHODS: We reviewed the recent literature on this topic, using the following research words: "tumor microenvironment" and "head and neck cancer or neoplasm or head and neck squamous cell carcinoma" and "immune cells" and "stromal cells". A search was conducted on the PubMed website and reports from international meetings, presentations and abstracts. RESULTS: The tumor microenvironment is a complex network in which myeloid cells, tumoral cells, growth factors and cytokines are involved in angiogenesis, the extracellular matrix and epithelial-to-mesenchymal transition. CONCLUSION: Immune resistance and rapid tumor growth depend on immunosuppressive and pro-tumoral environments. Further investigations to classify and adequately treat patients with head and neck cancer are required.

Exploratory analysis of circulating cytokines in patients with metastatic breast cancer treated with eribulin: the TRANSERI-GONO (Gruppo Oncologico del Nord Ovest) study.

BACKGROUND: Anticancer drugs can interact with the tumour microenvironment and their effects could be exploited to favour anticancer immune response. Eribulin contributes to tumour vasculature remodelling and transforming growth factor ß (TGF-ß) modulation in experimental models and in humans. We performed a prospective, translational, exploratory analysis of the levels of circulating cytokines at different time points in patients with metastatic breast cancer treated with eribulin. METHODS: TGF-ß, tumour necrosis factor α, vascular endothelial growth factor, IL-6, IL-8, IL-10, IL-21 and C-C motif chemokine ligand-2 levels were assessed in peripheral blood samples obtained from seven healthy volunteers and 41 patients at baseline (T0), after four cycles of eribulin (T1) and at disease progression (TPD). Baseline values and longitudinal changes in cytokine levels were then related to clinical outcome. RESULTS: In the 41 patients, high IL-6 and IL-8 (above the median) at T0 significantly correlated with worse survival. At T1, IL-21 significantly decreased in patients with TPD within the fourth course of treatment, compared with patients without progression. TGF-ß and IL-8 above the median and IL-21 below the median at T1 significantly correlates with worse progression free survival (PFS). Patients exhibiting an increase of TGF-ß or a decline of IL-21 between T0 and T1 showed a significantly worse PFS. Multivariate Cox regression analysis showed that only plasma TGF-ß changes at T1 correlated with survival. At TPD, TGF-ß significantly increased in all patients. CONCLUSIONS: We observed a significant correlation between TGF-ß decline during eribulin treatment and outcome in patients with metastatic breast cancer. Altogether, our data suggest that eribulin treatment might interfere with the tumour microenvironment.

DNA Methylation in the Diagnosis of Monogenic Diseases.

DNA methylation in the human genome is largely programmed and shaped by transcription factor binding and interaction between DNA methyltransferases and histone marks during gamete and embryo development. Normal methylation profiles can be modified at single or multiple loci, more frequently as consequences of genetic variants acting in cis or in trans, or in some cases stochastically or through interaction with environmental factors. For many developmental disorders, specific methylation patterns or signatures can be detected in blood DNA. The recent use of high-throughput assays investigating the whole genome has largely increased the number of diseases for which DNA methylation analysis provides information for their diagnosis. Here, we review the methylation abnormalities that have been associated with mono/oligogenic diseases, their relationship with genotype and phenotype and relevance for diagnosis, as well as the limitations in their use and interpretation of results.

Circulating cytokines and outcome in metastatic colorectal cancer patients treated with regorafenib.

BACKGROUND: Regorafenib is an oral small-molecule multikinase inhibitor approved in third or later line of treatment for patients with metastatic colorectal cancer (mCRC). Regorafenib has shown significant benefits in overall survival and progression free survival in two phase III trials compared to placebo in patients with mCRC who had progressed on previous therapy. AIM: To identify an immune profile that might specifically correlate with the outcome in patients treated with regorafenib. METHODS: Blood samples were collected from 17 patients before treatment with regorafenib and from 6 healthy volunteers. The proteins evaluated (TNF-α, TGF-ß, VEGF, CCL-2, CCL-4, and CCL-5) were selected on the basis of their roles in angiogenesis and colorectal cancer pathogenesis. RESULTS: We found that TNF-α basal level was significantly higher in mCRC patients compared to healthy individuals. Non Responder (NR) patients showing progression of disease (n = 12) had higher basal level of TGF-ß, TNF-α, VEGF, CCL-2 and CCL-5 compared to Responder (R) patients (complete response CR, n = 1; partial response PR, n = 1; Stable Disease SD, n = 3). On the contrary, plasma basal level of CCL-4 was higher in R compared to NR patients. High values of TGF-ß and TNF-α negatively correlated with progression free survival. CONCLUSION: These results suggest a cytokine signature potentially able to discriminate between R and NR patients to treatment with regorafenib.

Expression and subcellular localization of the bromodomain-containing protein 7 is a prognostic biomarker in breast cancer.

Bromodomain-containing protein 7 (BRD7) is a member of the bromodomain-containing protein family. Previous studies suggest that BRD7 is predominantly localized in the nucleus, wherein it functions as a transcriptional regulator. Several lines of evidence imply a tumour suppressor function for BRD7. However, the importance of BRD7 in the pathogenesis of breast cancer is not well understood. We have investigated the expression, CpG island methylation and subcellular localization of BRD7 in breast cancer cell lines and clinical cases and thereby assessed its prognostic significance by correlating with clinical-pathological features and time-dependent clinical outcomes. We show that nuclear exclusion of BRD7 occurs commonly in breast cancer and is strongly associated with cases expressing wild-type p53. Moreover, clinical outcomes are significantly less favourable in cases with nuclear exclusion or loss of expression than those in which there is nuclear expression of BRD7. Methylation of the CpG island of BRD7 increases in breast cancer relative to normal breast tissue, but there is not an obvious correlation between methylation and reduced expression or between methylation and clinical outcomes. Overall, our results suggest that nuclear exclusion, rather than transcriptional silencing, is a common mechanism by which the tumour suppressor function of wild-type p53 is inhibited in breast cancer, and show that BRD7 is a promising candidate biomarker in breast cancer.

NK-mediated antibody-dependent cell-mediated cytotoxicity in solid tumors: biological evidence and clinical perspectives.

The process of antibody-dependent cell-mediated cytotoxicity (ADCC) makes use of the innate immune cells providing antitumor cytotoxicity activated by antibodies linked to target cells. Natural killer (NK) cells are a small set of lymphocytes, but are considered the most important cells among those able to induce ADCC. They provoke innate immune responses and harmonise spontaneous cytotoxicity towards tumor and virus-infected cells. They are able to swiftly produce biochemical signals and cytokines so as to stimulate subsequent adaptive immune responses. Immunotherapeutics that target NK cells, augmenting their immune response, can cause the antitumor dynamics of the antibodies to be improved. The recent developments in the field of NK cell immunotherapy and genotypic factors which might affect patient responses to antibody-dependent immunotherapies are the main subject of this review, with a particular focus on the manipulations and strategies used to augment ADCC. In the next years combined treatment with monoclonal antibodies (mAbs) and immunomodulatory drugs will be an important part in antitumor therapy. The main challenge remains the difficulty in distinguishing in the clinical setting, between the target effect that many mAbs exert against specific cell membrane receptors and the ADCC effect that they too also can induce. Drugs able to activate NK cells, that are major actors in mAb-mediated ADCC, will improve the ADCC effect against tumors.

RET in breast cancer: pathogenic implications and mechanisms of drug resistance.

Initiation, progression, outcome and sensibility to therapies in breast cancer (BC), the most frequent cancer in women, are driven by somatic and germline mutations. Although the effectiveness of hormonal therapies is well-founded, it is prescribed for cancers which express steroid hormone receptors, such as estrogen receptor (ER). RET is a proto-oncogene encoding a transmembrane tyrosine kinase receptor that is activated by one of its four ligands (GDNF, neurturin, artemin or persephin) and one of its coreceptors (Gfrα1-4). Loss-of-function mutations in RET are responsible for Hirschsprung disease, while gain-of-function mutations for multiple endocrine neoplasia type 2. In addition, deregulation of its intracellular signaling, due to mutations, gene rearrangements, overexpression or transcriptional upregulation, can cause several neuroendocrine and epithelial tumors. In BC, amplification of receptor tyrosine kinases, such as ERBB2, EGFR, IGFR and FGFR1, and/or their upregulation contribute to cancer initiation and progression. RET can also have an important role in BC, but only in the subset of ER-positive (ER+) tumors, where it is found overexpressed. Targeting the RET pathway and shedding light on molecular basis of the resistance to hormone therapy may lead to new therapies in ER+ BC, improving treatment outcome and preventing tumor-related events. Thus, here, we review the state of the art of RET biology in BC and agents targeting RET tested in the clinical trials and discuss the specificity of the still available RET inhibitors and the molecular mechanisms underlying the BC resistance to endocrine therapy.

Collagen Prolyl Hydroxylases Are Bifunctional Growth Regulators in Melanoma.

Appropriate post-translational processing of collagen requires prolyl hydroxylation, catalyzed by collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase, and is essential for normal cell function. Here we have investigated the expression, transcriptional regulation, and function of the collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase families in melanoma. We show that the collagen prolyl 3-hydroxylase family exemplified by Leprel1 and Leprel2 is subject to methylation-dependent transcriptional silencing in primary and metastatic melanoma consistent with a tumor suppressor function. In contrast, although there is transcriptional silencing of P4HA3 in a subset of melanomas, the collagen prolyl 4-hydroxylase family members P4HA1, P4HA2, and P4HA3 are often overexpressed in melanoma, expression being prognostic of worse clinical outcomes. Consistent with tumor suppressor function, ectopic expression of Leprel1 and Leprel2 inhibits melanoma proliferation, whereas P4HA2 and P4HA3 increase proliferation, and particularly invasiveness, of melanoma cells. Pharmacological inhibition with multiple selective collagen prolyl 4-hydroxylase inhibitors reduces proliferation and inhibits invasiveness of melanoma cells. Together, our data identify the collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase families as potentially important regulators of melanoma growth and invasiveness and suggest that selective inhibition of collagen prolyl 4-hydroxylase is an attractive strategy to reduce the invasive properties of melanoma cells.

Long noncoding RNAs as regulators of cancer immunity.

Long noncoding RNAs (lncRNAs) are increasingly known to be important in cancer as they directly interact with the cell cycle, proliferation pathways and microbiome balance. Moreover, lncRNAs regulate the immune system: they do not directly encode proteins of innate or adaptive immunity, but regulate immune cell differentiation and function, such as dendritic cell activity, T cell ratio and metabolism. The result of this complex interaction is that lncRNAs regulate cancer processes through a complex multimodal system involving immunity, metabolism and infection. The possible functions of lncRNAs and their roles in the regulation of cancer immunity will be reported and discussed in the present review. Recent studies showed their function as regulators in the tumour microenvironment (TME), epithelial-mesenchymal transition, microbiota, metabolism and immune cell differentiation. However, there is not much knowledge regarding their roles in cancer immunity regulation. Thus, the main aim of this review is to describe lncRNAs that have specifically been associated with immunity, the immune cycle and the TME.

DUSP2 methylation is a candidate biomarker of outcome in head and neck cancer.

BACKGROUND: Biomarkers predictive of response to chemoradiotherapy (CRT) regimens for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) are urgently required to identify patients in whom this approach is likely to be effective. TP53 mutations and epidermal growth factor (EGFR) overexpression are common markers of disease. Dual-specificity-phosphatase-2 (DUSP2) has an essential role in cell proliferation, cancer and immune responses. METHODS: Aberrant DUSP2 methylation was investigated by pyrosequencing in 5 HNSCC cell lines, 112 LA-HNSCC tumours. EGFR was investigated by immunohistochemistry and TP53 was analysed by sequencing. RESULTS: We demonstrate methylation-dependent transcriptional silencing of DUSP2 in HNSCC cell lines. In LA-HNSCC patients, aberrant methylation in the DUSP2 CpG island was present in 51/112 cases (45.5%). LA-HNSCC cases with wild-type TP53, overexpression of EGFR and unmethylated DUSP2 had the worst overall survival (P≤0.001). CONCLUSIONS: DUSP2 methylation, when combined with EGFR and TP53, is a candidate biomarker of clinical outcome in LA-HNSCC treated with CRT.

Head and neck cancer: improving outcomes with a multidisciplinary approach.

For early-stage head and neck cancer (HNC), surgery (S) or radiotherapy (RT) is a standard treatment. The multidisciplinary approach, which includes multimodality treatment with S followed by RT, with or without chemotherapy (CT) or concurrent chemoradiotherapy (CRT), is required for locally advanced head and neck cancer (LAHNC). CRT improves prognosis, locoregional control (LRC), and organ function in LAHNC, compared to RT alone. Prognosis in recurrent/metastatic HNC (R/M HNC) is dismal. Platinum-based CT, combined with the anti-Epidermal Growth Factor Receptor (EGFR) antibody (Ab) cetuximab, is used in first-line setting, while no further validated options are available at progression. The complexity of disease is, in part, due to the heterogeneity of organs and functions involved and the need for a multimodality approach. In addition, the patient population (often elderly and/or patients with smoking and alcohol habits) argues for an individually tailored treatment plan. Furthermore, treatment goals - which include cure, organ, and function preservation, quality of life and palliation - must also be considered. Thus, optimal management of patients with HNC should involve a range of healthcare professionals with relevant expertise. The purpose of the present review is to 1) highlight the importance and necessity of the multidisciplinary approach in the treatment of HNC; 2) update the knowledge regarding modern surgical techniques, new medical and RT treatment approaches, and their combination; 3) identify the treatment scenario for LAHNC and R/M HNC; and 4) discuss the current role of immunotherapy in HNC.

Elevated basal antibody-dependent cell-mediated cytotoxicity (ADCC) and high epidermal growth factor receptor (EGFR) expression predict favourable outcome in patients with locally advanced head and neck cancer treated with cetuximab and radiotherapy.

BACKGROUND: Antibody-dependent cell-mediated cytotoxicity (ADCC) may contribute to the antitumor activity of cetuximab. However, the extent of this contribution is unclear. In this study, we investigated the impact of baseline ADCC on the outcome of patients with locally advanced squamous cell carcinoma treated with cetuximab and radiotherapy. METHODS: We determined baseline ADCC in 28 patients treated with cetuximab and radiotherapy and in 15 patients treated with chemoradiation. We linked the values observed with complete response and with overall survival. We also considered the role of epidermal growth factor receptor (EGFR) expression and studied the combined effect of EGFR and ADCC. RESULTS: We observed a wide range of baseline values of ADCC. Complete response did not correlate with either ADCC or EGFR expression. However, when ADCC and EGFR were considered together using a mixed score, they significantly correlated with achieving a complete response (p = 0.04). High baseline ADCC significantly correlated with outcome compared to low (p = 0.03), but not in patients treated without cetuximab. Patients showing high baseline levels of both ADCC and EGFR3+ achieved the best outcome compared to the others (p = 0.02). CONCLUSIONS: In this study, patients treated with cetuximab and radiotherapy, showing high baseline of both ADCC and EGFR3+, have significant higher probability of achieving a complete response and a long overall survival compared to the others.

MicroRNAs role as potential biomarkers and key regulators in melanoma.

Malignant melanoma (MM) is a highly aggressive skin cancer with high incidence worldwide. It originates from melanocytes and is characterized by invasion, early metastasis and despite the use of new drugs it is still characterized by high mortality. Since an early diagnosis determines a better prognosis, it is important to explore novel prognostic markers in the management of patients with MM. microRNAs (miRNAs) are small (∼22 nucleotides) single-stranded non-coding RNAs that negatively regulate the expression of more than 60% of human genes.miRNAs alterations are involved in several cancers, including MM, where a differential expression for some of them has been reported between healthy controls and MM patients. Moreover, since miRNAs are stable and easily detectable in body fluids, they might be considered as robust candidate biomarkers useful to identify risk of MM, to diagnose an early lesion and/or an early metastatic disease. This review highlights the importance of miRNAs as risk factors, prognostic factors and their role as molecular regulator in the development and progression of MM. © 2016 Wiley Periodicals, Inc.

Targeting the pro-angiogenic forms of VEGF or inhibiting their expression as anti-cancer strategies.

Tumor growth relies on oxygen and blood supply depending on neo-vascularization. This process is mediated by the Vascular Endothelial Growth Factor (VEGF) in many tumors. This paradigm has led to the development of specific therapeutic approaches targeting VEGF or its receptors. Despite their promising effects, these strategies have not improved overall survival of patients suffering from different cancers compared to standard therapies. We hypothesized that the existence of anti-angiogenic forms of VEGF VEGFxxxb which are still present in many tumors limit the therapeutic effects of the anti-VEGF antibodies bevacizumab/Avastin (BVZ). To test this hypothesis, we generated renal cell carcinoma cells (RCC) expressing VEGF165b. The incidence of tumors xenografts generated in nude mice and their growth were inferior to those obtained with control cells. Whereas BVZ had no effect on control tumors, it slowed-down the growth of tumor generated with VEGF165b expressing cells. A prophylactic immunization against the domain discriminating VEGF from VEGFxxxb isoforms inhibited the growth of tumor generated with two different syngenic tumor cell lines (melanoma (B16 cells) and RCC (RENCA cells)). Purified immunoglobulins from immunized mice also slowed-down tumor growth of human RCC xenografts in nude mice, producing a potent effect compared to BVZ in this model. Furthermore, down-regulating the serine-arginine-rich splicing factor 1 (SRSF1) or masking SRSF1 binding sites by 2'O-Methyl RNA resulted in the increase of the VEGFxxxb/VEGF ratio. Therefore, a vaccine approach, specific antibodies against pro-angiogenic forms of VEGF, or increasing the VEGFxxxb/VEGF ratio may represent new prophylactic or pro-active anti-cancer strategies.

Prognostic and predictive biomarkers in metastatic colorectal cancer anti-EGFR therapy.

AIM: To reviewing genetic and epigenetic make-up of metastatic colorectal cancers (mCRCs) addicted to epidermal growth factor receptor (EGFR) signalling. METHODS: The present study summarizes the potential value of prognostic and predictive biomarkers in selecting mCRC patients treated with anti-EGFR therapy. A meta-analysis was performed using a systematic search of PubMed, Medline and Web of Science to identify eligible papers until March 21(st), 2016 using these following terms: ''colorectal cancer'', "predictive biomarkers'', "anti-EGFR therapy", "KRAS", "NRAS'', "PIK3CA", "TP53", "PTEN", ''EGFR", "MET", "HER2", "epiregulin", "amphiregulin", "prognostic biomarkers", "BRAF", "miRNA" and "antibody-dependent cell-mediated cytotoxicity (ADCC) activity". Two investigators independently evaluated and extracted data from each identified studies based on selected criteria of inclusion and exclusion. RESULTS: The introduction of agents targeting EGFR such as cetuximab and panitumumab increased overall survival of mCRCs. Nevertheless, it has firstly became evident that response rates to cetuximab regimens in unselected patient populations were typically lower than 30%. Clinical data confirmed the predictive value of RAS mutations for resistance to cetuximab and panitumumab leading to the license of these monoclonal antibodies exclusively for the management of patients with RAS-wild type colorectal cancers. So far the identification of predictive biomarkers have generated interesting, though preliminary and, at times, conflicting data on the importance of tumour mRNA levels of EGFR ligands, of activating mutations in other genes such as NRAS and PIK3CA. The prognostic value of selected microRNAs level and ADCC activity is under investigation, while the prognostic impact of BRAF status remains controversial. CONCLUSION: This review focuses on the personalized treatment of mCRC and discusses the potential of new prognostic and predictive biomarkers in selecting patients treated with anti-EGFR therapy.

Inhibition of the Polyamine Synthesis Pathway Is Synthetically Lethal with Loss of Argininosuccinate Synthase 1.

Argininosuccinate synthase 1 (ASS1) is the rate-limiting enzyme for arginine biosynthesis. ASS1 expression is lost in a range of tumor types, including 50% of malignant pleural mesotheliomas. Starving ASS1-deficient cells of arginine with arginine blockers such as ADI-PEG20 can induce selective lethality and has shown great promise in the clinical setting. We have generated a model of ADI-PEG20 resistance in mesothelioma cells. This resistance is mediated through re-expression of ASS1 via demethylation of the ASS1 promoter. Through coordinated transcriptomic and metabolomic profiling, we have shown that ASS1-deficient cells have decreased levels of acetylated polyamine metabolites, together with a compensatory increase in the expression of polyamine biosynthetic enzymes. Upon arginine deprivation, polyamine metabolites are decreased in the ASS1-deficient cells and in plasma isolated from ASS1-deficient mesothelioma patients. We identify a synthetic lethal dependence between ASS1 deficiency and polyamine metabolism, which could potentially be exploited for the treatment of ASS1-negative cancers.