...emerging therapeutics have received intense research efforts and high medical interest and it is for these reasons that a dedicated space has been provided by the Journal of Translational ...Medicine. Yet another field of intense study is represented by gene therapy with viral vectors as well as, as mentioned above, by RNA and DNA therapeutics, where the development of nanotechnologies for the delivery of nucleic acids has been making huge progress in the few last years 9,10,11,12. ...our increasing understanding of the importance of microbiota in disease pathogenesis and response to therapy is opening up novel therapeutic avenues. ...we can expect an entire new wave of microbiota-modulating approaches based either on the delivery of selected bacterial strains or, alternatively, the identification of molecules capable to modify gut microbiota composition for the benefit of patients 15,16,17.
In the advent of Immune Checkpoint inhibitors (ICI) and of CAR-T adoptive T-cells, the new frontier in Oncology is Cancer Immunotherapy because of its ability to provide long term clinical benefit in ...metastatic disease in several solid and liquid tumor types. It is now clear that ICI acts by unmasking preexisting immune responses as well as by inducing de novo responses against tumor neoantigens. Thanks to theprogress made in genomics technologies and the evolution of bioinformatics, neoantigens represent ideal targets, due to their specific expression in cancer tissue and the potential lack of side effects. In this review, we discuss the promise of preclinical and clinical results with mutation-derived neoantigen cancer vaccines (NCVs) along with the current limitations from bioinformatics prediction to manufacturing an effective new therapeutic approach.
The very limited time allowed to face the COVID-19 pandemic poses a pressing challenge to find proper therapeutic approaches. However, synthesis and full investigation from preclinical studies to ...phase III trials of new medications is a time-consuming procedure, and not viable in a global emergency, such as the one we are facing.
Drug repurposing/repositioning, a strategy effectively employed in cancer treatment, can represent a valid alternative. Most drugs considered for repurposing/repositioning in the therapy of the COVID-19 outbreak are commercially available and their dosage and toxicity in humans is well known, due to years (or even decades) of clinical use. This can allow their fast-track evaluation in phase II-III clinical trials, or even within straightforward compassionate use. Several drugs being re-considered for COVID-19 therapy are or have been used in cancer therapy. Indeed, virus-infected cells are pushed to enhance the synthesis of nucleic acids, protein and lipid synthesis and boost their energy metabolism, in order to comply to the "viral program". Indeed, the same features are seen in cancer cells, making it likely that drugs interfering with specific cancer cell pathways may be effective as well in defeating viral replication.
To our knowledge, cancer drugs potentially suitable for facing SARS-CoV-2 infection have not been carefully reviewed. We present here a comprehensive analysis of available information on potential candidate cancer drugs that can be repurposed for the treatment of COIVD-19.
Cancer stem cells (CSCs) are an uncommon subset of tumor cells capable of self-renewal, differentiating, and recreating the parental tumor when transplanted into the murine background. Over the past ...two decades, efforts toward understanding CSC biology culminated into identifying a set of signaling pathways sustaining "stemness". Nevertheless, while metabolic rewiring is nowadays considered a hallmark of cancer, no consensus has been reached on the metabolic features underlying the plastic nature of CSCs, which are capable of residing in a dormant state, and able to rapidly proliferate when the need to repopulate the tumor mass arises. An emerging concept in the field of CSC metabolism is that these cells are extremely reliant on the activity of enzymes involved in lipid metabolism, such as stearoyl-CoA desaturase 1 (SCD1) and 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR). Indeed, SCD1 and HMG-CoAR have been described as key factors for the correct function of a number of concatenated pathways involved in CSC fate decision, such as Hippo and Wnt. In the present review, we describe metabolic futures of CSCs with a special focus on lipid metabolism, which until now represents an underappreciated force in maintaining CSCs and an attractive therapeutic target.
SCD1, autophagy and cancer: implications for therapy Ascenzi, Francesca; De Vitis, Claudia; Maugeri-Saccà, Marcello ...
Journal of Experimental and Clinical Cancer Research,
08/2021, Volume:
40, Issue:
1
Journal Article, Book Review
Peer reviewed
Open access
Autophagy is an intracellular degradation system that removes unnecessary or dysfunctional components and recycles them for other cellular functions. Over the years, a mutual regulation between lipid ...metabolism and autophagy has been uncovered.
This is a narrative review discussing the connection between SCD1 and the autophagic process, along with the modality through which this crosstalk can be exploited for therapeutic purposes.
Fatty acids, depending on the species, can have either activating or inhibitory roles on autophagy. In turn, autophagy regulates the mobilization of fat from cellular deposits, such as lipid droplets, and removes unnecessary lipids to prevent cellular lipotoxicity. This review describes the regulation of autophagy by lipid metabolism in cancer cells, focusing on the role of stearoyl-CoA desaturase 1 (SCD1), the key enzyme involved in the synthesis of monounsaturated fatty acids. SCD1 plays an important role in cancer, promoting cell proliferation and metastasis. The role of autophagy in cancer is more complex since it can act either by protecting against the onset of cancer or by promoting tumor growth. Mounting evidence indicates that autophagy and lipid metabolism are tightly interconnected.
Here, we discuss controversial findings of SCD1 as an autophagy inducer or inhibitor in cancer, highlighting how these activities may result in cancer promotion or inhibition depending upon the degree of cancer heterogeneity and plasticity.
Our view of cancer biology radically shifted from a “cancer-cell-centric” vision to a view of cancer as an organ disease. The concept that genetic and/or epigenetic alterations, at the basis of ...cancerogenesis, are the main if not the exclusive drivers of cancer development and the principal targets of therapy, has now evolved to include the tumor microenvironment in which tumor cells can grow, proliferate, survive, and metastasize only within a favorable environment. The interplay between cancer cells and the non-cellular and cellular components of the tumor microenvironment plays a fundamental role in tumor development and evolution both at the primary site and at the level of metastasis. The shape of the tumor cells and tumor mass is the resultant of several contrasting forces either pro-tumoral or anti-tumoral which have at the level of the tumor microenvironment their battle field. This crucial role of tumor microenvironment composition in cancer progression also dictates whether immunotherapy with immune checkpoint inhibitor antibodies is going to be efficacious. Hence, tumor microenvironment deconvolution has become of great relevance in order to identify biomarkers predictive of efficacy of immunotherapy. In this short paper we will briefly review the relationship between inflammation and cancer, and will summarize in 10 short points the key concepts learned so far and the open challenges to be solved.
Safety and immunogenicity of BNT162b2 mRNA vaccine are unknown in hematological patients; both were evaluated prospectively in 42 patients with multiple myeloma (MM) and 50 with myeloproliferative ...malignancies (MPM) (20 chronic myeloid leukemias and 30 myeloproliferative neoplasms), all of them on active anti-cancer treatment, in comparison with 36 elderly controls not suffering from cancer. Subjects serologically and/or molecularly (by nasal/throat swab) positives at basal for SARS-CoV-2 were excluded. Primary endpoint was to compare titers of neutralizing anti-SARS-CoV-2 IgG and seroprotection rates among the cohorts at 3 and 5 weeks from first dose.
Titration was done using LIAISON® SARS-CoV-2 S1/S2 IgG test, a quantitative chemiluminescent immunoassay approved by FDA on the basis of robust evidences of concordance (94.4%) between the test at cutoff of 15 AU/mL and the Plaque Reduction Neutralization Test 90% at 1:40 ratio. Cutoff of 15 AU/mL was assumed to discriminate responders to vaccination with a protective titer. Cohorts were compared using Fisher' exact test and the Mann-Whitney test as appropriated. Geometric mean concentrations (GMCs), geometric mean ratios and response rates after 1st and 2nd dose were compared in each cohort by Wilcoxon and McNemar tests, respectively.
At 5 weeks, GMC of IgG in elderly controls was 353.3 AU/mL versus 106.7 in MM (p = 0.003) and 172.9 in MPM patients (p = 0.049). Seroprotection rate at cutoff of 15 AU/mL was 100% in controls compared to 78.6% in MM (p = 0.003) and 88% in MPM patients (p = 0.038). In terms of logarithm of IgG titer, in a generalized multivariate linear model, no gender effect was observed (p = 0.913), while there was a significant trend toward lower titers by increasing age (p < 0.001) and in disease cohorts with respect to controls (MM: p < 0.001 and MPM: p < 0.001). An ongoing treatment without daratumumab was associated with higher likelihood of response in MM patients (p = 0.003). No swabs resulted positive on each time point. No safety concerns were observed.
BNT162b2 has demonstrated to be immunogenic at different extent among the cohorts. Response was 88% and robust in MPM patients. MM patients responded significantly less, particularly those on anti-CD38-based treatment. These latter patients should be advised to maintain masks and social distancing regardless of vaccination status, and their cohabiting family members need to be vaccinated in order to reduce the risk of contagion from the family. Additional boosters and titer monitoring could be considered. Trial registration Study was formally approved by the IRCCS Central Ethical Committee of Regione Lazio in January 2021 (Prot. N-1463/21).
Cancer stem cells (CSCs) have historically been defined as slow cycling elements that are able to differentiate into mature cells but without dedifferentiation in the opposite direction. Thanks to ...advances in genomic and non-genomic technologies, the CSC theory has more recently been reconsidered in a dynamic manner according to a “phenotype switching” plastic model. Transcriptional reprogramming rewires this plasticity and enables heterogeneous tumors to influence cancer progression and to adapt themselves to drug exposure by selecting a subpopulation of slow cycling cells, similar in nature to the originally defined CSCs. This model has been conceptualized for malignant melanoma tailored to explain resistance to target therapies. Here, we conducted a bioinformatics analysis of available data directed to the identification of the molecular pathways sustaining slow cycling melanoma stem cells. Using this approach, we identified a signature of 25 genes that were assigned to four major clusters, namely (1) kinases and metabolic changes, (2) melanoma-associated proteins, (3) Hippo pathway and (4) slow cycling/CSCs factors. Furthermore, we show how a protein−protein interaction network may be the main driver of these melanoma cell subpopulations. Finally, mining The Cancer Genome Atlas (TCGA) data we evaluated the expression levels of this signature in the four melanoma mutational subtypes. The concomitant alteration of these genes correlates with the worst overall survival (OS) for melanoma patients harboring BRAF-mutations. All together these results underscore the potentiality to target this signature to selectively kill CSCs and to achieve disease control in melanoma.
In the rapidly evolving coronavirus disease 2019 (COVID-19) outbreak, inherent literature has been increasing at an impressive rate. Such a dynamic scenario imposes the necessity to define a new ...framework for cancer care. The first emerging evidence has transmitted contrasting messages with regards to cancer care management. Some authors have hypothesized an increased infection risk for cancer patients, with a more severe disease, requiring a reorganization of health care system that could disrupt an established high quality cancer care routine in many developed countries. Other authors have attempted to interpret data related to cancer patients by better defining their "active status". We herein present our point of view in the light of current evidence and based on the experience matured at our cancer institute in managing cancer patients during the COVID-19 pandemic. Our core idea is that "active cancer" may be considered a proxy of more recent exposure to diagnostic or therapeutic procedures, and the frequency of access to health care facilities can be predicted as a function of the severity of cancer symptoms. Hence, COVID-19 screening program and the adjustment of cancer care provision in a cancer institutions should be led by this risk model, while awaiting new evidence.
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