Publications by authors named "Matteo Landriscina"

84 Publications

Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era.

Int J Mol Sci 2021 Jul 19;22(14). Epub 2021 Jul 19.

Unit of Medical Oncology and Biomolecular Therapy, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, 71122 Foggia, Italy.

Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.
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http://dx.doi.org/10.3390/ijms22147717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307359PMC
July 2021

Obstructive Sleep Apnea Worsens Progression-Free and Overall Survival in Human Metastatic Colorectal Carcinoma.

J Oncol 2021 2;2021:5528303. Epub 2021 Apr 2.

Institute of Respiratory Diseases, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.

Sleep disorders have emerged as highly prevalent conditions, and along with improved understanding of such disorders, increased attention has gained the evidence that perturbation in sleep architecture and continuity may initiate, exacerbate, or modulate the phenotypic expression of multiple diseases including cancer. Furthermore, obstructive sleep apnea (OSA) has recently been implicated in increased incidence and more adverse prognosis of cancer in humans. This study was designed to confirm the high prevalence of OSA in human malignancies and assess its prognostic relevance in metastatic colorectal carcinomas (mCRCs). A prospective cohort of 52 subjects, affected by solid histologically confirmed metastatic malignancies, was analyzed, and among them, 29 mCRCs were studied for the prognostic role of OSA. OSA was diagnosed in 34.6% (18/52) of patients with a statistically significant difference in apnea-hyponea index between OSA and non-OSA subgroups (14.2 ± 12.2 vs. 2.1 ± 1.5, < 0.01). Consistently, OSA was diagnosed in 34.5% (10/29) of mCRCs with lower rates of first-line therapy disease control in OSA compared to non-OSA patients (60% in OSA vs. 94.7% in non-OSA, =0.03). Of note, progression-free and overall survival rates were significantly shorter in OSA (respectively, 9 and 22 months) compared non-OSA (20 and 40 months) mCRC patients (HR = 2.63; 95% CI 0.88-7.84, =0.01 for PFS; HR = 3.93; 95% CI 1.13-13.73, < 0.001 for OS). Finally, the multivariate analysis showed that OSA is an independent prognostic factor for PFS (=0.0076) and OS (=0.0017) in this cohort. Altogether, these data suggest that OSA is a potential clinical marker predictor of poor prognosis in patients with mCRC.
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http://dx.doi.org/10.1155/2021/5528303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041522PMC
April 2021

Novel Epigenetic Eight-Gene Signature Predictive of Poor Prognosis and MSI-Like Phenotype in Human Metastatic Colorectal Carcinomas.

Cancers (Basel) 2021 Jan 5;13(1). Epub 2021 Jan 5.

Laboratory of Preclinical and Translational Research, Istituto di Ricovero e Cura a Carattere Scientifico Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), 85028 Potenza, Italy.

Epigenetics is involved in tumor progression and drug resistance in human colorectal carcinoma (CRC). This study addressed the hypothesis that the DNA methylation profiling may predict the clinical behavior of metastatic CRCs (mCRCs). The global methylation profile of two human mCRC subgroups with significantly different outcome was analyzed and compared with gene expression and methylation data from The Cancer Genome Atlas COlon ADenocarcinoma (TCGA COAD) and the NCBI GENE expression Omnibus repository (GEO) GSE48684 mCRCs datasets to identify a prognostic signature of functionally methylated genes. A novel epigenetic signature of eight hypermethylated genes was characterized that was able to identify mCRCs with poor prognosis, which had a CpG-island methylator phenotype (CIMP)-high and microsatellite instability (MSI)-like phenotype. Interestingly, methylation events were enriched in genes located on the q-arm of chromosomes 13 and 20, two chromosomal regions with gain/loss alterations associated with adenoma-to-carcinoma progression. Finally, the expression of the eight-genes signature and MSI-enriching genes was confirmed in oxaliplatin- and irinotecan-resistant CRC cell lines. These data reveal that the hypermethylation of specific genes may provide prognostic information that is able to identify a subgroup of mCRCs with poor prognosis.
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http://dx.doi.org/10.3390/cancers13010158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796477PMC
January 2021

TRAP1 Regulates Wnt/β-Catenin Pathway through LRP5/6 Receptors Expression Modulation.

Int J Mol Sci 2020 Oct 13;21(20). Epub 2020 Oct 13.

Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, Italy.

Wnt/β-Catenin signaling is involved in embryonic development, regeneration, and cellular differentiation and is responsible for cancer stemness maintenance. The HSP90 molecular chaperone TRAP1 is upregulated in 60-70% of human colorectal carcinomas (CRCs) and favors stem cells maintenance, modulating the Wnt/β-Catenin pathway and preventing β-Catenin phosphorylation/degradation. The role of TRAP1 in the regulation of Wnt/β-Catenin signaling was further investigated in human CRC cell lines, patient-derived spheroids, and CRC specimens. TRAP1 relevance in the activation of Wnt/β-Catenin signaling was highlighted by a TCF/LEF Cignal Reporter Assay in Wnt-off HEK293T and CRC HCT116 cell lines. Of note, this regulation occurs through the modulation of Wnt ligand receptors LRP5 and LRP6 that are both downregulated in TRAP1-silenced cell lines. However, while LRP5 mRNA is significantly downregulated upon TRAP1 silencing, LRP6 mRNA is unchanged, suggesting independent mechanisms of regulation by TRAP1. Indeed, LRP5 is regulated upon promoter methylation in CRC cell lines and human CRCs, whereas LRP6 is controlled at post-translational level by protein ubiquitination/degradation. Consistently, human CRCs with high TRAP1 expression are characterized by the co-upregulation of active β-Catenin, LRP5 and LRP6. Altogether, these data suggest that Wnt/β-Catenin signaling is modulated at multiple levels by TRAP1.
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http://dx.doi.org/10.3390/ijms21207526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589514PMC
October 2020

TRAP1 enhances Warburg metabolism through modulation of PFK1 expression/activity and favors resistance to EGFR inhibitors in human colorectal carcinomas.

Mol Oncol 2020 12 30;14(12):3030-3047. Epub 2020 Oct 30.

Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.

Metabolic rewiring is a mechanism of adaptation to unfavorable environmental conditions and tumor progression. TRAP1 is an HSP90 molecular chaperone upregulated in human colorectal carcinomas (CRCs) and responsible for downregulation of oxidative phosphorylation (OXPHOS) and adaptation to metabolic stress. The mechanism by which TRAP1 regulates glycolytic metabolism and the relevance of this regulation in resistance to EGFR inhibitors were investigated in patient-derived CRC spheres, human CRC cells, samples, and patients. A linear correlation was observed between TRAP1 levels and F-fluoro-2-deoxy-glucose ( F-FDG) uptake upon PET scan or GLUT1 expression in human CRCs. Consistently, TRAP1 enhances GLUT1 expression, glucose uptake, and lactate production and downregulates OXPHOS in CRC patient-derived spheroids and cell lines. Mechanistically, TRAP1 maximizes lactate production to balance low OXPHOS through the regulation of the glycolytic enzyme phosphofructokinase-1 (PFK1); this depends on the interaction between TRAP1 and PFK1, which favors PFK1 glycolytic activity and prevents its ubiquitination/degradation. By contrast, TRAP1/PFK1 interaction is lost in conditions of enhanced OXPHOS, which results in loss of TRAP1 regulation of PFK1 activity and lactate production. Notably, TRAP1 regulation of glycolysis is involved in resistance of RAS-wild-type CRCs to EGFR monoclonals. Indeed, either TRAP1 upregulation or high glycolytic metabolism impairs cetuximab activity in vitro, whereas TRAP1 targeting and/or inhibition of glycolytic pathway enhances cell response to cetuximab. Finally, a linear correlation between F-FDG PET uptake and poor response to cetuximab in first-line therapy in human metastatic CRCs was observed. These results suggest that TRAP1 is a key determinant of CRC metabolic rewiring and favors resistance to EGFR inhibitors through regulation of glycolytic metabolism.
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http://dx.doi.org/10.1002/1878-0261.12814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718945PMC
December 2020

Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment-Current State and Future Perspectives.

Molecules 2020 Aug 18;25(16). Epub 2020 Aug 18.

Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture (PZ), Italy.

Cholangiocarcinoma is a primary malignancy of the biliary tract characterized by late and unspecific symptoms, unfavorable prognosis, and few treatment options. The advent of next-generation sequencing has revealed potential targetable or actionable molecular alterations in biliary tumors. Among several identified genetic alterations, the mutation is arousing interest due to its role in epigenetic and metabolic remodeling. Indeed, some point mutations induce widespread epigenetic alterations by means of a gain-of-function of the enzyme, which becomes able to produce the oncometabolite 2-hydroxyglutarate, with inhibitory activity on α-ketoglutarate-dependent enzymes, such as DNA and histone demethylases. Thus, its accumulation produces changes in the expression of several key genes involved in cell differentiation and survival. At present, small-molecule inhibitors of mutated enzyme are under investigation in preclinical and clinical phases as promising innovative treatments for IDH1-mutated intrahepatic cholangiocarcinomas. This review examines the molecular rationale and the results of preclinical and early-phase studies on novel pharmacological agents targeting mutant in cholangiocarcinoma patients. Contextually, it will offer a starting point for discussion on combined therapies with metabolic and epigenetic drugs, to provide molecular support to target the interplay between metabolism and epigenetics, two hallmarks of cancer onset and progression.
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http://dx.doi.org/10.3390/molecules25163754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464324PMC
August 2020

Cholesterol Homeostasis Modulates Platinum Sensitivity in Human Ovarian Cancer.

Cells 2020 03 30;9(4). Epub 2020 Mar 30.

Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.

Despite initial chemotherapy response, ovarian cancer is the deadliest gynecologic cancer, due to frequent relapse and onset of drug resistance. To date, there is no affordable diagnostic/prognostic biomarker for early detection of the disease. However, it has been recently shown that high grade serous ovarian cancers show peculiar oxidative metabolism, which is in turn responsible for inflammatory response and drug resistance. The molecular chaperone TRAP1 plays pivotal roles in such metabolic adaptations, due to the involvement in the regulation of mitochondrial respiration. Here, we show that platinum-resistant ovarian cancer cells also show reduced cholesterol biosynthesis, and mostly rely on the uptake of exogenous cholesterol for their needs. Expression of FDPS and OSC, enzymes involved in cholesterol synthesis, are decreased both in drug-resistant cells and upon TRAP1 silencing, whereas the expression of LDL receptor, the main mediator of extracellular cholesterol uptake, is increased. Strikingly, treatment with statins to inhibit cholesterol synthesis reduces cisplatin-induced apoptosis, whereas silencing of LIPG, an enzyme involved in lipid metabolism, or withdrawal of lipids from the culture medium, increases sensitivity to the drug. These results suggest caveats for the use of statins in ovarian cancer patients and highlights the importance of lipid metabolism in ovarian cancer treatment.
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http://dx.doi.org/10.3390/cells9040828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226826PMC
March 2020

Modulation of Mitochondrial Metabolic Reprogramming and Oxidative Stress to Overcome Chemoresistance in Cancer.

Biomolecules 2020 01 14;10(1). Epub 2020 Jan 14.

Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.

Metabolic reprogramming, carried out by cancer cells to rapidly adapt to stress such as hypoxia and limited nutrient conditions, is an emerging concepts in tumor biology, and is now recognized as one of the hallmarks of cancer. In contrast with conventional views, based on the classical Warburg effect, these metabolic alterations require fully functional mitochondria and finely-tuned regulations of their activity. In turn, the reciprocal regulation of the metabolic adaptations of cancer cells and the microenvironment critically influence disease progression and response to therapy. This is also realized through the function of specific stress-adaptive proteins, which are able to relieve oxidative stress, inhibit apoptosis, and facilitate the switch between metabolic pathways. Among these, the molecular chaperone tumor necrosis factor receptor associated protein 1 (TRAP1), the most abundant heat shock protein 90 (HSP90) family member in mitochondria, is particularly relevant because of its role as an oncogene or a tumor suppressor, depending on the metabolic features of the specific tumor. This review highlights the interplay between metabolic reprogramming and cancer progression, and the role of mitochondrial activity and oxidative stress in this setting, examining the possibility of targeting pathways of energy metabolism as a therapeutic strategy to overcome drug resistance, with particular emphasis on natural compounds and inhibitors of mitochondrial HSP90s.
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http://dx.doi.org/10.3390/biom10010135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023176PMC
January 2020

Comparative Gene Expression Profiling of Tobacco-Associated HPV-Positive versus Negative Oral Squamous Carcinoma Cell Lines.

Int J Med Sci 2020 1;17(1):112-124. Epub 2020 Jan 1.

Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.

HPV-positive oral squamous cell carcinomas (OSCCs) are specific biological and clinical entities, characterized by a more favorable prognosis compared to HPV-negative OSCCs and occurring generally in non-smoking and non-drinking younger individuals. However, poor information is available on the molecular and the clinical behavior of HPV-positive oral cancers occurring in smoking/drinking subjects. Thus, this study was designed to compare, at molecular level, two OSCC cell lines, both derived from drinking and smoking individuals and differing for presence/absence of HPV infection. HPV-negative UPCI-SCC-131 and HPV16-positive UPCI-SCC-154 cell lines were compared by whole genome gene expression profiling and subsequently studied for activation of Wnt/βCatenin signaling pathway by the expression of several Wnt-target genes, βCatenin intracellular localization, stem cell features and miRNA let-7e. Gene expression data were validated in head and neck squamous cell carcinoma (HNSCC) public datasets. Gene expression analysis identified Wnt/βCatenin pathway as the unique signaling pathway more active in HPV-negative compared to HPV-positive OSCC cells and this observation was confirmed upon evaluation of several Wnt-target genes (i.e., and ). Interestingly, HPV-negative OSCC cells showed higher levels of total βCatenin and its active form, increase of its nuclear accumulation and more prominent stem cell traits. Furthermore, miRNA let-7e was identified as potential upstream regulator responsible for the downregulation of Wnt/βCatenin signaling cascade since its silencing in UPCI-SCC-154 cell resulted in upregulation of Wnt-target genes. Finally, the analysis of two independent gene expression public datasets of human HNSCC cell lines and tumors confirmed that Wnt/βCatenin pathway is more active in HPV-negative compared to HPV-positive tumors derived from individuals with smoking habit. These data suggest that lack of HPV infection is associated with more prominent activation of Wnt/βCatenin signaling pathway and gain of stem-like traits in tobacco-related OSCCs.
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http://dx.doi.org/10.7150/ijms.35133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945558PMC
October 2020

Gene Copy Number and Post-Transductional Mechanisms Regulate TRAP1 Expression in Human Colorectal Carcinomas.

Int J Mol Sci 2019 Dec 24;21(1). Epub 2019 Dec 24.

Laboratory of Preclinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Via Padre Pio 1, 85028 Rionero in Vulture, Italy.

Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1) is a heat shock protein 90 (HSP90) molecular chaperone overexpressed in 60-70% human colorectal carcinomas (CRCs) and the co-upregulation of TRAP1 and associated 6-related proteins identifies metastatic CRCs with poor prognosis. Since the molecular mechanisms responsible for TRAP1 regulation are still unknown, the significance of gene copy number (CN) and the role of post-transductional protein modifications were addressed. gene aneuploidy accounted for 34.5% of cases in a cohort of 58 human CRCs and CN correlated with its mRNA and protein expression, suggesting that transcriptional mechanisms are responsible for TRAP1 upregulation. Furthermore, the analysis of the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium/The Cancer Genome Atlas (CPTAC/TCGA) CRC database showed that polysomy significantly correlates with lymph node involvement. However, a subgroup of tumors showed TRAP1 protein levels independent from its CN. Of note, a direct correlation was observed between TRAP1 protein levels and the expression of S-nitrosoglutathione reductase (GSNOR), a denitrosylase involved in the regulation of protein S-nitrosylation. Furthermore, CRC cell lines exposed to hypoxia or dichloroacetate treatment showed the downregulation of TRAP1 upon GSNOR silencing and this resulted in increased TRAP1 mono/polyubiquitination. These data suggest that transcriptional and post-transductional mechanisms account for TRAP1 expression in human CRCs and GSNOR protects TRAP1 from S-nitrosylation and consequent proteasome degradation mostly in conditions of stress.
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http://dx.doi.org/10.3390/ijms21010145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981705PMC
December 2019

Heat shock proteins in thyroid malignancies: Potential therapeutic targets for poorly-differentiated and anaplastic tumours?

Mol Cell Endocrinol 2020 02 6;502:110676. Epub 2019 Dec 6.

Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy; Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy. Electronic address:

Thyroid cancer is the most common endocrine malignancy, with well-differentiated subtypes characterized by an excellent prognosis due to their optimal sensitivity to standard therapies whereas poorly differentiated and anaplastic tumours by chemo/radio-resistance and unfavourable outcome. Heat Shock Proteins (HSPs) are molecular chaperones overexpressed in thyroid malignancies and involved in crucial functions responsible for thyroid carcinogenesis, as protection from apoptosis, drug resistance and cell migration. Thus, HSPs inhibitors have been proposed as novel therapeutic agents in thyroid cancer to revert molecular mechanisms of tumour progression. In this review, we report an overview on the biological role of HSPs, and specifically HSP90s, in thyroid cancer and their potential involvement as biomarkers. We discuss the rationale to evaluate HSPs inhibitors as innovative anticancer agents in specific subtypes of thyroid cancer characterized by poor response to therapies with the objective to target single family chaperones to reduce, simultaneously, the expression/stability of multiple client proteins.
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http://dx.doi.org/10.1016/j.mce.2019.110676DOI Listing
February 2020

BRAF Inhibitors in Thyroid Cancer: Clinical Impact, Mechanisms of Resistance and Future Perspectives.

Cancers (Basel) 2019 Sep 18;11(9). Epub 2019 Sep 18.

Laboratory of Pre-Clinical and Translational Research, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, 85100 Potenza, Italy.

The Kirsten rat sarcoma viral oncogene homolog (RAS)/v-raf-1 murine leukemia viral oncogene homolog 1 (RAF)/mitogen-activated protein kinase 1 (MAPK) signaling cascade is the most important oncogenic pathway in human cancers. Tumors leading mutations in the gene encoding for v-raf murine sarcoma viral oncogene homolog B (BRAF) serine-threonine kinase are reliant on the MAPK signaling pathway for their growth and survival. Indeed, the constitutive activation of MAPK pathway results in continuous stimulation of cell proliferation, enhancement of the apoptotic threshold and induction of a migratory and metastatic phenotype. In a clinical perspective, this scenario opens to the possibility of targeting BRAF pathway for therapy. Thyroid carcinomas (TCs) bearing BRAF mutations represent approximately 29-83% of human thyroid malignancies and, differently from melanomas, are less sensitive to BRAF inhibitors and develop primary or acquired resistance due to mutational events or activation of alternative signaling pathways able to reactivate ERK signaling. In this review, we provide an overview on the current knowledge concerning the mechanisms leading to resistance to BRAF inhibitors in human thyroid carcinomas and discuss the potential therapeutic strategies, including combinations of BRAF inhibitors with other targeted agents, which might be employed to overcome drug resistance and potentiate the activity of single agent BRAF inhibitors.
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http://dx.doi.org/10.3390/cancers11091388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770736PMC
September 2019

Metabolic Dysregulations and Epigenetics: A Bidirectional Interplay that Drives Tumor Progression.

Cells 2019 07 30;8(8). Epub 2019 Jul 30.

Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata,85028 Rionero in Vulture, PZ, Italy.

Cancer has been considered, for a long time, a genetic disease where mutations in keyregulatory genes drive tumor initiation, growth, metastasis, and drug resistance. Instead, theadvent of high-throughput technologies has revolutionized cancer research, allowing to investigatemolecular alterations at multiple levels, including genome, epigenome, transcriptome, proteome,and metabolome and showing the multifaceted aspects of this disease. The multi-omics approachesrevealed an intricate molecular landscape where different cellular functions are interconnected andcooperatively contribute to shaping the malignant phenotype. Recent evidence has brought to lighthow metabolism and epigenetics are highly intertwined, and their aberrant crosstalk can contributeto tumorigenesis. The oncogene-driven metabolic plasticity of tumor cells supports the energeticand anabolic demands of proliferative tumor programs and secondary can alter the epigeneticlandscape via modulating the production and/or the activity of epigenetic metabolites. Conversely,epigenetic mechanisms can regulate the expression of metabolic genes, thereby altering themetabolome, eliciting adaptive responses to rapidly changing environmental conditions, andsustaining malignant cell survival and progression in hostile niches. Thus, cancer cells takeadvantage of the epigenetics-metabolism crosstalk to acquire aggressive traits, promote cellproliferation, metastasis, and pluripotency, and shape tumor microenvironment. Understandingthis bidirectional relationship is crucial to identify potential novel molecular targets for theimplementation of robust anti-cancer therapeutic strategies.
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http://dx.doi.org/10.3390/cells8080798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721562PMC
July 2019

Heat shock proteins in cancer stem cell maintenance: A potential therapeutic target?

Histol Histopathol 2020 Jan 19;35(1):25-37. Epub 2019 Jul 19.

Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy.

Cancer stem cells (CSCs) are a subpopulation of tumor cells with unlimited self-renewal capability, multilineage differentiation potential and long-term tumor repopulation capacity. CSCs reside in anatomically distinct regions within the tumor microenvironment, called niches, and this favors the maintenance of CSC properties and preserves their phenotypic plasticity. Indeed, CSCs are characterized by a flexible state based on their capacity to interconvert between a differentiated and a stem-like phenotype, and this depends on the activation of adaptive mechanisms in response to different environmental conditions. Heat Shock Proteins (HSPs) are molecular chaperones, upregulated upon cell exposure to several stress conditions and are responsible for normal maturation, localization and activity of intra and extracellular proteins. Noteworthy, HSPs play a central role in several cellular processes involved in tumor initiation and progression (i.e. cell viability, resistance to apoptosis, stress conditions and drug therapy, EMT, bioenergetics, invasiveness, metastasis formation) and, thus, are widely considered potential molecular targets. Furthermore, much evidence suggests a key regulatory function for HSPs in CSC maintenance and their upregulation has been proposed as a mechanism used by CSCs to adapt to unfavorable environmental conditions, such as nutrient deprivation, hypoxia, inflammation. This review discusses the relevance of HSPs in CSC biology, highlighting their role as novel potential molecular targets to develop anticancer strategies aimed at CSC targeting.
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http://dx.doi.org/10.14670/HH-18-153DOI Listing
January 2020

HSP90 Molecular Chaperones, Metabolic Rewiring, and Epigenetics: Impact on Tumor Progression and Perspective for Anticancer Therapy.

Cells 2019 06 3;8(6). Epub 2019 Jun 3.

Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, Italy.

Heat shock protein 90 (HSP90) molecular chaperones are a family of ubiquitous proteins participating in several cellular functions through the regulation of folding and/or assembly of large multiprotein complexes and client proteins. Thus, HSP90s chaperones are, directly or indirectly, master regulators of a variety of cellular processes, such as adaptation to stress, cell proliferation, motility, angiogenesis, and signal transduction. In recent years, it has been proposed that HSP90s play a crucial role in carcinogenesis as regulators of genotype-to-phenotype interplay. Indeed, HSP90 chaperones control metabolic rewiring, a hallmark of cancer cells, and influence the transcription of several of the key-genes responsible for tumorigenesis and cancer progression, through either direct binding to chromatin or through the quality control of transcription factors and epigenetic effectors. In this review, we will revise evidence suggesting how this interplay between epigenetics and metabolism may affect oncogenesis. We will examine the effect of metabolic rewiring on the accumulation of specific metabolites, and the changes in the availability of epigenetic co-factors and how this process can be controlled by HSP90 molecular chaperones. Understanding deeply the relationship between epigenetic and metabolism could disclose novel therapeutic scenarios that may lead to improvements in cancer treatment.
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http://dx.doi.org/10.3390/cells8060532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627532PMC
June 2019

Radium-223 for the treatment of bone metastases in castration-resistant prostate cancer: when and why.

Tumori 2019 Oct 16;105(5):367-377. Epub 2019 May 16.

Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Centro di Riferimento Oncologico della Basilicata (CROB), Rionero in Vulture, Italy.

Radium-223 dichloride (Ra) is the first, recently approved, α-particle-emitting radiopharmaceutical for the treatment of patients with bone metastases in castration-resistant prostate cancer (CRPC) and no evidence of visceral metastases. We explored MEDLINE, relevant congresses, and websites for data on Ra and prostate cancer therapies, focusing on therapeutic strategies and timing, bone metastases, and diagnostic assessment. Ra represents the only bone-targeting agent that has significantly extended patients' overall survival while reducing pain and symptomatic skeletal events. Unlike other radiopharmaceuticals, such as strontium-89 and samarium-153 EDTMP, Ra (11.4-days half-life) has shown a high biological efficiency mainly due to its short penetration range. These features potentially allow reduced bone marrow toxicity and limit undue exposure. Ra has been validated under the product name Xofigo by the US Food and Drug Administration and the European Medicines Agency. Patient selection, management, and treatment sequencing is recommended to be discussed in the context of a multidisciplinary environment, including oncology, urology, nuclear medicine, and radiation therapy physicians. No consensus has been achieved regarding the optimal timing and its administration as single agent or in combination with zoledronic acid or chemotherapy, so far. This review aims to provide a rationale for the use of Ra in treating metastases from CRPC, highlighting the crucial role of a multidisciplinary approach, the disputed inclusion and exclusion criteria on the basis of agencies regulations, and the value of diagnostics for therapy assessment.
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http://dx.doi.org/10.1177/0300891619851376DOI Listing
October 2019

Endoplasmic Reticulum Stress and Unfolded Protein Response in Breast Cancer: The Balance between Apoptosis and Autophagy and Its Role in Drug Resistance.

Int J Mol Sci 2019 Feb 16;20(4). Epub 2019 Feb 16.

Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy.

The unfolded protein response (UPR) is a stress response activated by the accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER) and its uncontrolled activation is mechanistically responsible for several human pathologies, including metabolic, neurodegenerative, and inflammatory diseases, and cancer. Indeed, ER stress and the downstream UPR activation lead to changes in the levels and activities of key regulators of cell survival and autophagy and this is physiologically finalized to restore metabolic homeostasis with the integration of pro-death or/and pro-survival signals. By contrast, the chronic activation of UPR in cancer cells is widely considered a mechanism of tumor progression. In this review, we focus on the relationship between ER stress, apoptosis, and autophagy in human breast cancer and the interplay between the activation of UPR and resistance to anticancer therapies with the aim to disclose novel therapeutic scenarios. The hypothesis that autophagy and UPR may provide novel molecular targets in human malignancies is discussed.
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http://dx.doi.org/10.3390/ijms20040857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412864PMC
February 2019

Protein Syndesmos is a novel RNA-binding protein that regulates primary cilia formation.

Nucleic Acids Res 2018 12;46(22):12067-12086

Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Napoli, Italy.

Syndesmos (SDOS) is a functionally poorly characterized protein that directly interacts with p53 binding protein 1 (53BP1) and regulates its recruitment to chromatin. We show here that SDOS interacts with another important cancer-linked protein, the chaperone TRAP1, associates with actively translating polyribosomes and represses translation. Moreover, we demonstrate that SDOS directly binds RNA in living cells. Combining individual gene expression profiling, nucleotide crosslinking and immunoprecipitation (iCLIP), and ribosome profiling, we discover several crucial pathways regulated post-transcriptionally by SDOS. Among them, we identify a small subset of mRNAs responsible for the biogenesis of primary cilium that have been linked to developmental and degenerative diseases, known as ciliopathies, and cancer. We discover that SDOS binds and regulates the translation of several of these mRNAs, controlling cilia development.
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http://dx.doi.org/10.1093/nar/gky873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294507PMC
December 2018

Adjuvant treatment for EGFR-mutated non-small cell lung cancer: do we have a major breakthrough?

J Thorac Dis 2018 Jul;10(Suppl 18):S2114-S2118

Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.

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http://dx.doi.org/10.21037/jtd.2018.06.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072936PMC
July 2018

IL6/STAT3 axis mediates resistance to BRAF inhibitors in thyroid carcinoma cells.

Cancer Lett 2018 10 2;433:147-155. Epub 2018 Jul 2.

Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy; Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy. Electronic address:

Thyroid carcinomas (TCs) bearing BRAF mutations represent approximately 26-53% of human thyroid malignancies and, differently from melanomas, are poorly sensitive to BRAF inhibitors (BRAFi), and develop acquired resistance through activation of alternative signaling pathways. A whole-genome gene expression analysis of TC BRAF V600E cells exposed to PLX4032 identified JAK/STAT among the most significantly modulated signaling pathways. Interestingly, both transient exposure and chronic adaptation to PLX4032 resulted in upregulation of IL6/STAT3 axis and this impaired the cytostatic activity of PLX4032. Mechanistically, exposure to PLX4032 enhanced IL6 secretion and this, in turn, was responsible for STAT3 upregulation, activation of ERK signaling and poor sensitivity to BRAF inhibition. Consistently, the dual blockade of STAT3 (by siRNA or pharmacological inhibition) or IL6 signaling (by the humanized anti-human IL6 receptor antibody, tocilizumab) and BRAF (by PLX4032) improved the inhibition of cell cycle progression compared to PLX4032 single agent. These data support the role of IL6/STAT3 signaling pathway in modulating TC cell response to PLX4032 and candidate IL6 targeting as a strategy to improve the activity of PLX4032 in BRAF V600E TC cells.
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http://dx.doi.org/10.1016/j.canlet.2018.06.038DOI Listing
October 2018

Cyclin-dependent kinase 1 targeting improves sensitivity to radiation in BRAF V600E colorectal carcinoma cells.

Tumour Biol 2018 Apr;40(4):1010428318770957

1 Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.

Objectives: Preoperative chemoradiation is currently the standard of care in locally advanced rectal carcinoma, even though a subset of rectal tumors does not achieve major clinically meaningful responses upon neoadjuvant chemoradiation. At present, no molecular biomarkers are available to predict response to neoadjuvant chemoradiation and select resistant tumors willing more intense therapeutic strategies. Thus, BRAF mutational status was investigated for its role in favoring resistance to radiation in colorectal carcinoma cell lines and cyclin-dependent kinase 1 as a target to improve radiosensitivity in BRAF V600E colorectal tumor cells.

Methods: Colony-forming assay and apoptotic rates were evaluated to compare the sensitivity of different colon carcinoma cell lines to ionizing radiation and their radiosensitivity upon exposure to BRAF and/or cyclin-dependent kinase 1 inhibitory/silencing strategies. Cyclin-dependent kinase 1 expression/subcellular distribution was studied by immunoblot analysis.

Results: Colon carcinoma BRAF V600E HT29 cells exhibited poor response to radiation compared to BRAF wild-type COLO320 and HCT116 cells. Interestingly, neither radiosensitizing doses of 5-fluoruracil nor BRAF inhibition/silencing significantly improved radiosensitivity in HT29 cells. Of note, poor response to radiation correlated with upregulation/relocation of cyclin-dependent kinase 1 in mitochondria. Consistently, cyclin-dependent kinase 1 inhibition/silencing as well as its targeting, through inhibition of HSP90 quality control pathway, significantly inhibited the clonogenic ability and increased apoptotic rates in HT29 cells upon exposure to radiation.

Conclusion: These data suggest that BRAF V600E colorectal carcinoma cells are poorly responsive to radiation, and cyclin-dependent kinase 1 represents a target to improve radiosensitivity in BRAF V600E colorectal tumor cells.
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http://dx.doi.org/10.1177/1010428318770957DOI Listing
April 2018

TRAP1 Regulation of Cancer Metabolism: Dual Role as Oncogene or Tumor Suppressor.

Genes (Basel) 2018 Apr 5;9(4). Epub 2018 Apr 5.

Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.

Metabolic reprogramming is an important issue in tumor biology. An unexpected inter- and intra-tumor metabolic heterogeneity has been strictly correlated to tumor outcome. Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1) is a molecular chaperone involved in the regulation of energetic metabolism in cancer cells. This protein is highly expressed in several cancers, such as glioblastoma, colon, breast, prostate and lung cancers and is often associated with drug resistance. However, TRAP1 is also downregulated in specific tumors, such as ovarian, bladder and renal cancers, where its lower expression is correlated with the worst prognoses and chemoresistance. TRAP1 is the only mitochondrial member of the Heat Shock Protein 90 (HSP90) family that directly interacts with respiratory complexes, contributing to their stability and activity but it is still unclear if such interactions lead to reduced or increased respiratory capacity. The role of TRAP1 is to enhance or suppress oxidative phosphorylation; the effects of such regulation on tumor development and progression are controversial. These observations encourage the study of the mechanisms responsible for the dualist role of TRAP1 as an oncogene or oncosuppressor in specific tumor types. In this review, TRAP1 puzzling functions were recapitulated with a special focus on the correlation between metabolic reprogramming and tumor outcome. We wanted to investigate whether metabolism-targeting drugs can efficiently interfere with tumor progression and whether they might be combined with chemotherapeutics or molecular-targeted agents to counteract drug resistance and reduce therapeutic failure.
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http://dx.doi.org/10.3390/genes9040195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924537PMC
April 2018

Uncommon frame-shift exon 19 EGFR mutations are sensitive to EGFR tyrosine kinase inhibitors in non-small cell lung carcinoma.

Med Oncol 2018 Jan 31;35(3):28. Epub 2018 Jan 31.

Laboratory of Pre-clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Via Padre Pio, 1, 85028, Rionero in Vulture, PZ, Italy.

Exons 19-21 EGFR activating mutations are predictive biomarkers of response to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, uncommon exon 19 EGFR mutations, due to their low frequency, have an uncertain biological and clinical significance and very little is known about their TKI sensitivity. This study was designed to describe the TKI sensitivity of a small cohort of lung adenocarcinomas bearing uncommon exon 19 mutations and to evaluate in silico the correlation between frame-shift exon 19 mutations and EGFR sequence/structure modification. Among 1168 NSCLCs screened for EGFR mutational status in our Institutions between 2011 and 2016, seven uncommon exon 19 EGFR mutations were further evaluated: five complex mutations, characterized by a deletion followed by a single-nucleotide insertion, a macrodeletion of 25 bp, and a 19 bp duplication. Interestingly, three patients harboring frame-shift mutations (i.e., one complex mutation, the macrodeletion, and the duplication) showed disease stability and considerably long PFS and OS upon TKI therapy. By contrast, three patients with in-frame complex deletions, independently of the mutation starting point, showed poor/lack of response to TKI therapy. In silico structural analysis showed that sensitivity to TKIs correlates with structural changes in the length and conformation of EGFR C-helix in frame-shift mutations. These data suggest that not all uncommon exon 19 EGFR mutations have the same TKI sensitivity and that frame-shift mutations are responsive to TKIs therapy.
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http://dx.doi.org/10.1007/s12032-018-1078-7DOI Listing
January 2018

Bladder Metastases from Breast Cancer: Managing the Unexpected. A Systematic Review.

Urol Int 2018 20;101(2):125-131. Epub 2017 Oct 20.

Department of Urology and Renal Transplantation, University Hospital, Foggia, Italy.

Breast cancer (BrC) has the highest incidence among females world over and it is one of the most common causes of death from cancer overall. Its high mortality is mostly due to its propensity to rapidly spread to other organs through lymphatic and blood vessels in spite of proper treatment. Bladder metastases from BrC are rare, with 50 cases having been reported in the last 60 years. This review aims to discuss some critical points regarding this uncommon condition. First, we performed a systematic review of the literature in order to draw a clinical and pathological profile of this entity. On this basis, its features in terms of diagnostic issues, imaging techniques, and survival are critically examined. Most bladder metastases from BrC are secondary lobular carcinoma, which mimic very closely the rare variant of urothelial cancer with lobular carcinoma-like features (uniform cells with an uncohesive single-cell, diffusely invasive growth pattern); thus, immunohistochemistry is mandatory to arrive at a correct diagnosis. This article summarizes the current knowledge regarding the incidence, clinical presentation, diagnosis, prognosis, and treatment of bladder metastases in patients with BrC.
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http://dx.doi.org/10.1159/000481576DOI Listing
December 2018

Dual EGFR and BRAF blockade overcomes resistance to vemurafenib in BRAF mutated thyroid carcinoma cells.

Cancer Cell Int 2017 4;17:86. Epub 2017 Oct 4.

Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Via Padre Pio, 1, Rionero in Vulture, 85028 Italy.

Background: BRAF inhibitors are effective anticancer agents in BRAF-mutated melanomas. By contrast, evidences about sensitivity of thyroid carcinomas to BRAF inhibition are conflicting and it has been proposed that BRAF V600E thyroid carcinoma cells are less sensitive to BRAF inhibitors due to activation of parallel signaling pathways. This study evaluated the hypothesis that feedback activation of EGFR signaling counteracts the cytostatic activity of vemurafenib (PLX4032) in BRAF V600E thyroid carcinoma cells.

Methods: Cell proliferation, cell cycle distribution, induction of apoptosis and EGFR and AKT signaling were evaluated in thyroid carcinoma cell lines bearing the BRAF V600E mutation in response to PLX4032.

Results: A partial and transient cytostatic response to PLX4032 was observed in thyroid carcinoma cell lines bearing the BRAF V600E mutation, with lack of full inhibition of ERK pathway. Interestingly, the exposure of thyroid carcinoma cells to PLX4032 resulted in a rapid feedback activation of EGFR signaling with parallel activation of AKT phosphorylation. Consistently, the dual inhibition of EGFR and BRAF, through combination therapy with PLX4032 and gefitinib, resulted in prevention of EGFR phosphorylation and sustained inhibition of ERK and AKT signaling and cell proliferation. Of note, the combined treatment with gefitinib and vemurafenib or the exposure of EGFR-silenced thyroid carcinoma cells to vemurafenib induced synthetic lethality compared to single agents.

Conclusions: These data suggest that the dual EGFR and BRAF blockade represents a strategy to by-pass resistance to BRAF inhibitors in thyroid carcinoma cells.
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http://dx.doi.org/10.1186/s12935-017-0457-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628448PMC
October 2017

Human monocyte-derived dendritic cells exposed to hyperthermia show a distinct gene expression profile and selective upregulation of .

Oncotarget 2017 Sep 1;8(37):60826-60840. Epub 2017 Jun 1.

Institute of Haematology, University of Perugia, Perugia, Italy.

Fever plays a role in activating innate immunity while its relevance in activating adaptive immunity is less clear. Even brief exposure to elevated temperatures significantly impacts on the immunostimulatory capacity of dendritic cells (DCs), but the consequences on immune response remain unclear. To address this issue, we analyzed the gene expression profiles of normal human monocyte-derived DCs from nine healthy adults subjected either to fever-like thermal conditions (39°C) or to normal temperature (37°C) for 180 minutes. Exposure of DCs to 39°C caused upregulation of 43 genes and downregulation of 24 genes. Functionally, the up/downregulated genes are involved in post-translational modification, protein folding, cell death and survival, and cellular movement. Notably, when compared to monocytes, DCs differentially upregulated transcription of the secreted protein IGFBP-6, not previously known to be specifically linked to hyperthermia. Exposure of DCs to 39°C induced apoptosis/necrosis and resulted in accumulation of IGFBP-6 in the conditioned medium at 48 h. IGFBP-6 may have a functional role in the hyperthermic response as it induced chemotaxis of monocytes and T lymphocytes, but not of B lymphocytes. Thus, temperature regulates complex biological DC functions that most likely contribute to their ability to induce an efficient adaptive immune response.
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http://dx.doi.org/10.18632/oncotarget.18338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617388PMC
September 2017

TRAP1 controls cell cycle G2-M transition through the regulation of CDK1 and MAD2 expression/ubiquitination.

J Pathol 2017 09 9;243(1):123-134. Epub 2017 Aug 9.

Laboratory of Pre-clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.

Regulation of tumour cell proliferation by molecular chaperones is still a complex issue. Here, the role of the HSP90 molecular chaperone TRAP1 in cell cycle regulation was investigated in a wide range of human breast, colorectal, and lung carcinoma cell lines, and tumour specimens. TRAP1 modulates the expression and/or the ubiquitination of key cell cycle regulators through a dual mechanism: (i) transcriptional regulation of CDK1, CYCLIN B1, and MAD2, as suggested by gene expression profiling of TRAP1-silenced breast carcinoma cells; and (ii) post-transcriptional quality control of CDK1 and MAD2, being the ubiquitination of these two proteins enhanced upon TRAP1 down-regulation. Mechanistically, TRAP1 quality control on CDK1 is crucial for its regulation of mitotic entry, since TRAP1 interacts with CDK1 and prevents CDK1 ubiquitination in cooperation with the proteasome regulatory particle TBP7, this representing the limiting factor in TRAP1 regulation of the G2-M transition. Indeed, TRAP1 silencing results in enhanced CDK1 ubiquitination, lack of nuclear translocation of CDK1/cyclin B1 complex, and increased MAD2 degradation, whereas CDK1 forced up-regulation partially rescues low cyclin B1 and MAD2 levels and G2-M transit in a TRAP1-poor background. Consistently, the CDK1 inhibitor RO-3306 is less active in a TRAP1-high background. Finally, a significant correlation was observed between TRAP1 and Ki67, CDK1 and/or MAD2 expression in breast, colorectal, and lung human tumour specimens. This study represents the first evidence that TRAP1 is relevant in the control of the complex machinery that governs cell cycle progression and mitotic entry and provides a strong rationale to regard TRAP1 as a biomarker to select tumours with deregulated cell cycle progression and thus likely poorly responsive to novel cell cycle inhibitors. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4936DOI Listing
September 2017

TRAP1: a viable therapeutic target for future cancer treatments?

Expert Opin Ther Targets 2017 08 18;21(8):805-815. Epub 2017 Jul 18.

a Laboratory of Pre-Clinical and Translational Research , IRCCS, Referral Cancer Center of Basilicata , Rionero in Vulture , Italy.

Introduction: HSP90 molecular chaperones (i.e., HSP90α, HSP90β, GRP94 and TRAP1) are potential therapeutic targets to design novel anticancer agents. However, despite numerous designed HSP90 inhibitors, most of them have failed due to unfavorable toxicity profiles and lack of specificity toward different HSP90 paralogs. Indeed, a major limitation in this field is the high structural homology between different HSP90 chaperones, which significantly limits our capacity to design paralog-specific inhibitors. Area covered: This review examines the relevance of TRAP1 in tumor development and progression, with an emphasis on its oncogenic/oncosuppressive role in specific human malignancies and its multifaceted and context-dependent functions in cancer cells. Herein, we discuss the rationale for considering TRAP1 as a potential molecular target and the strategies used to date, to achieve its compartmentalized inhibition directly in mitochondria. Expert opinion: TRAP1 targeting may represent a promising strategy for cancer therapy, based on the increasing and compelling evidence supporting TRAP1 involvement in human carcinogenesis. However, considering the complexity of TRAP1 biology, future strategies of drug discovery need to improve selectivity and specificity toward TRAP1 respect to other HSP90 paralogs. The characterization of specific human malignancies suitable for TRAP1 targeting is also mandatory.
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http://dx.doi.org/10.1080/14728222.2017.1349755DOI Listing
August 2017

Stress-Adaptive Response in Ovarian Cancer Drug Resistance: Role of TRAP1 in Oxidative Metabolism-Driven Inflammation.

Adv Protein Chem Struct Biol 2017 12;108:163-198. Epub 2017 Feb 12.

Università di Napoli Federico II, Napoli, Italy. Electronic address:

Metabolic reprogramming is one of the most frequent stress-adaptive response of cancer cells to survive environmental changes and meet increasing nutrient requirements during their growth. These modifications involve cellular bioenergetics and cross talk with surrounding microenvironment, in a dynamic network that connect different molecular processes, such as energy production, inflammatory response, and drug resistance. Even though the Warburg effect has long been considered the main metabolic feature of cancer cells, recent reports identify mitochondrial oxidative metabolism as a driving force for tumor growth in an increasing number of cellular contexts. In recent years, oxidative phosphorylation has been linked to a remodeling of inflammatory response due to autocrine or paracrine secretion of interleukines that, in turn, induces a regulation of gene expression involving, among others, molecules responsible for the onset of drug resistance. This process is especially relevant in ovarian cancer, characterized by low survival, high frequency of disease relapse and chemoresistance. Recently, the molecular chaperone TRAP1 (tumor necrosis factor-associated protein 1) has been identified as a key junction molecule in these processes in ovarian cancer: in fact, TRAP1 mediates a metabolic switch toward oxidative phosphorylation that, in turn, triggers cytokines secretion, with consequent gene expression remodeling, finally leading to cisplatin resistance and epithelial-to-mesenchymal transition in ovarian cancer models. This review summarizes how metabolism, chemoresistance, inflammation, and epithelial-to-mesenchymal transition are strictly interconnected, and how TRAP1 stays at the crossroads of these processes, thus shedding new lights on molecular networks at the basis of ovarian cancer.
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http://dx.doi.org/10.1016/bs.apcsb.2017.01.004DOI Listing
October 2017

ALK rearrangement in specific subtypes of lung adenocarcinoma: immunophenotypic and morphological features.

Med Oncol 2017 May 31;34(5):76. Epub 2017 Mar 31.

Pathology Unit, IRCCS, Referral Cancer Center of Basilicata, 85028, Rionero in Vulture, Italy.

Lung adenocarcinomas are characterized by a variety of genetic and epigenetic changes that lead to activation of specific signaling pathways. This allowed the classification of lung adenocarcinomas according to genetic alterations and the clinical development of novel anticancer agents that affect the activity of specific oncoproteins. In such a context, chromosomal rearrangements that cause constitutive activation of ALK gene define a category of lung adenocarcinomas that is amenable to targeted therapy with ALK inhibitors. Thus, a major issue of current research is to define the morphological and immunophenotypic features of lung ALK-rearranged adenocarcinomas to improve the selection of tumors suitable for molecular genotyping. ALK status was determined, by immunohistochemistry and fluorescence in situ hybridization, in 94 surgically resected lung adenocarcinomas and correlated with histomorphological parameters. Indeed, ALK rearrangement was observed in 10/94 (11%) lung adenocarcinomas and enriched in tumors with a predominant mucinous (46%; p < 0.05) and solid (29%; p < 0.05) pattern. By contrast, it was lacking or sporadically observed in lung adenocarcinomas with predominant acinar, papillary or lepidic pattern. Moreover, the presence of signet-ring cells was predominantly observed in ALK-rearranged tumors (47%; p < 0.05). These data suggest that ALK rearrangement is associated with specific and distinct clinical-pathological characters compared to other genotypes. Thus, the knowledge of these characteristics can improve the diagnostic accuracy and lead to a better understanding of the behavior of ALK-rearranged NSCLC.
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http://dx.doi.org/10.1007/s12032-017-0936-zDOI Listing
May 2017
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