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  • American Association for Cancer Research (AACR)  (8)
  • 1
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    Online Resource
    Abstract 5163: Characterization of NMS-E194, a selective and potent PERK inhibitor with efficacy in the KMS-11 multiple myeloma
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5163-5163
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5163-5163
    Abstract: PERK (PKR-like endoplasmic reticulum kinase) is a serine-threonine kinase associated to endoplasmic reticulum membrane. Together with ATF6 and IRE1, PERK is a key effector of the Unfolded Protein Response (UPR), a network of signaling pathways that ensures protein homeostasis in the endoplasmic reticulum. Multiple Myeloma (MM) and other protein-secreting tumors are highly dependent on UPR for survival, and inhibition of PERK may be an effective strategy to inhibit growth of these tumors. Here we describe the in vitro and in vivo properties of NMS-E194, a novel potent and selective ATP-competitive PERK inhibitor belonging to the arylsulfonamide chemical class. NMS-E194 inhibits PERK kinase with a Ki of ca 1.5 nM in biochemical assay and possesses high selectivity towards a panel of 54 kinases. When tested in cell proliferation assays, NMS-E194 is preferentially active on multiple myeloma (MM) and diffuse large B cell lymphoma cell lines. In mechanism of action studies, NMS-E194 shows a bi-phasic behaviour: at low nanomolar doses it activates PERK, causing ATF4 accumulation, while at & gt;200 nM it inhibits PERK and downstream pathway, inducing apoptosis. NMS-E194 possesses a favourable in vitro ADME profile and has promising PK properties in the mouse. NMS-E194 demonstrated strong anti-tumor activity following oral administration at 25 mg/kg daily to mice harbouring luciferized KMS-11 cells in a disseminated growth model of MM, with no overt toxicity. Overall, the data available so far warrant further development of NMS-E194 and support PERK inhibition as a novel therapeutic approach in MM and other PERK-dependent tumors. Citation Format: Claudia Perrera, Maurizio Pulici, Davide Carenzi, Ilaria Motto, Marina Fasolini, Elena Casale, Stefania Re Depaolini, Simona Rizzi, Daniela Asa, Fulvia Roletto, Simona Bindi, Daniele Casero, Patrizia Banfi, Elena Ardini, Nadia Amboldi, Dario Ballinari, Fabio Gasparri, Sabrina Cribioli, Laura Mancini, Marina Ciomei, Daniele Donati, Eduard Felder, Arturo Galvani, Antonella Isacchi, Barbara Valsasina. Characterization of NMS-E194, a selective and potent PERK inhibitor with efficacy in the KMS-11 multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5163. doi:10.1158/1538-7445.AM2017-5163
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-5163
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 2
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    Abstract CT025: NMS-03592088, a novel, potent FLT3, KIT and CSF1R inhibitor with activity in FLT3 positive acute myeloid leukemia patients with prior FLT3 inhibitor experience
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT025-CT025
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT025-CT025
    Abstract: Background: FLT3 mutations occur in approximately 30% of AML patients and are associated with aggressive disease. Despite the approval of midostaurin and gilteritinib, the prognosis for FLT3+ patients with relapsed or refractory disease is poor. NMS-088 is a novel, potent FLT3, KIT and CSF1R inhibitor with superior preclinical activity compared with approved FLT3 inhibitors in different FLT3-driven models. In addition, NMS-088 is active on FLT3 resistance mutation F691L. Dose escalation results from a Phase I/II study to establish safety, dose selection and preliminary clinical activity for NMS-088 in patients with R/R AML and CMML are described. Methods: In the Phase I 3+3 escalations, NMS-088 is administered daily for 21 of 28 days (schedule A) or continuously (schedule B). Patients must have R/R AML or CMML unsuitable for standard therapy. The primary objective is the MTD or MAD as assessed by DLTs. Secondary endpoints include safety, PK and ELN response. Results: as of January 26, 44 R/R AML or CMML patients were treated at doses from 20 to 360 mg/day in A or from 120 to 250 mg/day in B. Median age was 64 yrs, 41 pts had AML and 3 pts had CMML, median number of prior lines was 2 (range 1 to 10). FLT3 mutations were present in 24 out of 41 AML pts (20 FLT3-ITD, 2 FLT3 D835 and 2 FLT3-ITD and D835). The majority of pts with FLT3+ AML had received prior FLT3 inhibitors (86.4%). NMS-088 showed manageable safety with no MTD characterized. One pt had DLT (abnormal posture, decreased activity, dyspnea G3 and eyelid ptosis G1) at 360 mg in A (at day 21) and one pt had DLT (eyelid ptosis G3) at 180 mg in B (at day 29), both suggestive for myasthenic syndrome. Three additional pts experienced possible myasthenic syndrome at doses ≥ 180 mg. Overall the most frequent treatment emergent related adverse events (≥10%) were nausea (any grade 20.5%), vomiting (13.6%), asthenia (11.4%). Discontinuations due to related AEs were as follows: 2 DLT pts per protocol, 2 pts due to nausea (G1; day 161 at 270 mg) and myasthenia gravis (G3; day 39 at 300 mg in a pt with baseline AChR antibodies). There was a dose-dependent trend for response. A total of 5 out of 12 evaluable pts with FLT3+ AML treated at dose ≥ 300 mg achieved a response with 2 CRi, 1 CRi/MLFS and 2 MLFS. Remarkably, all these pts had received prior midostaurin and 2 pts received both midostaurin and gilteritinib. Two pts with response withdrew from treatment to receive HSCT (DoR 1.0+ mos each). For other responding pts DoR was 1.3, 2.8 and 7.9 mos. Conclusions: NMS-088 showed clinical efficacy in pts with FLT3+ R/R AML, including pts who have failed prior FLT3 inhibitors. Together with the manageable safety observed, these results warrant further development of this drug including potential as a novel valuable therapeutic option for pts who have exhausted available treatments. The trial is currently opened for enrollment (NTC03922100). Citation Format: Antonio Curti, Alessandro Rambaldi, Chiara Cattaneo, Roberto Cairoli, Matteo Della Porta, Patrizia Chiusolo, Federico Lussana, Marta Ubezio, Valentina Mancini, Isabel Cano, Carmen Besliu, Christian Hove Claussen, Rosalinda Gatto, Patrizia Crivori, Elena Colajori, Alessio Somaschini, Cristina Davite, Antonella Isacchi, Elena Ardini, Lisa Mahnke, Pau Montesinos. NMS-03592088, a novel, potent FLT3, KIT and CSF1R inhibitor with activity in FLT3 positive acute myeloid leukemia patients with prior FLT3 inhibitor experience [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT025.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-CT025
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 3
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    Abstract 4230: Targeting lung cancer stem cells through fatty acid metabolism
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4230-4230
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4230-4230
    Abstract: Distinctive features of CSC are capacity of self renewal, increased resistance to chemotherapy and the ability to form three dimensional non adherent spheroids in appropriate conditions. We have recently demonstrated that cell cultures derived from malignant pleural effusion (MPE’s) of patients with adenocarcinoma of the lung efficiently form spheroids in non-adherent conditions supplemented with growth factors. By expression profiling, we identified 18 genes whose expression is significantly upregulated in lung tumor spheroids versus adherent cultures. Among the upregulated genes we found five genes involved in lipid metabolism. SCD1, the enzyme involved in the conversion of saturated into monounsaturated fatty acids, was one of those strongly upregulated. We demonstrated that SCD1 inhibition leads to lung cancer spheroid collapse and to the selective apoptosis of ALDH+ cells, a marker enriched in cells with stem like properties. In line with these results we demonstrated by cell sorting that ALDH positive cells were more sensitive to SCD1 inhibition than ALDH negative cells and that treatment with an SCD1 inhibitor strongly enhanced sensitivity of spheroids cells to Cisplatin. Furthermore, we observed that SCD1 inhibited spheroids were strongly impaired in their in vivo tumorigenicity. Using public datasets from lung cancer we conducted a bioinformatics analysis demonstrating that the survival rate of patients expressing SCD1-high levels was significantly lower than that of the patients expressing low level in lung adenocarcinoma. Moreover, we found that the correlation of SCD1 and stemness markers (nanog, CD44, CD24) selects the patients with bad prognosis. These results overall, indicate that SCD1 could be considered a prognostic markers for lung adenocarcinoma and a potential target for therapeutic intervention. Our studies are currently directed to dissect the mechanism pathways leading to SCD1 upregulation in lung cancer stem cells. Citation Format: Alessia Noto, Maria Elena Pisanu, Claudia De Vitis, Debora Malpicci, Luigi Fattore, Nadia Lobello, Barbara Bonacci, Gennaro Ciliberto, Rita Mancini. Targeting lung cancer stem cells through fatty acid metabolism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4230. doi:10.1158/1538-7445.AM2015-4230
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-4230
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
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    Abstract 1052: Stearoyl-CoA-Desaturase (SCD1) regulates lung cancer stemness via stabilization and nuclear localization of YAP/TAZ
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 1052-1052
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 1052-1052
    Abstract: One of the most common traits of cancer is the radical change of cellular metabolism. A distinctive aspect of this altered metabolic status is the presence of a larger pool of monounsaturated fatty acids (MUFA), the precursors of the components of cell membranes necessary to sustained the rapidly dividing cancer cells. MUFA are largely generated from saturated fatty acids by the action of the two Stearoyl-CoA desaturases isoforms, namely SCD1 and SCD5. Recent evidences suggest that the major isoform SCD1 plays a role in several cancers. Our group has previously reported, using primary adenocarcinoma cell lines from malignant pleural effusions, that SCD1 inhibition selectively kills ALDH positive cells, a marker of cancer stem cells, causes spheroid 3D cultures collapse in vitro and impairs their growth in vivo. These results suggest that SCD1 may be a critical target in lung cancer tumor-initiating cells and further studies are needed to assess the role of this enzyme in lung cancer. An increasing number of literature points to the Hippo (and their effectors YAP/ TAZ) and to the Wnt/β-catenin signaling pathways as key factors in the development of cancer. Notably, SCD1 has been shown to be involved in the secretion and maturation of active wnt ligands, contributing to the activation of the β-catenin signaling. We report here, using primary cell cultures from adenocarcinoma of the lung, that YAP and TAZ are required for the generation of 3D cultures, as silencing of both genes completely abrogated the capability of generating lung cancer spheroids. Moreover, simultaneously silencing of YAP and TAZ reduced the mRNA levels of OCT4, Nanog and ALDH. We demonstrated that both silencing of SCD1 and its pharmacological inhibition determined a decrease in the expression and nuclear localization of both YAP and TAZ. Moreover, when SCD1 was inhibited, YAP and TAZ transcriptional activity was reduced. We also demonstrated that SCD1 blockade induced a dramatic reduction of the Axin2 mRNA level, one of the β-catenin target genes and a decreased in the β-catenin transcriptional activity, without affecting β-catenin protein expression. YAP and TAZ downregulation induced by SCD1 blockade could be rescued by the addition of exogenous wnt3a ligand, thus indicating that the active β-catenin signaling is necessary for YAP and TAZ stabilization. Ultimately, we observed that the ubiquitin ligase β-TrcP is involved in the SCD1 mediated degradation of YAP and TAZ. These data, overall, demonstrate for the first time the involvement of SCD1 in the regulation of the Hippo pathway and β-catenin pathway in lung cancer 3D spheroid cultures, pointing to lipid metabolism as regulator of cancer stem features. Moreover, these results can be the starting point for further studies focused on the regulation of SCD1 in cancer stem cells, suggesting a new perspective for improving chemotherapeutic responses in cancer treatment, centered on SCD1 inhibition. Citation Format: Alessia Noto, Maria Elena Pisanu, Claudia De Vitis, Giovanni Sorrentino, Giannino Del Sal, Alfredo Budillon, Gennaro Ciliberto, Rita Mancini. Stearoyl-CoA-Desaturase (SCD1) regulates lung cancer stemness via stabilization and nuclear localization of YAP/TAZ. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1052.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-1052
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 5
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    Abstract 3415: SIRT regulates the molecular interaction between c-MYC and HIF-1α in multiple myeloma.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3415-3415
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3415-3415
    Abstract: Multiple Myeloma (MM) is an incurable hematologic malignancy characterized by the accumulation of malignant plasma cells. Dysregulation of MYC by rearrangement or translocation are common somatic events described either in early or late stage of the disease, and transcriptional profiling of MYC pathway activation is observed in more than 60% of MM cell lines. Hypoxia Inducible Factor-1α (HIF-1α) overexpression has been described in several MM cell lines and in about 30% of MM patients samples. In solid tumours, deregulation of c-MYC has been associated with HIF-1α up-regulation. In the present study we explored the interaction between c-MYC and HIF-1α in a panel of MM cell lines. We had previously shown that treatment with EZN2968, an antisense oligonucleotide against HIF-1α, resulted in a significantly reduction of HIF-1α protein level as soon as 24h and lasted over 96h. To confirm the inhibition of HIF-1α activity, MM1S cells were treated with EZN2968 for 24h, lysed, co-precipitated with p300, and incubated with anti-HIF-1α antibody. We showed that HIF-1α was no longer associated p300 in EZN-treated compared to untreated samples, suggesting an inhibitory effect of HIF-1α activity. We next observed that treatment with EZN2968 induced a progressive accumulation of cells in S-phase with concomitant reduction of G2/M phase. By western blot analysis, we observed that p21, cell cycle check point negatively regulated by c-MYC, was up-regulated in treated samples. We further verified the effect of HIF-1α inhibition on c-MYC protein level by western blotting. After treatment with EZN2968, c-MYC protein expression was reduced in a time dependent manner, suggesting that c-MYC protein level is associated with inhibition of HIF-1α. To examine whether HIF-1α and c-MYC regulate each other promoter activity, we performed Chromatin Immunoprecipitation (ChIP) assays with HIF-1α or c-MYC antibodies. HIF-1A and MYC promoter amplification signals, were present in the controls samples, and decreased after EZN2968 exposure. Recently, it has been shown that SIRT1, a transcription factor involved in a development and cellular stress responses, can modulate HIF-1α and c-MYC activity. By Immunoblotting assay, we observed that SIRT1 physically interacts with both proteins and that, after 24h of exposure to EZN2968, c-MYC and HIF-1α were strongly associated to SIRT1. These results were also confirmed at the transcriptional level, by ChIP assay using an anti-SIRT1 antibody. After 24h of treatment with EZN2968, we observed a significant increase of HIF-1A and MYC promoter amplification signals in treated compared to untreated samples, suggesting that SIRT1 recruitment at both promoters is dependent on HIF inhibition. We showed that in MM cells the expression of HIF-1α and c-MYC are linked and mediated by SIRT1 deacetylase protein. The data suggests a new regulatory mechanism for controlling c-MYC and HIF-1α activity by SIRT1. Supported by PRIN. Citation Format: Enrica Borsi, Giulia Perrone, Carolina Terragna, Marina Martello, Manuela Mancini, Elisa Leo, Elena Zamagni, Paola Tacchetti, Annamaria Brioli, Lucia Pantani, Beatrice Zannetti, Giovanni Martinelli, Michele Cavo. SIRT regulates the molecular interaction between c-MYC and HIF-1α in multiple myeloma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3415. doi:10.1158/1538-7445.AM2013-3415
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-3415
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 6
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    Abstract 2091: Identification of a highly potent, selective and orally available RET inhibitor with antitumor efficacy in RET-dependent tumor models.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2091-2091
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2091-2091
    Abstract: The RET proto-oncogene encodes a receptor tyrosine kinase that is mainly expressed in neural crest-derived tissues where it plays an important role in cell differentiation, growth and survival. Germline activating point mutations of RET are associated with multiple endocrine neoplasia type 2 (MEN2), an inherited cancer syndrome characterized by development of medullary thyroid carcinoma (MTC), pheochromocytoma and parathyroid hyperplasia and are present in circa 50% of sporadic cases of MTC. More recently, a chromosomal rearrangement of the RET gene was identified in a subset of lung adenocarcinomas (1-2%) which is reported to result in expression of a fusion protein containing constitutively active RET kinase domain fused to the N-terminal portion of the kinesin KIF5B. We recently presented data on NMS-173, a very potent RET inhibitor characterized by an excellent in vivo activity profile upon i.v. administration. Here we describe the identification and the preclinical characterization of NMS-616, a novel analogue belonging to the same chemical class, suitable for oral administration. NMS-616 is a highly potent (IC50: 2 nM), ATP competitive RET inhibitor, characterized by high selectivity when tested against a panel of more than 50 kinases. NMS-616 potently blocked proliferation of MTC cell lines, such as the TT human cell line, which endogenously harbours constitutively activated RET, concomitant with abrogation of RET autophosphorylation and signaling pathway activation. The compound also inhibited the IL-3 independent proliferation of RET-driven Ba/F3 cells, with down-modulation of RET autophosphorylation and downstream signalling pathways. NMS-616 is characterized by a good in vitro ADME profile and in vivo pharmacokinetic parameters in the mouse, including oral bioavailability. When tested in vivo in a murine subcutaneous xenograft model employing TT cells, NMS-616 displayed dose-dependent tumor growth inhibition following daily oral administration at 50 and 100 mg/Kg, with tumor regression observed at both dose levels. In addition ex vivo analysis demonstrated dose-dependent target modulation following a single administration and the maintenance of RET phosphorylation inhibition for at least 24 hours. Citation Format: Elena Ardini, Patrizia Banfi, Francesca Quartieri, Paolo Polucci, Nilla Avanzi, Dario Ballinari, Laura Mancini, Edward Felder, Daniele Donati, Arturo Galvani, Enrico Pesenti, Antonella Isacchi, Maria Menichincheri. Identification of a highly potent, selective and orally available RET inhibitor with antitumor efficacy in RET-dependent tumor models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2091. doi:10.1158/1538-7445.AM2013-2091
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-2091
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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    detail.hit.zdb_id: 1432-1
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  • 7
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    Abstract 1070: miR-579-3p is a novel master regulator of melanoma progression and drug resistance in metastatic melanoma
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 1070-1070
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 1070-1070
    Abstract: Introduction: Malignant melanoma is the most aggressive form of skin cancer presenting in approximately 50% of cases activating mutations in the BRAF oncogene. For these patients new therapeutic options are represented by the combination of BRAF inhibitors and MEK-inhibitors. However, a major limitation is the occurrence of resistance related in the majority of cases to mutations causing either reactivation of the MAPK/ERK pathway or of the PI3K/PTEN/AKT pathway. This complex scenario is worsened by the absence, in a significant proportion of cases, of new mutations. This suggests the involvement also of epigenetic or post-transcriptional changes at the basis of resistance. We have focused our attention over the past years to adaptive changes occurring in melanoma cells upon exposure to BRAF and/or MEK inhibitors in order to identify new therapeutic targets. Here we hypothesize that miRNAs deregulation upon cell exposure to kinase inhibitors may contribute to the development of drug resistance. Experimental procedures: The involvement of specific miRNAs in the establishment of drug resistance in melanoma was investigated through the online software miRò while target predictions were performed with TargetScan and microrna.org. Impact on melanoma cell growth, migration and establishment of drug resistance was assessed through enforced-transient miR overexpression. Tumor biopsies were obtained from patients before therapy with kinase inhibitors or after relapse and used for RNA extraction. Results: We identified by bioinformatics analysis a novel miRNA, miR-579-3p, relevant for BRAF mutated melanoma progression and found that it targets both BRAF, the relevant oncoprotein in these melanomas, and MDM2. miR-579-3p expression levels are high in nevi, heavily decline in stage III-IV melanomas and further decrease in melanomacells selected in vitro for resistance to BRAF and/or MEK inhibitors. Through in vitro studies we obtained evidence that mir-579-3p is able to inhibit melanoma cell growth and migration and to induce apoptosis alone or in combination with BRAF and/or MEKi. Moreover we found that miR-579-3p overexpression impairs the establishment of resistance to BRAFi in human melanoma cells. Finally we found this miR to be down-regulated in tumor samples obtained from patients who developed resistance to target therapies and its expression to be inversely correlated to the expression levels of its target genes, BRAF and MDM2. Conclusions: Our results strongly demonstrate that miR-579-3p is a novel oncosuppressor miRNA, controlling melanoma progression and development of drug resistance and which could be used as a new therapeutic target for intervention. Citation Format: Luigi Fattore, Mario Acunzo, Giulia Romano, Alessandro Laganà, Debora Malpicci, Maria Elena Pisanu, Antonio Maria Grimaldi, Franco Fulciniti, Carlo Maria Croce, Rita Mancini, Paolo Antonio Ascierto, Gennaro Ciliberto. miR-579-3p is a novel master regulator of melanoma progression and drug resistance in metastatic melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1070.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-1070
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 8
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    Preventive Anti-inflammatory Diet to Reduce Gastrointestinal Inflammation in Familial Adenomatous Polyposis Patients: A Prospective Pilot Study
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Prevention Research Vol. 14, No. 10 ( 2021-10-01), p. 963-972
    Details
    In: Cancer Prevention Research, American Association for Cancer Research (AACR), Vol. 14, No. 10 ( 2021-10-01), p. 963-972
    Abstract: Familial adenomatous polyposis (FAP) is an autosomal-dominant hereditary condition associated with germline mutations in the adenomatous polyposis coli gene. Patient management involves prophylactic surgery and intensive life-long endoscopic surveillance. Diet is a major concern for patients with FAP, who are generally free of symptoms before surgery but tend to have issues related to bowel function postoperatively. We hypothesized that a low-inflammatory diet based on the principles and recipes of the Mediterranean diet would reduce markers of local and systemic inflammation. Twenty-eight patients with FAP over 18 years of age who underwent rectum-sparing prophylactic colectomy and were included in our surveillance program participated in a pilot dietary intervention study. Blood and stool samples at baseline (T0), at the end of the dietary intervention (T1, three months), and at the end of the study (T2, six months after T0) were collected. Gastrointestinal inflammation markers including fecal calprotectin, cyclooxygenase-2, and 15-hydroxyprostaglandin dehydrogenase were evaluated. Serum calprotectin, insulin, insulin-like growth factor-1, C-reactive protein, and glycated hemoglobin were also assessed. Significant changes in serum calprotectin, insulin, and insulin-like growth factor-1 levels occurred over time. Borderline significant changes were observed in the neutrophil–lymphocyte ratio. These changes were noticeable immediately at the end of the 3-month active dietary intervention (T1). A significant increase in 15-hydroxyprostaglandin dehydrogenase expression in the normal crypts of matched samples was also observed between T0 and T2. This pilot study supports the hypothesis that a low-inflammatory diet can modulate gastrointestinal markers of inflammation in individuals with FAP. Prevention Relevance: Cancer is known to be related to inflammatory conditions. This study suggests that anti-inflammatory dietary intervention may potentially prevent adenomas and cancer in FAP patients by reducing systemic and tissue inflammatory indices.
    Type of Medium: Online Resource
    ISSN: 1940-6207 , 1940-6215
    URL: Article
    DOI: 10.1158/1940-6207.CAPR-21-0076
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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