Carlos M Galmarini

Mario Negri Institute for Pharmacological Research, Milano, Lombardy, Italy

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Publications (117)584.38 Total impact

  • Carlos M Galmarini, Olivier Tredan, Felipe C Galmarini
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    ABSTRACT: In any disease, the knowledge of the natural history of untreated cases provides a real background against which the real advantages of a new treatment itself are judged. Fortunately, in the present days, there are scant data on outcomes in patients with untreated breast cancer. In an attempt to provide this background against which the virtues of current curative and palliative treatments can be more accurately assessed, we have reviewed the literature regarding published untreated breast cancer series. Taking into consideration all the difficulties of analyzing reports written on the last half of the nineteenth century or on the first half of the twentieth century, in most reports, patients survived almost 3-4 years without any type of treatment. Worth mentioning, approximately 5-10 % of untreated patients lived longer than 10 years. Thus, the spectrum of clinical aggressiveness of untreated breast cancer varies between virulence and chronic disease. These facts should be taken into account when considering the value of current treatments for early-stage disease.
    Medical Oncology 02/2015; 32(2):466. DOI:10.1007/s12032-014-0466-x · 2.06 Impact Factor
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    M D'Incalci, N Badri, C M Galmarini, P Allavena
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    ABSTRACT: Trabectedin is the first marine-derived anti-neoplastic drug approved for the treatment of advanced soft tissue sarcoma and, in combination with pegylated liposomal doxorubicin, for the treatment of patients with relapsed platinum-sensitive ovarian cancer. From the beginning of its development, trabectedin showed some peculiar properties that clearly distinguished it from other anti-cancer drugs. In this mini-review, we will outline the current state of knowledge regarding the mode of action of trabectedin, which appears to represent a new class of anti-neoplastic drugs acting both on cancer cells and on the tumour microenvironment.British Journal of Cancer advance online publication 22 April 2014; doi:10.1038/bjc.2014.149
    British Journal of Cancer 04/2014; 111(4). DOI:10.1038/bjc.2014.149 · 5.08 Impact Factor
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    Carlos M Galmarini, Maurizio D'Incalci, Paola Allavena
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    ABSTRACT: The prevailing paradigm states that cancer cells acquire multiple genetic mutations in oncogenes or tumor suppressor genes whose respective activation/up-regulation or loss of function serve to impart aberrant properties, such as hyperproliferation or inhibition of cell death. However, a tumor is now considered as an organ-like structure, a complex system composed of multiple cell types (e.g., tumor cells, inflammatory cells, endothelial cells, fibroblasts, etc.) all embedded in an inflammatory stroma. All these components influence each other in a complex and dynamic cross-talk, leading to tumor cell survival and progression. As the microenvironment has such a crucial role in tumor pathophysiology, it represents an attractive target for cancer therapy. In this review, we describe the mechanism of action of trabectedin and plitidepsin as an example of how these specific drugs of marine origin elicit their antitumor activity not only by targeting tumor cells but also the tumor microenvironment.
    Marine Drugs 02/2014; 12(2):719-33. DOI:10.3390/md12020719 · 3.51 Impact Factor
  • Molecular Cancer Therapeutics 01/2014; 12(11_Supplement):A177-A177. DOI:10.1158/1535-7163.TARG-13-A177 · 6.11 Impact Factor
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    ABSTRACT: PM060184 belongs to a new family of tubulin-binding agents originally isolated from the marine sponge Lithoplocamia lithistoides. This compound is currently produced by total synthesis and is under evaluation in clinical studies in patients with advanced cancer diseases. It was recently published that PM060184 presents the highest known affinities among tubulin-binding agents, and that it targets tubulin dimers at a new binding site. Here, we show that PM060184 has a potent antitumor activity in a panel of different tumor xenograft models. Moreover, PM060184 is able to overcome P-gp mediated resistance in vivo, an effect that could be related to its high binding affinity for tubulin. To gain insight into the mechanism responsible of the observed antitumor activity, we have characterized its molecular and cellular effects. We have observed that PM060184 is an inhibitor of tubulin polymerization that reduces microtubule dynamicity in cells by 59%. Interestingly, PM060184 suppresses microtubule shortening and growing at a similar extent. This action affects cells in interphase and mitosis. In the first case, the compound induces a disorganisation and fragmentation of the microtubule network and the inhibition of cell migration. In the second case, it induces the appearance of multipolar mitosis and lagging chromosomes at the metaphase plate. These effects correlate with prometaphase arrest and induction of caspase-dependent apoptosis or appearance of cells in a multinucleated interphase-like state unrelated to classical apoptosis pathways. Taken together, these results indicate that PM060184 represents a new tubulin binding agent with promising potential as an anticancer agent.
    Biochemical pharmacology 01/2014; DOI:10.1016/j.bcp.2014.01.026 · 4.25 Impact Factor
  • Molecular Cancer Therapeutics 01/2014; 12(11_Supplement):A174-A174. DOI:10.1158/1535-7163.TARG-13-A174 · 6.11 Impact Factor
  • Carlos M Galmarini, Olivier Tredan, Felipe C Galmarini
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    ABSTRACT: The dynamics of disease recurrence shows a bimodal pattern with a fairly broad dominant peak at about 1.5-2 years after surgery followed by a second peak at about 5 years. Nowadays, this clinical pattern is explained by assuming that primary breast tumours as well as their metastases have phases of both arrested (tumour dormancy) and active Gompertzian growth. Tumour dormancy at metastatic sites is currently ascribed to biological particularities of local tissue microenvironments that inhibit the growth of tumour cells. However, in some patients, tumour dormancy appears to also depend on the direct interplay between the primary tumour and those metastases, a biological phenomenon called "concomitant resistance". Concomitant resistance is related to three biological processes: concomitant immunity, tumour-induced angiogenesis and athrepsia. Concomitant resistance can explain the bimodal relapse pattern of breast cancer patients as well as many other clinical phenomena such as the better clinical outcome among patients surgically treated during the putative early luteal phase, or the worse clinical outcome of African-American premenopausal women. Any therapeutic interventions (even surgery) can affect concomitant resistance with the potential to induce a worse as well as a better clinical outcome. This should be taken into account when planning new treatment strategies.
    CANCER AND METASTASIS REVIEW 12/2013; DOI:10.1007/s10555-013-9449-1 · 9.35 Impact Factor
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    ABSTRACT: The mechanism of action of elisidepsin (PM02734, Irvalec®) is assumed to involve membrane permeabilization via attacking lipid rafts and hydroxylated lipids. Here we investigate the role of hypoxia in the mechanism of action of elisidepsin. Culturing under hypoxic conditions increased the half-maximal inhibitory concentration and decreased the drug's binding to almost all cell lines which was reversed by incubation of cells with 2-hydroxy palmitic acid. The expression of fatty acid 2-hydroxylase was strongly correlated with the efficiency of the drug and inversely correlated with the effect of hypoxia. Number and brightness analysis and fluorescence anisotropy experiments showed that hypoxia decreased the clustering of lipid rafts and altered the structure of the plasma membrane. Although the binding of elisidepsin to the membrane is non-cooperative, its membrane permeabilizing effect is characterized by a Hill coefficient of ~3.3. The latter finding is in agreement with elisidepsin-induced clusters of lipid raft-anchored GFP visualized by confocal microscopy. We propose that the concentration of elisidepsin needs to reach a critical level in the membrane above which elisidepsin induces the disruption of the cell membrane. Testing for tumor hypoxia or the density of hydroxylated lipids could be an interesting strategy to increase the efficiency of elisidepsin.
    Marine Drugs 12/2013; 11(12):4858-75. DOI:10.3390/md11124858 · 3.51 Impact Factor
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    ABSTRACT: To elucidate the mechanisms behind the high sensitivity of myxoid/round cell liposarcoma (MRCL) to trabectedin and the suggested selectivity for specific subtypes, we have developed and characterized three MRCL xenografts, namely ML017, ML015 and ML004 differing for the break point of the fusion gene FUS-CHOP, respectively of type I, II and III. FUS-CHOP binding to the promoters of some target genes such as Pentraxin 3 or Fibronectin 1, assessed by chromatin immunoprecipitation, was strongly reduced in the tumor 24 h after the first or the third weekly dose of trabectedin, indicating that the drug at therapeutic doses causes a detachment of the FUS-CHOP chimera from its target promoters as previously shown in vitro. Moreover, the higher sensitivity of MRCL types I and II appears to be related to a more prolonged block of the transactivating activity of the fusion protein. Doxorubicin did not affect the binding of FUS-CHOP to target promoters. Histologically, the response to trabectedin in ML017 and ML015 was associated with a marked depletion of non-lipogenic tumoral cells and vascular component, as well as lipidic maturation as confirmed by PPARγ2 expression in western Blot. By contrast, in ML004 no major changes either in the cellularity or in the amount of mature were found, and consistently PPARγ2 was null. In conclusion, the data support the view that the selective mechanism of action of trabectedin in MRCL is specific and related to its ability to cause a functional inactivation of the oncogenic chimera with consequent derepression of the adypocytic differentiation.Oncogene advance online publication, 11 November 2013; doi:10.1038/onc.2013.462.
    Oncogene 11/2013; DOI:10.1038/onc.2013.462 · 8.56 Impact Factor
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    ABSTRACT: This study investigated the relationship between 13 proteins involved in DNA damage and the outcomes of patients with recurrent ovarian cancer (ROC). Patients and methods Immunohistochemistry staining was performed in 114 diagnostic samples from patients with serous ROC who participated in the OVA-301 study, which compared pegylated liposomal doxorubicin (PLD) with a combination of trabectedin plus PLD. Percentage of positive cells for every marker was calculated and correlated with overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). A statistically significant correlation between high levels of nibrin and lower ORR (P=0.03), shorter PFS (P=0.007) and shorter OS (P=0.01) was observed. After stratification, in patients with platinum-sensitive disease treated with the combination of trabectedin plus PLD, high levels of nibrin correlated with lower ORR (P=0.01) and shorter PFS (P=0.02). A better clinical outcome (ORR, PFS and OS) was also associated to low levels of CHK2 in trabectedin plus PLD treated patients. No correlations were found in PLD-treated patients. According to the results of a multivariate analysis, there was a statistically significant correlation between high nibrin (P=0.001) and low BRCA2 levels (P=0.03) and a worse PFS, and between high nibrin levels and a worse OS (P=0.006). Our results indicate that high nibrin expression seems to be associated with a worse clinical outcome in serous ROC, particularly in patients treated with the combination trabectedin plus PLD. Prospective studies to determine clinical usefulness of nibrin as a possible biomarker in other series of patients with ROC are warranted.
    Gynecologic Oncology 11/2013; DOI:10.1016/j.ygyno.2013.10.032 · 3.69 Impact Factor
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    ABSTRACT: This study: i) investigated the in vitro cytotoxicity and mode of action of lurbinectedin (PM01183) and Zalypsis® (PM00104) compared to trabectedin in cell lines deficient in specific mechanisms of repair, ii) evaluated their in vivo antitumor activity against a series of murine tumours and human xenografts. The antiproliferative activity, the DNA damage and the cell cycle perturbations induced by the three compounds on tumour lines were very similar. Nucleotide Excision Repair (NER) deficient cells were ~4-fold more resistant to trabectedin, lurbinectedin and Zalypsis®. Cells deficient in Non-Homologous End Joining (NHEJ), MRN complex and Translesion Synthesis (TLS) were slightly more sensitive to the three compounds (~ 5-fold) while cells deficient in Homologous Recombination (HR) were markedly more sensitive (150-200-fold). All three compounds showed a good antitumor activity in several in vivo models. Lurbinectedin and trabectedin had a similar pattern of antitumor activity in murine tumours and in xenografts, whereas Zalypsis® appeared to have a distinct spectrum of activity. The fact that no relationship whatsoever was found between the in vitro cytotoxic potency and the in vivo antitumor activity, suggests that in addition to direct cytotoxic mechanisms other host-mediated effects are involved in the in vivo pharmacological effects. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 11/2013; 133(9). DOI:10.1002/ijc.28213 · 6.20 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):5498-5498. DOI:10.1158/1538-7445.AM2013-5498 · 9.28 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):2129-2129. DOI:10.1158/1538-7445.AM2013-2129 · 9.28 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):5499-5499. DOI:10.1158/1538-7445.AM2013-5499 · 9.28 Impact Factor
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    ABSTRACT: We have previously shown that cells deficient in the Fanconi anemia (FA) pathway are hypersensitive to trabectedin, a DNA-binding anticancer tetrahydroisoquinoline (DBAT) whose adducts functionally mimic a DNA inter-strand crosslink (ICL). Now we expand our observations to new DBATs and investigate whether our findings in primary untransformed cells can be reproduced in human cancer cells. The sensitivity of FA-competent and FA-deficient transformed and untransformed cells to mitomycin C (MMC) and to three DBATs, trabectedin, Zalypsis and PM01183, was first assessed. Additionally, the functional interaction of these drugs with the FA pathway was comparatively investigated. While untransformed FA-deficient hematopoietic cells were hypersensitive to both MMC and DBATs, the response of FA-deficient squamous cell carcinoma (SCC) cells to DBATs was similar to that of their respective FA-competent counterparts, even though these FA-deficient SCC cells showed the expected hypersensitivity to MMC. Furthermore, while MMC always activated the FA pathway, DBATs inhibited FA pathway in the cancer cell lines tested and this enhanced their response to MMC. Taken together, our data show that although DBATs may functionally interact with DNA like agents that generate classical ICL, these drugs should be considered as FA pathway inhibitors, rather than activators. Moreover, this effect was most significant in a variety of cancer cells. We propose that the inhibitory effects of DBATs on the FA pathway could be exploited clinically with the aim of "fanconizing" cancer cells in order to make them more sensitive to other antitumor drugs.
    British Journal of Pharmacology 08/2013; 170(4). DOI:10.1111/bph.12331 · 5.07 Impact Factor
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    ABSTRACT: We have investigated the target and mechanism of action of a new family of cytotoxic small molecules of marine origin. PM050489 and its dechlorinated analogue PM060184 inhibit the growth of relevant cancer cell lines at subnanomolar concentrations. We found that they are highly potent microtubule inhibitors that impair mitosis with a distinct molecular mechanism. They bind with nanomolar affinity to unassembled alphabeta-tubulin dimers and PM050489 binding is inhibited by known Vinca domain ligands. NMR TR-NOESY data indicated that a hydroxyl-containing analogue, PM060327, binds in an extended conformation and STD results define its binding epitopes. Distinctly from vinblastine, these ligands only weakly induce tubulin self-association, in a manner more reminiscent of isohomohalichondrin B than of eribulin. PM050489, possibly acting like a hinge at the association interface between tubulin heterodimers, reshapes Mg2+-induced 42 S tubulin double rings into smaller 19 S single rings made of 7±1 alphabeta-tubulin dimers. PM060184-resistant mutants of Aspergillus nidulans map to beta-tubulin Asn100, suggesting a new binding site different from vinblastine at the associating beta-tubulin end. Inhibition of assembly dynamics by a few ligand molecules at the microtubule plus end would explain the antitumor activity of these compounds, of which PM060184 is undergoing clinical trials.
    ACS Chemical Biology 07/2013; 8(9). DOI:10.1021/cb400461j · 5.44 Impact Factor
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    ABSTRACT: Plitidepsin is an antitumor drug of marine origin currently in Phase III clinical trials in multiple myeloma. In cultured cells, plitidepsin induces cell cycle arrest or an acute apoptotic process in which sustained activation of c-Jun N-terminal kinase (JNK) plays a crucial role. With a view to optimizing clinical use of plitidepsin, we have therefore evaluated the possibility of using JNK activation as an in vivo biomarker of response. In this study, we show that administration of a single plitidepsin dose to mice xenografted with human cancer cells does indeed lead to increased phosphorylation of JNK in tumors at 4 to 12 h. By contrast, no changes were found in other in vitro plitidepsin targets such as the levels of phosphorylated-ERK, -p38MAPK or the protein p27KIP1. Interestingly, plitidepsin also increased JNK phosphorylation in spleens from xenografted mice showing similar kinetics to those seen in tumors, thereby suggesting that normal tissues might be useful for predicting drug activity. Furthermore, plitidepsin administration to rats at plasma concentrations comparable to those achievable in patients also increased JNK phosphorylation in peripheral mononuclear blood cells. These findings suggest that changes in JNK activity provide a reliable biomarker for plitidepsin activity and this could be useful for designing clinical trials and maximizing the efficacy of plitidepsin.
    Marine Drugs 05/2013; 11(5):1677-1692. DOI:10.3390/md11051677 · 3.51 Impact Factor
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    ABSTRACT: Elisidepsin (PM02734, Irvalec®) is a synthetic marine-derived cyclic peptide of the Kahalalide F family currently in phase II clinical development. Elisidepsin was shown to induce rapid oncosis in ErbB3-expressing cells. Other predictive factors of elisidepsin sensitivity remained unknown. A panel of 23 cancer cell lines of different origin was assessed for elisidepsin cytotoxicity and correlated with mutational state, mRNA and protein expression of selected genes. Elisidepsin showed potent and broad cytotoxic effects in our cancer cell line panel, being active at concentrations ranging from 0.4 to 2 μM that may be relevant for clinical settings. We have shown that elisidepsin is more active in cells harboring epithelial phenotype with high E-cadherin and low vimentin expression. In addition, high ErbB3 and Muc1 expression was correlated with sensitivity to elisidepsin, whereas the presence of KRAS activating mutations was associated with resistance. In DU-PM cells with acquired resistance to elisidepsin, ErbB3 expression was decreased, while Bcl2 was increased. DU-PM cells displayed higher sensitivity to ErbB1-inhibitors suggesting possible cross-talk of ErbB1 and ErbB3 signaling pathways. Combinations of elisidepsin with lapatinib and several chemotherapies including 5-FU and oxaliplatin resulted in synergistic effects that offer the potential of clinical use of elisidepsin in combination settings.
    Marine Drugs 03/2013; DOI:10.3390/md11030944 · 3.51 Impact Factor
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    ABSTRACT: There is widespread interest in macrophages as a therapeutic target in cancer. Here, we demonstrate that trabectedin, a recently approved chemotherapeutic agent, induces rapid apoptosis exclusively in mononuclear phagocytes. In four mouse tumor models, trabectedin caused selective depletion of monocytes/macrophages in blood, spleens, and tumors, with an associated reduction of angiogenesis. By using trabectedin-resistant tumor cells and myeloid cell transfer or depletion experiments, we demonstrate that cytotoxicity on mononuclear phagocytes is a key component of its antitumor activity. Monocyte depletion, including tumor-associated macrophages, was observed in treated tumor patients. Trabectedin activates caspase-8-dependent apoptosis; selectivity for monocytes versus neutrophils and lymphocytes is due to differential expression of signaling and decoy TRAIL receptors. This unexpected property may be exploited in different therapeutic strategies.
    Cancer cell 02/2013; 23(2):249-62. DOI:10.1016/j.ccr.2013.01.008 · 25.29 Impact Factor
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    ABSTRACT: XPG (Xeroderma pigmentosum group G complementing factor) is a protein associated with DNA repair and transcription. Point mutations in ERCC5, the gene coding for XPG, cause the cancer-prone disorder xeroderma pigmentosum (XP) while truncation mutations give rise to individuals with the combined clinical features of XP and Cockayne syndrome. Polymorphisms of ERCC5 or alterations in XPG mRNA expression were also associated to an increase risk of different cancers types and to prognosis of cancer patients. However, the expression of XPG protein in different normal or tumor human tissues is not well known. In the present work, we have validated an immunohistochemistry (IHC) assay for detection of expression levels of XPG protein in FFPE human tissue samples. We have also tested this IHC assay in different normal and tumor human tissues. On a microarray containing 28 normal cores, positive staining was observed in 60% of the samples. The highest staining was detected in adrenal gland, breast, colon, heart, kidney, thyroid and tongue. In tumors, positive staining was observed in 9 of 10 breast cancer samples and in all 5 ovarian cancer and 5 sarcomas samples. Subcellular localization was predominantly nuclear. The use of this validated methodology would help to interpret the role of XPG in tumorogenesis and its use as a possible prognostic or predictive factor.
    International journal of clinical and experimental pathology 01/2013; 6(2):199-211. · 1.78 Impact Factor

Publication Stats

3k Citations
584.38 Total Impact Points


  • 2013
    • Mario Negri Institute for Pharmacological Research
      • Department of Oncology
      Milano, Lombardy, Italy
    • Istituto Clinico Humanitas IRCCS
      • Department of Immunology and Inflammation
      Rozzano, Lombardy, Italy
  • 2012
    • NCI-Frederick
      Фредерик, Maryland, United States
  • 2004–2011
    • University of Lyon
      Lyons, Rhône-Alpes, France
    • Hospices Civils de Lyon
      Lyons, Rhône-Alpes, France
  • 2010
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2003–2007
    • Claude Bernard University Lyon 1
      • Institut de chimie et biochimie moléculaires et supramoléculaires (ICBMS)
      Villeurbanne, Rhône-Alpes, France
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2004–2006
    • Centre Léon Bérard
      Lyons, Rhône-Alpes, France
  • 2005
    • Université Paris-Sud 11
      Orsay, Île-de-France, France
  • 2001–2004
    • Unité Inserm U1077
      Caen, Lower Normandy, France