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ABSTRACT: The mechanisms of genetically determined mechanisms of resistance to several target drugs were discussed in breast cancer, melanoma, colorectal and prostate cancers, CML, SCLC and medulloblastoma. In each case, heterogeneity of mechanisms was emphasized. In melanoma therapeutic interference with the effects of BRAF mutations was repeatedly discussed. It was also reported that anti CTLA4 antibodies provided the first treatment improving survival of patients with stage IV melanoma. Epithelial Mesemchimal Transition (EMT) was introduced as a mechanism of resistance particularly in lung and pancreatic cancer, where the role of microenvironment factors was also indicated. In colorectal and prostate cancers the use of liquid biopsies, namely, measurements of tumor nucleic acid in blood was indicated as a way to obtain whole tumor assessment instead of the partial assessment obtainable with traditional biopsies. Knowledge of the mechanisms of drug action and resistance was stressed to be essential for the design of new agents and combination of agents aimed at increasing antitumor effectiveness and overcoming resistance.
Cancer Research 12/2012; · 7.86 Impact Factor
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ABSTRACT: The cross-disciplinary focus of the meeting highlighted recent progress in physical and genetic analysis and engineering of cancer disease models. As the central theme, mechanical forces affecting cell signaling, growth, differentiation, and metastasis were discussed with emphasis on the tumor microenvironment and cellular immunity, taking into account novel nanotechnology, biosensing, and intravital microscopy tools to monitor animal cancer models and human cancer. Emerging themes were the role of extracellular matrix imposing mechanical mechanisms on tumor cell function, including microenvironmental cues controlling the movement of tumor and immune cells, advanced genetic animal models for cancer that better recapitulate human disease, and preclinical and clinical molecular imaging of tumor architecture and stiffness, as well as novel nanotechnologies for anticancer drug delivery.
Cancer Research 02/2012; 72(4):841-4. · 7.86 Impact Factor
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ABSTRACT: The 22nd annual Pezcoller Symposium titled "RNA Biology and Cancer" was held in Trento, Italy, on June 10-12, 2010. The program of the symposium was developed by Drs. Rene Bernards, Witold Filipowicz, and David Livingston; they cochaired the meeting in cooperation with Dr. Enrico Mihich. The topics discussed included the opportunities offered by small RNA as tools for cancer drug development, the role of noncoding RNAs, the biochemistry of small RNAs, the function of micro RNA in cancer, and RNAs as diagnostics and therapeutics in cancer.
Cancer Research 12/2010; 70(24):10034-7. · 7.86 Impact Factor
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ABSTRACT: The 21st Pezcoller Symposium, entitled "Unconventional Therapeutic Targets in Cancer," was held in Trento, Italy, on June 11-13, 2009. The focus of the Symposium was on identifying nontraditional targets for anticancer drug action and using new concepts for drug development.
Cancer Research 12/2009; 70(1):14-7. · 7.86 Impact Factor
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Enrico Mihich
Cancer Research 02/2009; 69(2):407-10. · 7.86 Impact Factor
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ABSTRACT: This symposium was held in Trento, Italy, from June 14 to 16, 2007, and was co chaired by William G. Kaelin, Enrico Mihich, and Charles L. Sawyers. A session was devoted to the proof of concept derived from successes in target-oriented therapeutics. Molecular targets must be identified in each patients because they are equally present in all patients with the same tumor type. A session was devoted to the identification of markers of drug effectiveness. Two sessions were focused on opportunities for developing new specific molecular target-oriented therapies.
Cancer Research 01/2008; 67(23):11102-5. · 7.86 Impact Factor
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ABSTRACT: This symposium was held in Trento, Italy, from June 27 to 29, 2006, and was co-chaired by Robert Weinberg and Enrico Mihich. The interactions between tumor cells and their microenvironment were discussed with particular emphasis on their molecular mechanisms. The roles of transforming growth factor beta signaling, urokinase, and matrix metalloproteinases in matrix remodeling; the effects of matrix-tumor interactions on cell proliferation and migration; the tumor-promoting effects of inflammation and of related host cell and cytokine functions; the signaling mechanisms affecting the biology of the stroma; and the mechanisms governing angiogenesis were discussed.
Cancer Research 01/2007; 66(24):11550-3. · 7.86 Impact Factor
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ABSTRACT: As recently characterized, following s.c. implantation into syngeneic C57BL/6 mice, E0771 tumor invades locally into dermal layers and peritoneum, metastasizes to the lung, and induces a nonspecific immunosuppression in the host. Using this breast medullar adenocarcinoma model, a therapy consisting of a single moderate dose of doxorubicin followed by twice daily moderate doses of interleukin-2 for 30 days was examined for efficacy and mechanism of action when given to animals with established disease. This combination treatment, but not combinants alone, resulted in tumor-free long-term survival of 40% of the mice without significant toxicity and 83% of survivors had immune memory specific for E0771 cells. Treatment also decreased immune suppression induced by E0771 tumor. Full response to treatment required functional CD8(+) T cells, whereas depletion of natural killer cells caused only a reduction in response rate. A serum "biomarker" profile that correlated with, and seemed predictive of, response to treatment was identified by nuclear magnetic resonance-based metabonomic analysis. The efficacy of this nontoxic treatment and the potential to be able to predict which individual is responding to treatment are characteristics that make this chemoimmunotherapy attractive for clinical testing.
Cancer Research 06/2006; 66(10):5419-26. · 7.86 Impact Factor
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Cancer Immunology and Immunotherapy 03/2006; 55(2):229-33. · 3.70 Impact Factor
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Cancer Research 01/2006; 65(24):11251-4. · 7.86 Impact Factor
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ABSTRACT: The administration of 5-fluorouracil (FU) and leucovorin (LV) to rats induced a previously unreported sialoadenitis-like toxicity. Four different treatment regimens were used: daily-times-5 iv or ip injections of LV (200 mg/kg) followed 30 minutes later by FU (27.5 mg/kg or 35 mg/kg). These treatments resulted in 3 severity levels of systemic toxicity indicated by changes in body weight. In addition to the well known FU+LV-induced diarrhea, myelosuppression, and stomatitis, facial edema, and enlargement of the submandibular salivary gland were consistently seen. Facial edema occurred almost exclusively in rats that subsequently underwent excessive weight loss and were euthanized. The submandibular, but not parotid or sublingual, salivary gland was enlarged and the severity of this effect changed in a bell-shaped relationship with respect to increasing FU+LV induced loss of body weight. Histologic examination of affected glands established the occurrence of bacterial infection, sialoadenitis and destruction of gland tissue. This paper provides the first known documentation of FU+LV treatment-induced selective pathology of the submandibular salivary gland. The selectivity of this toxicity, apparently not normally seen in humans, to the submandibular salivary gland of the rat is of interest and its mechanism warrants further investigation.
Toxicologic Pathology 02/2005; 33(4):507-15. · 1.91 Impact Factor
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ABSTRACT: In the postgenomic era of cancer biology, it is becoming increasingly evident that epigenetic controls of gene expression play an important role in determining the phenotype of cancer cells, also indicating the possibility of restoring epigenetically a normal phenotype in cancer cells. Related to these mechanisms of control and their dynamic changes during carcinogenesis and tumor progression are the phenomena determining the relationships between stem cells and cancer cells. This symposium focused on epigenetic mechanisms affecting cancer development and possibly providing a basis for intervention. The basic biology of stem cells and the relationships between stem cells and cancer were discussed. Epigenetic control mechanisms affecting gene expression with emphasis on DNA methylation and histone function were considered. Therapeutic strategies stemming from the knowledge acquired in the basic topics discussed also were outlined.
Cancer Research 12/2004; 64(22):8474-7. · 7.86 Impact Factor
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Enrico Mihich
Cancer biology & therapy 10/2004; 3(9):911-5. · 2.64 Impact Factor
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ABSTRACT: Recent advances in the understanding of the molecular phenomena underlying neoplastic development are leading to the recognition of metabolic features characteristic of the cancer cell. It has become possible to visualize the presence of these cells in vivo and to follow their progression toward increasing anaplastic behavior through measurements of molecular markers that can be achieved by physical or biochemical means.
Cancer Research 05/2004; 64(8):2929-33. · 7.86 Impact Factor
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Enrico Mihich
Cancer Immunology and Immunotherapy 12/2003; 52(11):661-2. · 3.70 Impact Factor
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ABSTRACT: To examine the basis of the immune modulation induced by the anticancer agent doxorubicin (DOX), the immunophenotype, tumoricidal activity, cytokine protein and mRNA expression were determined using peritoneal exudate cells (PEC) from saline-treated (untreated) and DOX-treated mice. A greater percentage of PEC from DOX-treated mice than from untreated mice were adherent to plastic, had characteristics of granulocytes, and were positive for the NK1.1, CD11b/Mac-1, and CD3 markers. DOX decreased the percentage of CD45R/B220+ cells. PEC from DOX-treated mice had greater tumoricidal potential than those from untreated mice since IL2, LPS, or IFNgamma alone increased the cytolytic activity of PEC from DOX-treated mice, whereas PEC from untreated mice required both LPS and IFNgamma to become cytolytic. DOX treatment modulated the expression of specific cytokines. Following stimulation in culture, PEC from DOX-treated mice produced more TNF, IL1, and IFNgamma than PEC from untreated mice. DOX treatment increased the levels of TNF, but not IL1, mRNA and decreased the levels of IL6 mRNA and protein. These data demonstrate that a single DOX injection induces specific effects in PEC and, as a consequence, increases the tumoricidal potential of cells of the macrophage and natural killer types.
Cancer Immunology and Immunotherapy 08/2003; 52(7):463-72. · 3.70 Impact Factor
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ABSTRACT: The main focus of the Symposium was the fact that cell types of the innate and adaptive immune systems can have tumor-favoring as well as tumor antagonistic effects, both in a preventive and therapeutic mode. It was shown that macrophages (Mphi) and dendritic cells within a tumor exert tumor-favoring effects through the action of certain cytokines. Inflammatory reactions could favor the onset and growth of tumors. Dual immune functions were shown with CD4+ T cells and certain matrix metalloproteinase (MMP) activities favoring tumor progression and CD8+ T cells and certain heat shock proteins having antitumor action. Lack of antitumor action despite positive immune stimulation was also shown to depend on the existence of barriers to tumor infiltration by lymphocytes; remodeling of vasculature, e.g., by IFNgamma-induced cytokines like MIG and IPIO, reversed this type of impediment. Certain CXC cytokines increased tumor progression, whereas others, particularly those induced by IFNgamma, had the opposite effect; stromal-derived factor-1 and its receptor CXCR4 affected tumor propensity to metastasize in certain organs. Stromal-derived factor-1 induced MMP9, which in turn regulated the bioavailability of vascular endothelial growth factor and the cascade of its tumor-favoring effects, whereas granulocyte colony-stimulating factor decreased MMP9 and the consequences of its action. The effects of certain proinflammatory cytokines and vascular endothelial growth factor functions in angiogenesis and lymphoangiogenesis were also discussed. The favoring effects of fever-like thermal stress on the function of molecules instrumental in lymphoid cell adhesion to vessels and infiltration into sites of immune actions were described. The mechanisms involved in the development of immune memory and those conditioning Type I and CTL responses were also discussed. A number of presentations were concerned with laboratory studies aimed at developing clinical regimens with potential activity in the prevention or treatment of cancer. Prevention of Her2/neu breast cancer in transgenic mice was achieved by suitable regimens with IL12 combined with vaccines, including DNA-based vaccines administered in conjunction with electroporation. Vaccination with shared tumor antigen MUCI or cyclin B was discussed, and its clinical translation was described. The prevention of TRAMP prostate tumor in transgenic mice by anti-CTLA4 antibody plus vaccine was described, as was the translation of these regimens to the clinics. Clinical successes in melanoma patients using antimelanoma antigen antibodies in a therapeutic mode and precautions to be exerted in evaluating in vivo immune responses based on in vitro assays were emphasized. The symposium was concluded with an overall discussion focused on basic questions related to the capability of immunity to exert tumor-favoring or antitumor effects depending on conditions determined by both tumor and host functions.
Cancer Research 07/2003; 63(11):3005-8. · 7.86 Impact Factor
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ABSTRACT: The physiopathology of cancer cells is the result of very complex signaling networks that represent in many cases distortions of the orderly networks regulating the physiology of normal cells. These networks are the consequence of the expression of, or the lack of expression of, genes, mutated or not, which represent the genomic profile of different types of or of individual cancers. The complex signaling pathways, the cross-talks among them, and the redundancies existing for several of them mediate not only the transmission of signals from the cell environment to the nucleus but also that from the nucleus to the other cellular components whose function is involved in cell proliferation, apoptosis, or differentiation. Modern approaches to cancer therapy and also prevention are aimed at identifying new molecular targets, pivotal to the life of the cancer cell, which would provide for specific sites of intervention. In the face of the enormous complexity of the phenomena on which the life of cancer cells is based, it is both difficult to identify unique specific target for intervention and important to develop analytical tools and approaches capable to identify them for further exploitation. This was the main subject of the Symposium. Consideration was given to: (a) tumor genotypic analysis through expression array evaluation and definition of cancer transcriptomes in studies aimed at identifying determinants of specific characteristics of cancer cells; (b) approaches based on the knowledge gained in this analysis that would lead to the visualization of new targets exploitable for antitumor action; and (c) multifactorial analysis of the complex interactions regulating cancer cells and methods to comprehend the complexity of molecular models and validate their functional relevance.
Cancer Research 08/2002; 62(13):3883-7. · 7.86 Impact Factor
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ABSTRACT: Breast cancer treatments are most effective when initiated early, with very poor efficacy against metastatic disease. In seeking a readily metastasizing mouse breast cancer model to facilitate the search for effective therapies, E0771 medullary adenocarcinomas implanted subcutaneously in syngeneic C57BL/6 mice were studied.
Standard pathological, histological and immunological methodologies were used.
The aggressive estrogen receptor-positive tumor invaded locally into the peritoneal cavity in 56% of mice, as well as metastasizing to the lungs in 52% of mice. The metastasis was a spontaneous event and immunosuppression was seen (e.g. generation of lyphokine activated killer cells and allogeneic cytotoxic T lymphocytes cytolytic activities ex vivo were suppressed). Other pathological events noted as the tumor progressed were: bloody ascites (56%) and shock (72%), both attributed to local (peritoneal) tumor invasion.
The E0771 metastatic breast cancer model, which mimics the human disease, should be useful in testing new treatments against this disease and/or in examining the metastatic process.
Anticancer research 25(6B):3905-15. · 1.73 Impact Factor
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