Antitumour activity of trabectedin in myelodysplastic/myeloproliferative neoplasms

Romano, Michela; Porta, Matteo Giovanni Della; Gallì, Anna; Panini, Nicolò; Licandro, Simonetta Andrea; Bello, Ezia; Craparotta, Ilaria; Rosti, Vittorio; Bonetti, Elisa; Tancredi, Richard; Rossi, Marianna; Mannarino, Laura; Marchini, Sergio; Porcu, Luca; Galmarini, Carlos M.; Zambelli, Alberto; Zecca, Marco; Locatelli, Franco; Cazzola, Mario; Biondi, Andrea; Allavena, Paola; Erba, Eugenio; D’Incalci, Maurizio

doi:10.1038/bjc.2016.424

Cited by 18 publications

(15 citation statements)

References 51 publications

(72 reference statements)

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“…In many experimental models, the drug strongly reduces the number and function of tumor-associated macrophages, 42 with decreased production of inflammatory cytokines and of angiogenic, growth, and immunosuppressive factors responsible for the resistance to proapoptotic treatments; and evasion from the adaptive immune response and the induction of EMT, reportedly associated with resistance to therapies and short survival in patients with ovarian cancer. These observations, which have been confirmed in several preclinical systems and corroborated by the finding that trabectedin modifies the transcription regulation of genes involved in inflammation, like interleukin 6, and in EMT, such as q-guanosine triphosphatases, 49 could also play a role in improving the effectiveness of sequential treatment with trabectedin followed by PCs.…”

Section: Why Trabectedin?supporting

confidence: 58%

Restoring platinum sensitivity in recurrent ovarian cancer by extending the platinum‐free interval: Myth or reality?

Tomao

D’Incalci

Biagioli

et al. 2017

Cancer

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The platinum-free interval is the most important predictive factor of a response to subsequent lines of chemotherapy and the most important prognostic factor for progression-free and overall survival in patients with recurrent epithelial ovarian cancer. A nonplatinum regimen is generally considered the most appropriate approach when the disease recurs very early after the end of chemotherapy, whereas platinum-based chemotherapy is usually adopted when the platinum-free interval exceeds 12 months. However, the therapeutic management of patients with intermediate sensitivity (ie, when the relapse occurs between 6 and 12 months) remains debatable. Preclinical and clinical data suggest that the extension of platinum-free interval (using a nonplatinum-based regimen) might restore platinum sensitivity, thus allowing survival improvement. The objective of this review was to critically analyze preclinical and clinical evidences supporting this hypothesis. Cancer 2017;123:3450-9. © 2017 American Cancer Society.

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Section: Why Trabectedin?supporting

confidence: 58%

Restoring platinum sensitivity in recurrent ovarian cancer by extending the platinum‐free interval: Myth or reality?

Tomao

D’Incalci

Biagioli

et al. 2017

Cancer

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“…An adenosine-containing cyclic dinucleotide induces the selective apoptosis of monocytes, in vitro and in vivo, 139 whereas trabectedin, a DNA minor groove binder that has been tested in solid tumor patients, could selectively deplete myelomonocytic cells by inhibiting their growth and triggering their apoptosis. 140 …”

Section: Currently Explored Therapeutic Strategies In Cmml Patientsmentioning

confidence: 99%

How I treat chronic myelomonocytic leukemia

Solary

Itzykson

2017

Blood

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Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy that may deserve specific management. Defined by a persistent peripheral blood monocytosis ≥1 × 109/L and monocytes accounting for ≥10% of the white blood cells, this aging-associated disease combines cell proliferation as a consequence of myeloid progenitor hypersensitivity to granulocyte-macrophage colony-stimulating factor with myeloid cell dysplasia and ineffective hematopoiesis. The only curative option for CMML remains allogeneic stem cell transplantation. When transplantation is excluded, CMML is stratified into myelodysplastic (white blood cell count <13 × 109/L) and proliferative (white blood cell count ≥13 × 109/L) CMML. In the absence of poor prognostic factors, the management of myelodysplastic CMML is largely inspired from myelodysplastic syndromes, relying on erythropoiesis-stimulating agents to cope with anemia, and careful monitoring and supportive care, whereas the management of proliferative CMML usually relies on cytoreductive agents such as hydroxyurea, although ongoing studies will help delineate the role of hypomethylating agents in this patient population. In the presence of excessive blasts and other poor prognostic factors, hypomethylating agents are the preferred option, even though their impact on leukemic transformation and survival has not been proved. The therapeutic choice is illustrated by 4 clinical situations among the most commonly seen. Although current therapeutic options can improve patient’s quality of life, they barely modify disease evolution. Improved understanding of CMML pathophysiology will hopefully lead to the exploration of novel targets that potentially would be curative.

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“…Trabectedin was shown to re-sensitize resistant cells in some tumors (40). In sarcoma (41)(42)(43)(44), recurrent ovarian cancer (45), metastatic breast cancer (46), juvenile myelomonocytic leukemia, and chronic myelomonocytic leukemia (47), trabectedin has also been shown as efficacious. Trabectedin was effective in PDOX mouse models of sarcoma and pancreatic cancer (23)(24)(25)(26)(27)(28) and colon cancer (22).…”

Section: Discussionmentioning

confidence: 99%

Combination of Trabectedin With Irinotecan, Leucovorin and 5-Fluorouracil Arrests Primary Colorectal Cancer in an Imageable Patient-derived Orthotopic Xenograft Mouse Model

et al. 2019

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Background/Aim: The aim of the present study was to determine the efficacy of trabectedin combined with FOLFIRI (irinotecan, leucovorin and 5-fluorouracil) on a colorectal cancer (CRC) patient-derived orthotopic xenograft (iPDOX) mouse model. Materials and Methods: A CRC tumor from a patient previously established in nude mice was implanted subcutaneously in transgenic green fluorescence protein (GFP)expressing nude mice in order to label the tumor stromal cells with GFP. Mice were randomized into four groups: Group 1, untreated control; group 2, FOLFIRI; group 3, trabectedin alone; group 4, trabectedin plus FOLFIRI. Tumor width, length, and mouse body weight was measured twice every week. Results: All three treatment groups showed inhibited tumor growth compared to the untreated control group. Only the combination of FOLFIRI and trabectedin arrested tumor growth. No significant changes was observed in body weight in any group. Conclusion: These findings suggest that the combination of trabectedin plus FOLFIRI has clinical potential for patients with CRC. In order to improve cancer therapy, we have developed the patient-derived orthotopic xenograft (PDOX) nude mouse model for many cancer types (1-10). The PDOX nude mouse model is advantageous compared to subcutaneous implantation patient-derived xenograft models in various aspects, in particular metastasis (10). We also developed the colorectal cancer (CRC) PDOX model to improve treatment for this disease (1-17). Trabectedin has been used to treat many cancer types (18, 19). Trabectedin is highly active against many tumors resistant to alkylating agents (20). However, there are few studies on trabectedin in CRC. Izbicka et al. (19) and Twelves et al. (21) showed that patients with CRC could benefit from trabectedin. In a PDOX model of colon cancer, we recently showed that the combination of oxaliplaninum and 5-fluorouracil with trabectedin was highly effective (22). In PDOX models of sarcoma and pancreatic cancer, we have shown trabectedin to be an efficacious drug (23-28). In this present study, we investigated the effectiveness of trabectedin on a CRC imageable PDOX mouse model in combination with irinotecan, leucovorin and 5-fluorouracil (FOLFIRI). Materials and Methods Mice. Non-transgenic and transgenic green fluorescence protein (GFP)-expressing athymic nude nu/nu mice (4-to 6-week-old) were obtained from AntiCancer Inc. (San Diego, CA, USA). All mice were fed under high efficiency particulate arrestance (HEPA)filtered racks under standard conditions of 12 h light/dark cycles. All animal experiments were carried out in accordance with AntiCancer Inc. Institutional Animal Care and Use Committee (IACUC)-protocol specifically approved for this study, and in accordance with the principles and procedures outlined in the 6463 This article is freely accessible online.

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Antitumour activity of trabectedin in myelodysplastic/myeloproliferative neoplasms

Cited by 18 publications

References 51 publications

Restoring platinum sensitivity in recurrent ovarian cancer by extending the platinum‐free interval: Myth or reality?

Restoring platinum sensitivity in recurrent ovarian cancer by extending the platinum‐free interval: Myth or reality?

How I treat chronic myelomonocytic leukemia

Combination of Trabectedin With Irinotecan, Leucovorin and 5-Fluorouracil Arrests Primary Colorectal Cancer in an Imageable Patient-derived Orthotopic Xenograft Mouse Model

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