Maire V.,University Pierre and Marie Curie |
Maire V.,Breast Cancer Biology Group |
Nemati F.,University Pierre and Marie Curie |
Nemati F.,Laboratory of Preclinical Investigation |
And 40 more authors.
Cancer Research | Year: 2013
Breast cancers are composed of molecularly distinct subtypes with different clinical outcomes and responses to therapy. To discover potential therapeutic targets for the poor prognosis-associated triple-negative breast cancer (TNBC), gene expression profiling was carried out on a cohort of 130 breast cancer samples. Polo-like kinase 1 (PLK1) was found to be significantly overexpressed in TNBC compared with the other breast cancer subtypes. High PLK1 expression was confirmed by reverse phase protein and tissue microarrays. In triple-negative cell lines, RNAi-mediated PLK1 depletion or inhibition of PLK1 activity with a small molecule (BI-2536) induced an increase in phosphorylated H2AX, G 2-M arrest, and apoptosis. A soft-agar colony assay showed that PLK1 silencing impaired clonogenic potential of TNBC cell lines. When cells were grown in extracellular matrix gels (Matrigel), and exposed to BI-2536, apoptosis was observed specifically in TNBC cancerous cells, and not in a normal cell line. When administrated as a single agent, the PLK1 inhibitor significantly impaired tumor growth in vivo in two xenografts models established from biopsies of patients with TNBC. Most importantly, the administration of BI-2536, in combination with doxorubicin + cyclophosphamide chemotherapy, led to a faster complete response compared with the chemotherapy treatment alone and prevented relapse, which is the major risk associated with TNBC. Altogether, our observations suggest PLK1 inhibition as an attractive therapeutic approach, in association with conventional chemotherapy, for the management of patients with TNBC. © 2012 AACR.
Dahmani A.,Laboratory of Preclinical Investigation |
Plater L.D.,Laboratory of Preclinical Investigation |
Guyader C.,Laboratory of Preclinical Investigation |
Fontaine J.-J.,National Veterinary School of Alfort |
And 10 more authors.
Anti-Cancer Drugs | Year: 2010
Androgen-dependent and castration-resistant prostate cancer (PC) is usually sensitive to docetaxel chemotherapy. Nevertheless, docetaxel resistance frequently appears after several cycles of treatment, raising the problem of salvage treatment for docetaxel-resistant PC patients. Although the combination of docetaxel and estramustine prolongs metastasis-free and overall survival of patients with androgen-independent PC, the use of this modality remains limited in elderly patients or patients with several comorbidities, especially vascular disease or gastrointestinal toxicity, because of unacceptable toxicity including venous thrombosis. The aims of this study were therefore (i) to evaluate the in-vivo efficacy of estramustine combined with docetaxel since initial tumor growth and following the appearance of docetaxel resistance in the androgen-dependent human PC xenograft PAC120, and (ii) to evaluate the efficacy of estramustine in six human androgen-independent PC models derived from PAC120. In docetaxel-resistant tumor-bearing mice, estramustine alone induced a TGD2 of 18 days, whereas the combination of docetaxel and estramustine induced a TGD2 of 50 days (P < 0.05) with no significantly different overall survival of mice treated by docetaxel and estramustine since day 1 or since the onset of resistance to docetaxel. Among the six human androgen-independent tumors treated with estramustine alone, two highly sensitive models, two intermediate responding tumors, and two resistant models were observed. Altogether, these results suggest that estramustine should be combined with docetaxel in PC patients, but the use of this treatment could be limited, particularly in elderly patients, to docetaxel-resistant cases. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.
PubMed | Genosplice;, Affymetrix, National Veterinary School of Alfort, University Pierre and Marie Curie and 2 more.
Type: Journal Article | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2014
Patients with luminal breast cancer (LBC) often become endocrine resistant over time. We investigated the molecular changes associated with acquired hormonoresistances in patient-derived xenografts of LBC.Two LBC xenografts (HBCx22 and HBCx34) were treated with different endocrine treatments (ET) to obtain xenografts with acquired resistances to tamoxifen (TamR) and ovariectomy (OvaR). PI3K pathway activation was analyzed by Western blot analysis and IHC and responses to ET combined to everolimus were investigated in vivo. Gene expression analyses were performed by RT-PCR and Affymetrix arrays.HBCx22 TamR xenograft was cross-resistant to several hormonotherapies, whereas HBCx22 OvaR and HBCx34 TamR exhibited a treatment-specific resistance profile. PI3K pathway was similarly activated in parental and resistant xenografts but the addition of everolimus did not restore the response to tamoxifen in TamR xenografts. In contrast, the combination of fulvestrant and everolimus induced tumor regression in vivo in HBCx34 TamR, where we found a cross-talk between the estrogen receptor (ER) and PI3K pathways. Expression of several ER-controlled genes and ER coregulators was significantly changed in both TamR and OvaR tumors, indicating impaired ER transcriptional activity. Expression changes associated with hormonoresistance were both tumor and treatment specific and were enriched for genes involved in cell growth, cell death, and cell survival.PDX models of LBC with acquired resistance to endocrine therapies show a great diversity of resistance phenotype, associated with specific deregulations of ER-mediated gene transcription. These models offer a tool for developing anticancer therapies and to investigate the dynamics of resistance emerging during pharmacologic interventions. Clin Cancer Res; 20(16); 4314-25. 2014 AACR.
PubMed | Laboratory of Preclinical Investigation, University Paris - Sud and University Pierre and Marie Curie
Type: Journal Article | Journal: Ocular oncology and pathology | Year: 2016
Retinoblastoma is a rare cancer that occurs during childhood. The goal of current and future therapeutic strategies is to conserve the eye and visual function without using external beam radiotherapy, which is known to increase the risk of secondary cancers in genetically predisposed patients. Multimodality therapy (usually intravenous but also intra-arterial and intravitreal chemotherapy, transpupillary thermotherapy, cryotherapy, or brachytherapy) has recently improved the eye salvage rate in retinoblastoma and has led to a decreased need for external beam radiotherapy. However, the treatment of advanced intraocular retinoblastoma remains a real challenge, especially in cases of vitreous and subretinal seeding. There is a need for alternative and less toxic therapies as well as for better ways to administer the drugs. Animal models are an integral part of preclinical research in the field of oncology. This paper describes the different xenograft rodent models published in the literature so far. We will also describe a new orthotopic xenografted retinoblastoma model in immunodeficient mice, which is suitable for preclinical assays. The xenograft model was established from tumor tissue obtained directly from surgical samples and closely mimics human retinoblastoma.
Decaudin D.,Laboratory of Preclinical Investigation |
Decaudin D.,University Pierre and Marie Curie
Anti-Cancer Drugs | Year: 2011
The treatment of cancer is continually improving as a result of a better understanding of oncogenesis and the development of new targeted compounds. Early clinical trials evaluating such candidate compounds require a large number of patients, and are expensive, time consuming, and expose patients to certain risks. To select the most effective molecules, preclinical investigation of antitumor compounds is an important step in the drug development process. Three main categories of preclinical cancer models are generally used in preclinical investigations, namely genetically engineered models, xenografts derived from human tumor cell lines, and human tumor fragments from patients implanted directly into immunodeficient mice, known as tumorgrafts. The establishment of tumorgrafts constitutes a long-term process consisting of various steps, in which the final objective is to show that the validated model accurately reproduces human cancer, with a high predictive value of therapeutic efficacy (regardless of the type of treatment), and closely mimics clinical situations frequently observed in patients with cancer, such as resistance to standard treatments, metastases, and relapse after initial therapies (involving residual tumor-initiating cells). The aim of this study is therefore to discuss the proposed criteria for the establishment and validation of preclinical models of human cancers that should be used for further pharmacological assessments. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Baldeyron C.,University Pierre and Marie Curie |
Baldeyron C.,Breast Cancer Biology Group |
Brisson A.,University Pierre and Marie Curie |
Brisson A.,Breast Cancer Biology Group |
And 31 more authors.
Molecular Oncology | Year: 2015
Triple-negative breast cancer (TNBC) is the breast cancer subgroup with the most aggressive clinical behavior. Alternatives to conventional chemotherapy are required to improve the survival of TNBC patients. Gene-expression analyses for different breast cancer subtypes revealed significant overexpression of the Timeless-interacting protein (TIPIN), which is involved in the stability of DNA replication forks, in the highly proliferative associated TNBC samples. Immunohistochemistry analysis showed higher expression of TIPIN in the most proliferative and aggressive breast cancer subtypes including TNBC, and no TIPIN expression in healthy breast tissues. The depletion of TIPIN by RNA interference impairs the proliferation of both human breast cancer and non-tumorigenic cell lines. However, this effect may be specifically associated with apoptosis in breast cancer cells. TIPIN silencing results in higher levels of single-stranded DNA (ssDNA), indicative of replicative stress (RS), in TNBC compared to non-tumorigenic cells. Upon TIPIN depletion, the speed of DNA replication fork was significantly decreased in all BC cells. However, TIPIN-depleted TNBC cells are unable to fire additional replication origins in response to RS and therefore undergo apoptosis. TIPIN knockdown in TNBC cells decreases tumorigenicity in vitro and delays tumor growth in vivo. Our findings suggest that TIPIN is important for the maintenance of DNA replication and represents a potential treatment target for the worst prognosis associated breast cancers, such as TNBC. © 2015 Federation of European Biochemical Societies.
Decaudin D.,Laboratory of Preclinical Investigation
Expert Review of Ophthalmology | Year: 2010
There has been considerable interest, in the recent literature, in ocular adnexal lymphomas (OALs) and their biological and clinical characteristics. A possible association between OAL and Chlamydia psittaci infection has suggested new mechanisms of lymphomagenesis, leading the way to specific targeted treatments. Similarly, the role of rituximab monoclonal antibody therapy and more conventional chemotherapy, as well as a wait-and-see policy in a few clearly defined situations, must be described in relation to the standard treatment option consisting of radiotherapy for low-grade lymphomas. The aims of this review are therefore to present the current knowledge on the biology of these lymphomas, their clinical features and prognostic factors, and finally the available treatment options. © 2010 Expert Reviews Ltd.