Characterization of the effect of mammary gland irridiation on experimental brest cancer progression and analysis of the implicated mechanisms

SUMMARY Radiotherapy is commonly and efficiently used to treat solid cancer in the clinic. Experimental evidence however suggests that radiation can promote tumor progression by inducing chronic modifications of the tumor microenvironment. Clinically, these observations are highly relevant to aggressive tumoral lesions relapsing after radiation therapy, a leading cause of patients' death. The investigation and understanding of the biological mechanisms implicated in the malignant progression of post-radiation relapses are therefore of major importance. Here we used a syngeneic (immunocompetent) breast cancer orthotopic xenograft model, to show that local irradiation of the mammary gland promotes the appearance of an invasive and metastatic tumor phenotype. Previous studies in our laboratory revealed that inhibition of tumor-induced angiogenesis and consequent increase in tumor hypoxia promotes metastasis formation through the activation of pro-invasive programs in the tumor cells. Our results extend these observations suggesting that mammary gland irradiation induces the recruitment of CD11b+ cells to both the primary tumor and the lungs at pre-metastatic stages through the hypoxia-dependent induction of Kit-ligand (KITL) expression in primary tumors. Abrogation of KITL expression in tumor cells prevented CD11 b+ cells accumulation in both the primary tumor and lungs and significantly reduced metastases of tumors growing in irradiated mammary gland. Importantly, irradiated mammary gland enhanced tumor-induced mobilization of circulating CD11b+cKit+ myelomonocytic cells through a HIF1- and KITL-dependent process. By cell transfer experiments, mobilized circulating CD11b+cKit+ cells were shown to supply both tumor- and lungs infiltrating CD11b+ cells. Using a blocking antibody against cKit (the KITL receptor), the mobilization of CD11b+cKit+ ceils was prevented as well as lung metastases derived from tumors growing in irradiated mammary gland. Taken together, these results indicate that tumors growing in a pre-irradiated mammary gland partially promote their malignant progression through the distant mobilization of circulating myelomonocytic precursor cells. They identify KITL inhibition and/or cKit receptor neutralization as potentially promising therapeutic approaches for post-radiation relapses. RESUME La radiothérapie est largement utilisée comme traitement de choix de nombreux types de cancers. L'agressivité des récidives tumorales observée en clinique après radiothérapie suggère cependant que le recours à l'irradiation pourrait dans certains cas accélérer la progression tumorale. De récents travaux expérimentaux ont en effet permis d'appuyer cette hypothèse, en montrant notamment l'effet néfaste des modifications chroniques de l'environnement induites par l'irradiation sur la progression tumorale. A l'aide d'un modèle murin syngénique orthotopique de cancer de sein, nous avons pu montrer que l'irradiation locale de la glande mammaire facilite l'invasion et la dissémination métastatique des cellules tumorales en favorisant le recrutement de cellules myéloïdes CD11 b+ vers la tumeur primaire et les poumons à un stade pré-métastatique. Comme mécanisme impliqué dans le recrutement des cellules CD11b+, nous avons pu observer après irradiation locale de la glande mammaire une expression augmentée de Kit-ligand (KITL) dans la tumeur (induite par l'hypoxie) ainsi que la mobilisation de cellules myéloïdes circulantes exprimant le récepteur cKit et précurseurs des cellules CD11b+ infiltrant la tumeur et les poumons. En empêchant la mobilisation par la tumeur de cellules circulantes cKit+ par des approches à la fois génétique et pharmacologique nous avons pu prévenir l'accumulation de cellules myéloïdes CD11 b+ dans la tumeur primaire et les poumons ainsi que la dissémination métastatique induites par' l'irradiation de la glande mammaire. De façon générale, ces résultats montrent que la progression agressive des tumeurs qui se développent dans un environnement irradié repose à la fois sur l'expression tumorale de KITL et la mobilisation de cellules myéloïdes précurseurs cKit*. Ils auront permis d'identifier KITL et/ou cKit comme des cibles thérapeutiques potentielles intéressantes pour le traitement des récidives tumorales après radiothérapie.

Transanal endoscopic microsurgery versus conventional transanal excision for patients with early rectal cancer.

OBJECTIVE: To compare transanal endoscopic microsurgery (TEMS) with conventional transanal excision (TAE) in terms of the quality of resection, local recurrence, and survival rates in patients with stage I rectal cancer. BACKGROUND: Although TEMS is often considered a superior surgical technique to TAE, it is poorly suited for excising tumors in the lower third of the rectum. Such tumors may confer a worse prognosis. METHODS: We retrospectively reviewed information on all patients with stage pT1 and pT2 rectal adenocarcinoma who underwent local excision from 1997 through mid-2006. We excluded patients with node-positive, metastatic, recurrent, previously irradiated, or snare-excised tumors. RESULTS: Our study included 42 TEMS and 129 TAE patients. We found no significant differences in patient characteristics, adjuvant therapy, tumor stage, or adverse histopathologic features. In the TAE group, 52 (40%) of tumors were <5 cm from the anal verge (AV); in the TEMS group, only 1 (2%) (P = 0.0001). Surgical margins were less often positive in the TEMS group (2%) than in the TAE group (16%) (P = 0.017). For patients with tumors > or =5 cm from the AV, the estimated 5-year disease-free survival (DFS) rate was similar between the TEMS group (84.1%) and the TAE group (76.1%) (P = 0.651). But within the TAE group, the estimated 5-year DFS rate was better for patients with tumors > or =5 cm from the AV (76.1%) vs. <5 cm from the AV (60.5%) (P = 0.029). In our multivariate analysis, the tumor distance from the anal verge, the resection margin status, the T stage, and the use of adjuvant therapy--but not the surgical technique (i.e., TEMS or TAE) itself--were independent predictors of local recurrence and DFS. CONCLUSIONS: The quality of resection is better with TEMS than with TAE. However, the apparently better oncologic outcomes with TEMS can be partly explained by case selection of lower-risk tumors of the upper rectum.

Pharmacotherapeutic management of locally advanced prostate cancer: current status.

Locally advanced prostate cancer (LAPC) is a heterogeneous entity usually embracing T3-4 and/or pelvic lymph-node-positive disease in the absence of established metastases. Outcomes for LAPC with single therapies have traditionally been poor, leading to the investigation of adjuvant therapies. Prostate cancer is a hormonally sensitive tumour, which usually responds to pharmacological manipulation of the androgen receptor or its testosterone-related ligands. As such, androgen deprivation therapy (ADT) has become an important adjuvant strategy for the treatment of LAPC, particularly for patients managed primarily with radiotherapy. Such results have generally not been replicated in surgical patients. With increased use of ADT has come improved awareness of the numerous toxicities associated with long-term use of these agents, as well as the development of strategies for minimizing ADT exposure and actively managing adverse effects. Several trials are exploring agents to enhance radiation cell sensitivity as well as the application of adjuvant docetaxel, an agent with proven efficacy in the metastatic, castrate-resistant setting. The recent work showing activity of cabazitaxel, sipuleucel-T and abiraterone for castrate-resistant disease in the post-docetaxel setting will see these agents investigated in conjunction with definitive surgery and radiotherapy.

Oral versus intravenous empirical antimicrobial therapy for fever in patients with granulocytopenia who are receiving cancer chemotherapy. International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer.

BACKGROUND: Intravenously administered antimicrobial agents have been the standard choice for the empirical management of fever in patients with cancer and granulocytopenia. If orally administered empirical therapy is as effective as intravenous therapy, it would offer advantages such as improved quality of life and lower cost. METHODS: In a prospective, open-label, multicenter trial, we randomly assigned febrile patients with cancer who had granulocytopenia that was expected to resolve within 10 days to receive empirical therapy with either oral ciprofloxacin (750 mg twice daily) plus amoxicillin-clavulanate (625 mg three times daily) or standard daily doses of intravenous ceftriaxone plus amikacin. All patients were hospitalized until their fever resolved. The primary objective of the study was to determine whether there was equivalence between the regimens, defined as an absolute difference in the rates of success of 10 percent or less. RESULTS: Equivalence was demonstrated at the second interim analysis, and the trial was terminated after the enrollment of 353 patients. In the analysis of the 312 patients who were treated according to the protocol and who could be evaluated, treatment was successful in 86 percent of the patients in the oral-therapy group (95 percent confidence interval, 80 to 91 percent) and 84 percent of those in the intravenous-therapy group (95 percent confidence interval, 78 to 90 percent; P=0.02). The results were similar in the intention-to-treat analysis (80 percent and 77 percent, respectively; P=0.03), as were the duration of fever, the time to a change in the regimen, the reasons for such a change, the duration of therapy, and survival. The types of adverse events differed slightly between the groups but were similar in frequency. CONCLUSIONS: In low-risk patients with cancer who have fever and granulocytopenia, oral therapy with ciprofloxacin plus amoxicillin-clavulanate is as effective as intravenous therapy.

Therapeutic advances in non-small cell lung cancer.

Despite decades of research, therapeutic advances in non-small cell lung cancer (NSCLC) have progressed at a painstaking slow rate with few improvements in standard surgical resection for early stage disease and chemotherapy or radiotherapy for patients with advanced disease. In the past 18 months, however, we seemed to have reached an inflexion point: therapeutic advances that are centred on improvements in the understanding of patient selection, surgery that is undertaken through smaller incisions, identification of candidate mutations accompanied by the development of targeted anticancer treatments with a focus on personalised medicine, improvements to radiotherapy technology, emergence of radiofrequency ablation (RFA), and last but by no means least, the recognition of palliative care as a therapeutic modality in its own right. The contributors to this review are a distinguished international panel of experts who highlight recent advances in each of the major disciplines.

Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial.

BACKGROUND: Platinum-based doublet chemotherapy is recommended to treat advanced non-small-cell lung cancer (NSCLC) in fit, non-elderly adults, but monotherapy is recommended for patients older than 70 years. We compared a carboplatin and paclitaxel doublet chemotherapy regimen with monotherapy in elderly patients with advanced NSCLC. METHODS: In this multicentre, open-label, phase 3, randomised trial we recruited patients aged 70-89 years with locally advanced or metastatic NSCLC and WHO performance status scores of 0-2. Patients received either four cycles (3 weeks on treatment, 1 week off treatment) of carboplatin (on day 1) plus paclitaxel (on days 1, 8, and 15) or five cycles (2 weeks on treatment, 1 week off treatment) of vinorelbine or gemcitabine monotherapy. Randomisation was done centrally with the minimisation method. The primary endpoint was overall survival, and analysis was done by intention to treat. This trial is registered, number NCT00298415. FINDINGS: 451 patients were enrolled. 226 were randomly assigned monotherapy and 225 doublet chemotherapy. Median age was 77 years and median follow-up was 30.3 months (range 8.6-45.2). Median overall survival was 10.3 months for doublet chemotherapy and 6.2 months for monotherapy (hazard ratio 0.64, 95% CI 0.52-0.78; p<0.0001); 1-year survival was 44.5% (95% CI 37.9-50.9) and 25.4% (19.9-31.3), respectively. Toxic effects were more frequent in the doublet chemotherapy group than in the monotherapy group (most frequent, decreased neutrophil count (108 [48.4%] vs 28 [12.4%]; asthenia 23 [10.3%] vs 13 [5.8%]). INTERPRETATION: Despite increased toxic effects, platinum-based doublet chemotherapy was associated with survival benefits compared with vinorelbine or gemcitabine monotherapy in elderly patients with NSCLC. We feel that the current treatment paradigm for these patients should be reconsidered. FUNDING: Intergroupe Francophone de Cancérologie Thoracique, Institut National du Cancer.

Phase I safety and pharmacodynamic of inecalcitol, a novel VDR agonist with docetaxel in metastatic castration-resistant prostate cancer patients.

PURPOSE: We conducted a phase I multicenter trial in naïve metastatic castrate-resistant prostate cancer patients with escalating inecalcitol dosages, combined with docetaxel-based chemotherapy. Inecalcitol is a novel vitamin D receptor agonist with higher antiproliferative effects and a 100-fold lower hypercalcemic activity than calcitriol. EXPERIMENTAL DESIGN: Safety and efficacy were evaluated in groups of three to six patients receiving inecalcitol during a 21-day cycle in combination with docetaxel (75 mg/m2 every 3 weeks) and oral prednisone (5 mg twice a day) up to six cycles. Primary endpoint was dose-limiting toxicity (DLT) defined as grade 3 hypercalcemia within the first cycle. Efficacy endpoint was ≥30% PSA decline within 3 months. RESULTS: Eight dose levels (40-8,000 μg) were evaluated in 54 patients. DLT occurred in two of four patients receiving 8,000 μg/day after one and two weeks of inecalcitol. Calcemia normalized a few days after interruption of inecalcitol. Two other patients reached grade 2, and the dose level was reduced to 4,000 μg. After dose reduction, calcemia remained within normal range and grade 1 hypercalcemia. The maximum tolerated dose was 4,000 μg daily. Respectively, 85% and 76% of the patients had ≥30% PSA decline within 3 months and ≥50% PSA decline at any time during the study. Median time to PSA progression was 169 days. CONCLUSION: High antiproliferative daily inecalcitol dose has been safely used in combination with docetaxel and shows encouraging PSA response (≥30% PSA response: 85%; ≥50% PSA response: 76%). A randomized phase II study is planned.

Place du pathologiste dans la prise en charge néoadjuvante des cancers du sein [Neoadjuvant treatment of breast cancer: implications for the pathologist].

These past few years, neoadjuvant strategy has taken an increasing place in the management of breast cancer patients. This strategy is mainly indicated to obtain a tumour bulk regression allowing a breast conserving surgery in patients that otherwise would have undergone mastectomy. Of note, development of new chemotherapy agents and targeted therapies has critically helped in the progress of neoadjuvant strategy as it is currently associated with better pathological response rates. In this context, the pathologist is at the crossroad of this multidisciplinary process. First, he provides on the initial core needle biopsy the tumour pathological characteristics that are critical for the choice of treatment strategy, i.e. histological type, histological grade, proliferative activity (mitotic count and Ki67/MIB1 index labeling), hormone receptor status (oestrogen receptor and progesterone receptor) and HER2 status. Secondly, the pathologist evaluates the pathological response and the status of surgical margins with regards to the residual tumour on the surgical specimen after neoadjuvant treatment. These parameters are important for the management of the patient, since it has been shown that complete pathological response is associated with improved disease free survival. Several grading systems are used to assess the pathological response in breast and axillary lymph nodes. The most frequently used in France are currently the systems described by Sataloff et al. and Chevallier et al. In this review, we detail the different steps involving the pathologist in neoadjuvant setting, with special regards to the quality process and future perspectives such as emerging predictive biomarkers.

Extensive (8 to 12 cm2) noncircumferential endoscopic mucosal resection for early esophageal cancer.

Background: Endoscopic mucosal resection (EMR) is an appealing method for treating intramucosal esophageal cancer but must comply with the following stringent requirements: proper preoperative staging, complete resection of the lesion, obtaining a resected specimen for histologic analysis of safety margins, and squamous reepithelialization without stricture formation. Methods: A rigid esophagoscope was created to resect up to 12 cm(2) of esophageal mucosa in a single specimen and at a constant depth through the submucosa. Under visual control, the esophageal mucosa is sucked into a transparent window and resected with a thin diathermy wire loop in 10 seconds. After extensive preclinical studies in a sheep model, this article reports our early experience in humans. Results: Twenty-one hemi-circumferential EMRs were performed for 11 dysplastic Barrett's esophagi and 10 early squamous cell carcinomas with no perforation, one hemorrhage controlled by embolization of the left gastric artery, and one incomplete resection. Deep safety margins were clear in 19 of 21 resected specimens (2 patients, unfit for operations, had submucosal invasion of squamous cell carcinoma and adenocarcinoma, respectively). Lateral margins were not clear by definition in 7 circumferential Barrett's esophagi, but were clear in 4 incomplete Barrett's esophagi and 10 early squamous cell carcinomas. Conclusions: Large EMRs of 12 cm(2) can safely be performed at the submucosal level in the esophagus. Although feasible in one session, circumferential EMR in humans is not yet advisable because of the risk of stricture formation during the healing phase. The rate of complications of this series of 21 EMRs in humans is acceptable. (Ann Thorac Surg 2010; 89: S2151-5) (C) 2010 by The Society of Thoracic Surgeons

Caspofungin first-line therapy for invasive aspergillosis in allogeneic hematopoietic stem cell transplant patients: an European Organisation for Research and Treatment of Cancer study.

Caspofungin at standard dose was evaluated as first-line monotherapy of mycologically documented probable/proven invasive aspergillosis (IA) (unmodified European Organisation for Research and Treatment of Cancer/Mycosis Study Group criteria) in allogeneic hematopoietic SCT patients. The primary efficacy end point was complete or partial response at end of caspofungin treatment. Response at week 12, survival and safety were additional end points. Enrollment was stopped prematurely because of low accrual, with 42 enrolled and 24 eligible, giving the study a power of 85%. Transplant was from unrelated donors in 16 patients; acute or chronic GVHD was present in 15. In all, 12 patients were neutropenic (<500/microl) at baseline, 10 received steroids and 16 calcineurin inhibitors or sirolimus. Median duration of caspofungin treatment was 24 days. At the end of caspofungin therapy, 10 (42%) patients had complete or partial response (95% confidence interval: 22-63%); 1 (4%) and 12 (50%) had stable and progressing disease, respectively; one was not evaluable. At week 12, eight patients (33%) had complete or partial response. Survival rates at week 6 and 12 were 79 and 50%, respectively. No patient had a drug-related serious adverse event or discontinued because of toxicity. Caspofungin first-line therapy was effective and well tolerated in allogeneic hematopoietic SCT patients with mycologically documented IA.

Impact of induction therapy on airway complications after sleeve lobectomy for lung cancer.

BACKGROUND: Sleeve lobectomy is a valid alternative to pneumonectomy for the treatment of centrally located operable non-small cell lung cancer (NSCLC), but concern has been evoked regarding a potentially increased risk of bronchial anastomosis complications after induction therapy. This study examined the impact of induction therapy on airway healing after sleeve lobectomy for NSCLC. METHODS: Bronchial anastomosis complications were recorded with respect to the induction regimen applied (neoadjuvant chemotherapy vs chemoradiotherapy) in a consecutive series of patients with sleeve lobectomy for NSCLC. RESULTS: Ninety-nine patients underwent sleeve resection, 28 of them after induction therapy. Twelve patients received chemotherapy alone, and 16 patients had radiochemotherapy. There were no significant differences in postoperative 90-day mortality (3.6% vs 2.8%) and morbidity (54% vs 49%) for patients with and without induction therapy. Bronchial anastomosis complications occurred in 3 patients (10.8%) with neoadjuvant therapy and in 2 (2.8%) without (p = 0.3). In the induction therapy group, two bronchial stenoses occurred after radiochemotherapy and one bronchopleural fistula after chemotherapy alone. In patients without induction therapy, one bronchial stenosis and one bronchopleural fistula were observed. All bronchial stenoses were successfully treated by dilatation, and both bronchopleural fistulas occurring after right lower lobectomy were successfully treated by reoperation and completion sleeve bilobectomy with preservation of the upper lobe. CONCLUSIONS: Sleeve lobectomy for NSCLC can be safely performed after induction chemotherapy and radiochemotherapy with mortality and incidence of airway complications similar to that observed in nonpretreated patients. The treatment of airway complications does not differ for patients with and without induction therapy.

A prospective development study investigating focal irreversible electroporation in men with localised prostate cancer: Nanoknife Electroporation Ablation Trial (NEAT).

INTRODUCTION: Focal therapy may reduce the toxicity of current radical treatments while maintaining the oncological benefit. Irreversible electroporation (IRE) has been proposed to be tissue selective and so might have favourable characteristics compared to the currently used prostate ablative technologies. The aim of this trial is to determine the adverse events, genito-urinary side effects and early histological outcomes of focal IRE in men with localised prostate cancer. METHODS: This is a single centre prospective development (stage 2a) study following the IDEAL recommendations for evaluating new surgical procedures. Twenty men who have MRI-visible disease localised in the anterior part of the prostate will be recruited. The sample size permits a precision estimate around key functional outcomes. Inclusion criteria include PSA ≤ 15 ng/ml, Gleason score ≤ 4 + 3, stage T2N0M0 and absence of clinically significant disease outside the treatment area. Treatment delivery will be changed in an adaptive iterative manner so as to allow optimisation of the IRE protocol. After focal IRE, men will be followed during 12 months using validated patient reported outcome measures (IPSS, IIEF-15, UCLA-EPIC, EQ-5D, FACT-P, MAX-PC). Early disease control will be evaluated by mpMRI and targeted transperineal biopsy of the treated area at 6 months. DISCUSSION: The NEAT trial will assess the early functional and disease control outcome of focal IRE using an adaptive design. Our protocol can provide guidance for designing an adaptive trial to assess new surgical technologies in the challenging landscape of health technology assessment in prostate cancer treatment.

Design of new tools to improve the efficacy of DNA-damaging drugs used in cancer therapy

Résumé Les tumeurs sont diverses et hétérogènes, mais toutes partagent la capacité de proliférer sans contrôle. Une prolifération dérégulée de cellules couplée à une insensibilité à une réponse apoptotique constitue une condition minimale pour que l'évolution d'une tumeur se produise. Un des traitements les plus utilisés pour traité le cancer à l'heure actuelle sont les chimiothérapies, qui sont fréquemment des composés chimiques qui induisent des dommages dans l'ADN. Les agents anticancéreux sont efficaces seulement quand les cellules tumorales sont plus aisément tuées que le tissu normal environnant. L'efficacité de ces agents est en partie déterminée par leur capacité à induire l'apoptose. Nous avons récemment démontré que la protéine RasGAP est un substrat non conventionnel des caspases parce elle peut induire à la fois des signaux anti et pro-apoptotiques, selon l'ampleur de son clivage par les caspases. A un faible niveau d'activité des caspases, RasGAP est clivé, générant deux fragments (le fragment N et le fragment C). Le fragment N semble être un inhibiteur général de l'apoptose en aval de l'activation des caspases. À des niveaux plus élevés d'activité des caspases, la capacité du fragment N de contrecarrer l'apoptose est supprimée quand il est clivé à nouveau par les caspases. Ce dernier clivage produit deux nouveaux fragments, N 1 et N2, qui contrairement au fragment N sensibilisent efficacement des cellules cancéreuses envers des agents chimiothérapeutiques. Dans cette étude nous avons prouvé qu'un peptide, appelé par la suite TAT-RasGAP317-326, qui est dérivé du fragment N2 de RasGAP et est rendu perméable aux cellules, sensibilise spécifiquement des cellules cancéreuses à trois génotoxines différentes utilisées couramment dans des traitements anticancéreux, et cela dans des modèles in vitro et in vivo. Il est important de noté que ce peptide semble ne pas avoir d'effet sur des cellules non cancéreuses. Nous avons également commencé à caractériser les mécanismes moléculaires expliquant les fonctions de sensibilisation de TAT-RasGAP317-326. Nous avons démontré que le facteur de transcription p53 et une protéine sous son activité transcriptionelle, nommée Puma, sont indispensables pour l'activité de TAT-RasGAP317-326. Nous avons également prouvé que TAT-RasGAP317-326 exige la présence d'une protéine appelée G3BP1, une protéine se liant a RasGAP, pour potentialisé les effets d'agents anticancéreux. Les données obtenues dans cette étude montrent qu'il pourrait être possible d'augmenter l'efficacité des chimiothérapies à l'aide d'un composé capable d'augmenter la sensibilité des tumeurs aux génotoxines et ainsi pourrait permettre de traiter de manière plus efficace des patients sous traitement chimiothérapeutiques. Summary Tumors are diverse and heterogeneous, but all share the ability to proliferate without control. Deregulated cell proliferation coupled with suppressed apoptotic sensitivity constitutes a minimal requirement upon which tumor evolution occurs. One of the most commonly used treatments is chemotherapy, which frequently uses chemical compounds that induce DNA damages. Anticancer agents are effective only when tumors cells are more readily killed than the surrounding normal tissue. The efficacy of these agents is partly determined by their ability to induce apoptosis. We have recently demonstrated that the protein RasGAP is an unconventional caspase substrate because it can induce both anti- and pro-apoptotic signals, depending on the extent of its cleavage by caspases. At low levels of caspase activity, RasGAP is cleaved, generating an N-terminal fragment (fragment N) and a C-terminal fragment (fragment C). Fragment N appears to be a general Mocker of apoptosis downstream of caspase activation. At higher levels of caspase activity, the ability of fragment N to counteract apoptosis is suppressed when it is further cleaved. This latter cleavage event generates two fragments, N1 and N2, which in contrast to fragment N potently sensitizes cancer cells toward DNA-damaging agents induced apoptosis. In the present study we show that a cell permeable peptide derived from the N2 fragment of RasGAP, thereafter called TAT-RasGAP317-326, specifically sensitizes cancer cells to three different genotoxins commonly used in chemotherapy in vitro and in vivo models. Importantly this peptide seems not to have any effect on non cancer cells. We have also started to characterize the molecular mechanisms underlying the sensitizing functions of TAT-RasGAP317-326. We have demonstrated that the p53 transcription factor and a protein under its transcriptional activity, called Puma, are required for the activity of TATRasGAP317-326. We have also showed that TAT-RasGAP317-326 requires the presence of a protein called G3BP1, which have been shown to interact with RasGAP, to increase the effect of the DNA-damaging drug cisplatin. The data obtained in this study showed that it is possible to increase the efficacy of current used chemotherapies with a compound able to increase the efficacy of genotoxins which could be beneficial for patients subjected to chemotherapy.

New insights into the mechanisms of organ-specific breast cancer metastasis.

Despite the substantial advances obtained in the treatment of localized malignancies, metastatic disease still lacks effective treatment and remains the primary cause of cancer mortality, including in breast cancer. Thus, in order to improve the survival of cancer patients it is necessary to effectively improve prevention or treatment of metastasis. To achieve this goal, complementary strategies can be envisaged: the first one is the eradication of established metastases by adding novel modalities to current treatments, such as immunotherapy or targeted therapies. A second one is to prevent tumor cell dissemination to secondary organs by targeting specific steps governing the metastatic cascade and organ-specific tropism. A third one is to block the colonization of secondary organs and subsequent cancer cell growth by impinging on the ability of disseminated cancer cells to adapt to the novel microenvironment. To obtain optimal results it might be necessary to combine these strategies. The development of therapeutic approaches aimed at preventing dissemination and organ colonization requires a deeper understanding of the specific genetic events occurring in cancer cells and of the host responses that co-operate to promote metastasis formation. Recent developments in the field disclosed novel mechanisms of metastasis. In particular the crosstalk between disseminated cancer cells and the host microenvironment is emerging as a critical determinant of metastasis. The identification of tissue-specific signals involved in metastatic progression will open the way to new therapeutic strategies. Here, we will review recent progress in the field, with particular emphasis on the mechanisms of organ specific dissemination and colonization of breast cancer.