Emmanuel Seront

Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects.

Venous malformations (VMs) are composed of ectatic veins with scarce smooth muscle cell coverage. Activating mutations in the endothelial cell tyrosine kinase receptor TIE2 are a common cause of these lesions. VMs cause deformity, pain, and local intravascular coagulopathy, and they expand with time. Targeted pharmacological therapies are not available for this condition. Here, we generated a model of VMs by injecting HUVECs expressing the most frequent VM-causing TIE2 mutation, TIE2-L914F, into immune-deficient mice. TIE2-L914F-expressing HUVECs formed VMs with ectatic blood-filled channels that enlarged over time. We tested both rapamycin and a TIE2 tyrosine kinase inhibitor (TIE2-TKI) for their effects on murine VM expansion and for their ability to inhibit mutant TIE2 signaling. Rapamycin prevented VM growth, while TIE2-TKI had no effect. In cultured TIE2-L914F-expressing HUVECs, rapamycin effectively reduced mutant TIE2-induced AKT signaling and, though TIE2-TKI did target the WT receptor, it only weakly suppressed mutant-induced AKT signaling. In a prospective clinical pilot study, we analyzed the effects of rapamycin in 6 patients with difficult-to-treat venous anomalies. Rapamycin reduced pain, bleeding, lesion size, functional and esthetic impairment, and intravascular coagulopathy. This study provides a VM model that allows evaluation of potential therapeutic strategies and demonstrates that rapamycin provides clinical improvement in patients with venous malformation.

PTEN deficiency is associated with reduced sensitivity to mTOR inhibitor in human bladder cancer through the unhampered feedback loop driving PI3K/Akt activation.

Background:Preclinical studies have shown that PTEN loss enhances sensitivity to mammalian target of Rapamycin (mTOR) inhibitors because of facilitated PI3K (phosphatidylinositol-3 kinase)/Akt activation and consecutive stimulation of the mTOR pathway. In patients with advanced transitional cell carcinoma (TCC) treated with the mTOR inhibitor everolimus, PTEN loss was, however, associated with resistance to treatment.Methods:Transitional cell carcinoma specimens, human bladder cancer cells and derived mouse xenografts were used to evaluate how the PTEN status influences the activity of mTOR inhibitors.Results:Transitional cell carcinoma patients with a shorter progression-free survival under everolimus exhibited PTEN deficiency and increased Akt activation. Moreover, PTEN-deficient bladder cancer cells were less sensitive to rapamycin than cells expressing wild-type PTEN, and rapamycin strikingly induced Akt activation in the absence of functional PTEN. Inhibition of Akt activation by the PI3K inhibitor wortmannin interrupted this rapamycin-induced feedback loop, thereby enhancing the antiproliferative effects of the mTOR inhibitor both in vitro and in vivo.Conclusion:Facilitation of Akt activation upon PTEN loss can have a more prominent role in driving the feedback loop in response to mTOR inhibition than in promoting the mTOR pathway. These data support the use of both PI3K and mTOR inhibitors to treat urothelial carcinoma, in particular in the absence of functional PTEN.

Antitumor activity of 7-aminocarboxycoumarin derivatives, a new class of potent inhibitors of lactate influx but not efflux.

High lactate concentration in tumors is associated with bad prognosis. Lactate is released by glycolytic cells in tumors and recaptured by oxidative cancer cells to feed the tricarboxylic acid (TCA) cycle after conversion into pyruvate. Monocarboxylate transporters (MCT) mediate these fluxes of proton-linked lactate and represent attractive targets to interrupt lactate shuttle and to inhibit tumor growth. Here, we investigated the properties of 7-aminocarboxycoumarins (7ACC) developed to selectively interfere with lactate fluxes in the lactate-rich tumor microenvironment. The pharmacologic properties of two compounds of this family, including their effects on lactate influx and efflux and antitumor activity, were investigated using human cancer cell lines and mouse xenograft models. Contrary to the reference MCT1 inhibitor AR-C155858, 7ACC unexpectedly inhibited lactate influx but not efflux in tumor cells expressing MCT1 and MCT4 transporters. 7ACC delayed the growth of cervix SiHa tumors, colorectal HCT116 tumors, and orthoptopic MCF-7 breast tumors. MCT target engagement was confirmed by the lack of activity of 7ACC on bladder UM-UC-3 carcinoma that does not express functional MCT. 7ACC also inhibited SiHa tumor relapse after treatment with cisplatin. Finally, we found that contrary to AR-C155858, 7ACC did not prevent the cell entry of the substrate-mimetic drug 3-bromopyruvate (3BP) through MCT1, and contributed to the inhibition of tumor relapse after 3BP treatment. In conclusion, our results indicate that 7ACC selectively affects a single part of the MCT symporter translocation cycle, leading to strict inhibition of lactate influx. This singular activity is associated with antitumor effects less prone to resistance and side effects. Mol Cancer Ther; 13(6); 1410–8. ©2014 AACR.

Tumour hypoxia determines the potential of combining mTOR and autophagy inhibitors to treat mammary tumours.

Background:Hypoxia can activate autophagy, a self-digest adaptive process that maintains cell turnover. Mammalian target of rapamycin (mTOR) inhibitors are used to treat cancer but also stimulate autophagy.Methods:Human mammary cancer cells and derived xenografts were used to examine whether hypoxia could exacerbate autophagy-mediated resistance to the mTOR inhibitor rapamycin.Results:Rapamycin exerted potent antitumour effects in MCF-7 and MDA-MB-231 mammary tumours through a marked inhibition of angiogenesis, but the autophagy inhibitor chloroquine (CQ) failed to further sensitise tumours to mTOR inhibition. Rapamycin treatment actually led to tumour reoxygenation, thereby preventing the development of autophagy. Chloroquine alone, however, blocked the growth of MCF-7 tumours and in vitro blunted the hypoxia-induced component of autophagy in these cells. Finally, when initiating CQ treatment in large, hypoxic tumours, a robust antitumour effect could be observed, which also further increased the antiproliferative effects of rapamycin.Conclusion:The mTOR inhibitor rapamycin significantly contributes to tumour growth inhibition and normalisation of the tumour vasculature through potent antiangiogenic effects. The resulting reduction in hypoxia accounts for a lack of sensitisation by the autophagy inhibitor CQ, except if the tumours are already at an advanced stage, and thus largely hypoxic at the initiation of the combination of rapamycin and CQ treatment.

Liver-directed therapies: does it make sense in the current therapeutic strategy for patients with confined liver colorectal metastases?

Nearly half of patients with colorectal cancer will have metastases in the course of their disease and the liver appears to be the most common location for metastases. For patients with confined hepatic colorectal metastases, complete surgical resection is the only chance for cure, with a 5-year postoperative survival rate between 35% and 50%. Over the past 5 years, combinations of chemotherapy with targeted therapies have succeeded in inducing tumoral response and have made curative surgery of initially unresectable liver metastases possible. However despite optimal preoperative treatment, disease in the majority of patients remains unresectable. For patients with liver-limited or liver-dominant metastatic colorectal cancer (mCRC), the current challenges are to explore different locoregional treatments to improve local control, overall survival (OS), and curative resection. In this way, liver-directed therapy, which is defined by injection, infusion, or embolization of chemotherapy or loaded radionuclide (with radioactive yttrium-90) microspheres into the arterial liver vasculature, has been an appealing investigational method for patients with liver-confined mCRC, in whom it has yielded reproducibly higher response rates (RRs) than conventional intravenous therapy. In this article, we propose to review, compare, and discuss the clinical benefit, the current indications, and the optimal use of liver-directed therapies for patients with liver-dominant mCRC.

Targeted therapies in the treatment of advanced renal cell carcinoma

Renal cell carcinoma (RCC) represents five percent of adult epithelial cancers and clear cell RCC is the most frequent histological subtype. Improved understanding of the molecular pathways implicated in the pathogenesis of RCC has led to the development of specific targeted therapies to treat the disease. Five new medications have been shown to increase progression-free survival (PFS) in patients with metastatic clear cell RCC: bevacizumab, sorafenib, sunitinib, everolimus, and temsirolimus. Bevacizumab (+ interferon-alpha), sunitinib, and temsirolimus (in poor-risk groups) have proven to be effective as first-line palliative treatments. Sorafenib has demonstrated benefits in patients that have failed prior therapy, as has everolimus after failure of sorafenib and/or sunitinib. This paper provides a comprehensive review of the new targeted therapies currently available in clinical practice to treat patients with metastatic unresectable renal cell carcinoma. The relevant patents are discussed.

Randomized Phase II Study of Cabazitaxel Versus Methotrexate in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck Previously Treated With Platinum-Based Therapy

Lessons Learned Cabazitaxel has activity in squamous cell carcinoma of the head and neck (SCCHN) and taxane-resistant cell lines. For the first time, cabazitaxel was investigated in incurable patients with recurrent SCCHN. Patients were randomly assigned to cabazitaxel every 3 weeks or weekly methotrexate. This phase II study did not meet its primary endpoint. Cabazitaxel has low activity in SCCHN. The toxicity profile in this population also was not favorable owing to the high rate of febrile neutropenia observed (17%). Background. Cabazitaxel is a second-generation taxane that improves the survival of patients with metastatic castrate-resistant prostate cancer following docetaxel therapy. Cabazitaxel has activity in squamous cell carcinoma of the head and neck (SCCHN) and taxane-resistant cell lines. In this randomized phase II trial, we investigated cabazitaxel in patients with recurrent SCCHN. Methods. Patients with incurable SCCHN with progression after platinum-based therapy were randomly assigned to cabazitaxel every 3 weeks (cycle 1, 20 mg/m2, increased to 25 mg/m2 for subsequent cycles in the absence of nonhematological adverse events [AEs] greater than grade 2 and hematological AEs greater than grade 3) or methotrexate (40 mg/m2/week). The patients were stratified according to their performance status and previous platinum-based chemotherapy for palliation versus curative intent. The primary endpoint was the progression-free survival rate (PFSR) at 18 weeks. Results. Of the 101 patients, 53 and 48, with a median age of 58.0 years (range, 41–80), were randomly assigned to cabazitaxel or methotrexate, respectively. The PFSR at 18 weeks was 13.2% (95% confidence interval [CI], 5%–25%) for cabazitaxel and 8.3% (95% CI, 2%–20%) for methotrexate. The median progression-free survival was 1.9 months in both arms. The median overall survival was 5.0 and 3.6 months for cabazitaxel and methotrexate, respectively. More patients experienced serious adverse events with cabazitaxel than with methotrexate (54% vs. 36%). The most common drug-related grade 3–4 AE in the cabazitaxel arm was febrile neutropenia (17.3%). Conclusion. This study did not meet its primary endpoint. Cabazitaxel has low activity in recurrent SCCHN.

Rapamycin as Novel Treatment for Refractory-to-Standard-Care Slow-Flow Vascular Malformations.

METHODS: Informed consent was obtained and approved by our ethical committee. The trial is registered under VASCA-LM at clinicaltrials.gov (NCT01811667). Eighteen patients aged from 3 to 64 years with refractory-to-standard-care LMs (n=6), VMs (n=7) and/or complex vascular anomalies (n=5) were enrolled. Clinical symptoms included: chronic daily debilitating pain (n=12), functional impairment (n=9), recurrent infections (n=5), daily gastrointestinal bleeding (n=4), and chronic ulceration with oozing and bleeding (n=2), despite several sessions of sclerotherapies and/or surgery. Patients were seen on a monthly basis by the plastic surgeon and the oncologist. Efficacy was evaluated by anamnesis of symptoms (functional, cosmetic and psychological), pain evolution (frequency and intensity), quality of life questionnaire, clinical parameters, photos of the visible clinical lesions and blood sampling. A global self-evaluation percentage of increase/decrease in quality of life (including social and physical function, vitality, and pain) was recorded at each follow-up as well as side effects. Volumetric MRI using ITK-SNAP software was performed before initiation and at a yearly base.

Lactate-Induced IL-8 Pathway in Endothelial Cells—Response

In a recent publication ([1][1]), we have documented the capacity of lactate to enter endothelial cells via the monocarboxylate transporter MCT1 and to signal by stimulating an autocrine proangiogenic NF-κB/interleukin-8 (IL-8) pathway. In this mechanistic study, the reason why we used human

New drugs in medical oncology: new difficulties to distinguish drug-induced side effects from cancer complications: a case-report

Abstract We report the case of a woman with a metastatic breast cancer, who started a third-line treatment with dasatinib, a new oral tyrosine kinase inhibitor, and who developed, one week later, a progressive breathless sensation. Workup demonstrated pleuropericardial effusion that turned out to be a side effect of this new investigational drug. Although this dasatinib-induced side effect is well known, this case clearly illustrates the importance of an accurate diagnosis and adequate treatment of complications of new agents which are easy to use since most of them are orally taken, and the difficulty to clearly separate drug origin and cancer morbidities. The patient recovered completely one month after discontinuation of dasatinib. In this report, we will review the differential diagnosis and management of pleuropericardial effusion.