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Hidalgo M.,Johns Hopkins University | Hidalgo M.,Centro Integral Oncologico Clara Campal | Hidalgo M.,Clinical Research Program | Hidalgo M.,University of San Pablo - CEU | And 10 more authors.
Molecular Cancer Therapeutics | Year: 2011

Patients with many advanced solid cancers have very poor prognosis, and improvements in life expectancy are measured only in months. We have recently reported the remarkable clinical outcome of a patient with advanced, gemcitabine-resistant, pancreatic cancer who was later treated with DNA-damaging agents, on the basis of the observation of significant activity of this class of drugs against a personalized tumorgraft generated from the patient's surgically resected tumor. Here, we extend the approach to patients with other advanced cancers. Tumors resected from 14 patients with refractory advanced cancers were propagated in immunodeficient mice and treated with 63 drugs in 232 treatment regimens. An effective treatment regimen in the xenograft model was identified for 12 patients. One patient died before receiving treatment, and the remaining 11 patients received 17 prospectively guided treatments. Fifteen of these treatments resulted in durable partial remissions. In 2 subjects, no effective treatments were found. Overall, there was a remarkable correlation between drug activity in the model and clinical outcome, both in terms of resistance and sensitivity. The data support the use of the personalized tumorgraft model as a powerful investigational platform for therapeutic decision making and to efficiently guide cancer treatment in the clinic. ©2011 AACR.


Rodriguez-Antona C.,Hereditary Endocrine Cancer Group | Rodriguez-Antona C.,Research Center Biomedica En Red Of Enfermedades Raras Ciberer | Garcia-Donas J.,Centro Integral Oncologico Clara Campal
Pharmacogenomics | Year: 2012

The development of specific angiogenesis inhibitors has drastically improved renal cancer treatment in recent years. Currently, four VEGF receptor inhibitors (sorafenib, sunitinib, pazopanib and axitinib), one anti-VEGF monoclonal antibody (bevacizumab) and two inhibitors of the mTOR pathway (temsirolimus and everolimus) have been approved to treat renal cell carcinoma (RCC), and several other molecules are under investigation. However, lack of response to antiangiogenic drugs and adverse drug reactions leading to treatment suspension are critical clinical problems that need to be solved. Because antiangiogenic drugs act on nonmalignant endothelial cells, the genetic background of the patient may play a crucial role determining the efficacy of these drugs. This article focuses on the identification of polymorphisms associated with antiangiogenic drugs outcome in RCC patients. It reviews and summarizes our current knowledge on this area and discusses future strategies to identify new biomarkers that could be used to personalize RCC management. © 2012 Future Medicine Ltd.


Von Hoff D.D.,Translational Genomics Research Institute | Von Hoff D.D.,Virginia per Cancer Center | Ervin T.,Cancer Specialists | Arena F.P.,Arena Oncology Associates | And 21 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: In a phase 1-2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer. METHODS: We randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performance status) to nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter) on days 1, 8, and 15 every 4 weeks or gemcitabine monotherapy (1000 mg per square meter) weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients received the study treatment until disease progression. The primary end point was overall survival; secondary end points were progression-free survival and overall response rate. RESULTS: A total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel- gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel-gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel-gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days. CONCLUSIONS: In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. Copyright © 2013 Massachusetts Medical Society.


Estevez L.,Centro Integral Oncologico Clara Campal | Alvarez I.,Hospital Donostia | Tusquets I.,Hospital del Mar | Segui M.A.,Corporacio Sanitaria Parc Tauli | And 2 more authors.
Cancer Treatment Reviews | Year: 2013

Fulvestrant is a selective estrogen receptor downregulator, behaving as a complete antagonist. It was initially approved, at a dose of 250. mg, to treat hormone dependant breast cancer in second line setting. However, a series of pharmacological and pre-clinical studies have suggested that a higher dose of 500. mg may be more effective. The present work summarizes and discusses clinical trials that have aimed to test the benefits of administering fulvestrant at a higher dose. The data support the use of a higher, and more possibly, effective dose of the agent. © 2012 Elsevier Ltd.


Rodriguez-Pascual J.,Centro Integral Oncologico Clara Campal | Cheng E.,Centro Integral Oncologico Clara Campal | Maroto P.,Hospital Of La Santa Creu Y Sant Pau | Duran I.,Centro Integral Oncologico Clara Campal
Anti-Cancer Drugs | Year: 2010

The inhibitors of the mammalian target of rapamycin (mTOR) improve outcomes in patients with advanced renal cell carcinoma. These agents are associated with unusual class-adverse events that represent a challenge to the clinician, making it critical to recognize and treat them appropriately. This study aims to highlight the clinical management of these toxicities by presenting evidence from the literature and suggesting treatment recommendations. A critical review of the literature is performed and a summary of the most relevant emergent toxicities and their management is presented. Treatment recommendations of metabolic disturbances induced by mTOR inhibitors, such as hypophosphatemia, hyperglycemia, and hyperlipidemia along with the management of drug-induced pneumonitis and possible pharmacological interactions are presented. Most of these toxicities, if recognized and treated accordingly, should resolve with minimal impact on patients quality of life and in the efficacy of this anticancer therapy. Oncologists should be familiar with the recognition and appropriate medical management of these clinical scenarios. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Diaz-Padilla I.,University of Toronto | Diaz-Padilla I.,Centro Integral Oncologico Clara Campal | Duran I.,Centro Integral Oncologico Clara Campal | Clarke B.A.,University of Toronto | Oza A.M.,University of Toronto
Cancer Treatment Reviews | Year: 2012

Advanced recurrent gynecological malignancies have a poor prognosis despite systemic treatment, which is usually cytotoxic chemotherapy. Responses are generally short-lived and more effective treatments are needed. Rationally designed molecularly targeted therapy is an emerging and important option in this setting. The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase of the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway with a critical role in controlling cancer cellular growth, metabolism and cell cycle progression. Aberrant PI3K-dependent signaling occurs frequently in a wide range of tumor types, including ovarian, endometrial and cervical cancer. Early clinical studies of first-generation mTOR inhibitors have shown promising clinical activity in endometrial cancer. However, the molecular basis of sensitivity and resistance to these agents remains largely unknown. In this review, we will update the clinical and biological data underlying the development of first generation mTOR inhibitors in the treatment of gynecological tumors. The role of potential new combination regimens with mTOR inhibitors in gynecological cancers will also be discussed. © 2012 Elsevier Ltd.


Jimeno A.,Johns Hopkins University | Rubio-Viqueira B.,Centro Integral Oncologico Clara Campal | Rajeshkumar N.V.,Johns Hopkins University | Chan A.,Johns Hopkins University | And 3 more authors.
Molecular Cancer Therapeutics | Year: 2010

This work aimed to discover targets for combination treatment with gemcitabine in pancreatic cancer. We selected 11 tumors from our live collection of freshly generated pancreatic cancer xenografts with known degrees of varying gemcitabine sensitivity. We briefly (6 h) exposed fine-needle aspiration material to control vehicle or gemcitabine (1 μmol/L) and compared the gene expression of the treated and untreated samples using a reverse transcription-PCR-based, customized low-density array with 45 target genes of therapeutic interest. The gene expression of the untreated sample (which can be considered a baseline/static readout) was not predictive of gemcitabine efficacy in these tumors. Altogether, the only gene that differentiated sensitive versus resistant cases was polo-like kinase 1 (Plk1), showing >50% downregulation in sensitive cases and no change in the resistant cases. Inhibition of Plk1 by either small interfering RNA gene knockdown or with the Plk1 pathway modulator (ON 01910.Na) synergized with gemcitabine in gemcitabine-refractory in vitro models providing mechanistic proof of concept. In vivo experiments in gemcitabine-resistant xenografts showed synergistic activity decreasing cell proliferation and tumor regressions. A quantitative gene expression-based vulnerability assay identified Plk1 as a relevant target dictating the susceptibility of pancreatic cancer to gemcitabine. Dynamic interrogation of cancer has the potential to provide key information about mechanisms of resistance and to enhance individualization of treatment. ©2010 AACR.


Diaz-Padilla I.,University of Toronto | Diaz-Padilla I.,Centro Integral Oncologico Clara Campal | Amir E.,University of Toronto | Marsh S.,University of Alberta | And 2 more authors.
Gynecologic Oncology | Year: 2012

Purpose: Numerous studies have explored the potential role of genetic polymorphisms as predictive or prognostic biomarkers in gynecologic malignancies. A systematic review for all eligible polymorphisms has not yet been reported. The aim of this study was to summarize the current status of the field and provide direction for future research. Design: We searched literature databases (MEDLINE, EMBASE, Cochrane) from 2006 to April 2011 to identify studies evaluating the association between gene polymorphisms and clinical outcome in ovarian, endometrial, cervical, or vulvar cancer. The main outcome measures were overall survival (OS) and progression-free survival (PFS). Studies reporting relationships between polymorphisms and toxicity were also included. Results: Sixty two studies met the inclusion criteria. The median sample size was 140. Most of the included studies (n = 50, 81%) were conducted in ovarian cancer patients. Almost a third assessed potential predictive associations between gene polymorphism and outcome in ovarian cancer. The most commonly evaluated genes were ERCC1, VEGF, ABCB1 (MDR), and GSTP1. Most studies (n = 44, 71%) were observational case-series. Only four studies (6%) included a validation arm and patient population ethnicity was explicitly stated only in 27% of included studies. Conclusion: No consistent association between any gene polymorphism and clinical outcome in gynecological cancers has been found across studies. There is incomplete adherence to the REMARK guidelines and inadequate methodology reporting in most studies. Moving forward, analysis of large trial-based clinical samples; adherence to the highest methodological standards, and focus on validation analyses are necessary to identify clinically useful pharmacogenomic biomarkers of outcome. © 2011 Elsevier Inc. All rights reserved.


White D.A.,Sloan Kettering Cancer Center | Camus P.,Hopital Le Bocage and Pneumotox | Endo M.,Shizuoka Cancer Center | Escudier B.,Institute Gustave Roussy | And 8 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2010

Rationale: Noninfectious pneumonitis is a known class effect of mammalian target of rapamycin (mTOR) inhibitors. Objectives: To assess the incidence, radiographic patterns, management, and outcome of pneumonitis in patients with advanced renal cell carcinoma receiving everolimus. Methods: Clinical study data from 416 patients, randomized to receive everolimus versus placebo, were analyzed for adverse events of pneumonitis. Radiographic studies performed every 8 weeks were subject to a prospective, independent, blinded central review for the presence of findings indicative of pneumonitis. Measurements and Main Results:Of 274 patients receiving everolimus, clinical pneumonitis was suspected for 37 patients (13.5%) (none with placebo). Nine cases (3.3%) were grade 1 (asymptomatic), 18 (6.6%) were grade 2 (not interfering with daily living), and 10 (3.6%) were grade 3 (interfering with daily living or oxygen indicated). No grade 4 (life-threatening) pneumonitis was observed. Of the 10 patients with grade 3 pneumonitis, 5 had baseline radiological evidence of pneumonitis before everolimus therapy. Twenty of the 37 cases (54.0%) were reversible within the follow-up period; resolution followed dose reduction for 20 patients and treatment discontinuation in 10 patients. Corticosteroid therapy was initiated in 16 cases. Dedicated radiological review of available serial radiographic studies (245 patients receiving everolimus and 132 receiving placebo) found a higher percentage of new radiographic findings even in patients without a diagnosis of clinical pneumonitis who were receiving everolimus versus placebo (38.9 vs. 15.2%). Conclusions: Early recognition, prompt intervention, and a conservative approach are important in managing the risk associated with noninfectious pneumonitis in association with everolimus. Clinical trial registered with www.clinicaltrials.gov (NCT 00410124).


Lluch A.,Hospital Clinico Universitario Of Valencia | Alvarez I.,Hospital Universitario Of Donostia | Segui M.T.,Corporacio Sanitaria Parc Tauli | Tusquets I.,Hospital Del Mar Parc Of Salut Mar | Garcia-Estevez L.,Centro Integral Oncologico Clara Campal
Critical Reviews in Oncology/Hematology | Year: 2014

In spite of recent advances in the treatment of metastatic breast cancer, this disease remains essentially incurable. Anthracyclines and taxanes have been widely demonstrated to be the most active cytotoxic drugs for the treatment of breast cancer. Paclitaxel and docetaxel are both hydrophobic drugs that need to be administered with detergent-like substances as solvents. In contrast, nanoparticle albumin-bound (nab) paclitaxel uses the natural characteristics of albumin to reversibly bind paclitaxel, transport it across endothelial cells and concentrate the active ingredient within the tumor. Several trials have demonstrated that nab-paclitaxel results in superior efficacy, with more complete responses, prolonged time to recurrence and survival, than paclitaxel and docetaxel in MBC. As second-line treatment, the novel formulation has almost doubled overall response rate, increased time to progression and overall survival in comparison with paclitaxel. Due to these results, to date nab-paclitaxel stands out as a promising treatment of metastatic breast cancer. © 2013.

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