Roberto Pili

Roswell Park Cancer Institute, Buffalo, New York, United States

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Publications (131)648.31 Total impact

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    Society of Basic Urologic Research (SBUR); 11/2014
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    ABSTRACT: Alternative pathways to the vascular endothelial grow factor (VEGF), such as hepatocyte growth factor or HGF/c-met, are emerging as key players in tumor angiogenesis and resistance to anti-VEGF therapies. The aim of this study was to assess the effects of a combination strategy targeting VEGF and c-met pathway in clear cell renal cell carcinoma (ccRCC) models. Male SCID mice (8/group) were implanted with 786-O tumor pieces and treated with either a selective VEGF receptor tyrosine kinase inhibitor, axitinib (36 mg/kg, 2x/day), a c-met inhibitor, crizotinib (25 mg/kg, 1x/day), or combination. We further tested this drug combination in a human ccRCC patient derived xenograft, RP-R-01, in both VEGF-targeted therapy sensitive and resistant models. To evaluate the resistance phenotype, we established RP-R-01 sunitinib resistant model by continuous sunitinib treatment (60 mg/kg, 1x/day) of RP-R-01 bearing-mice. Treatment with single agent crizotinib reduced tumor vascularization but failed to inhibit tumor growth in either model, despite also a significant increase of c-met expression and phosphorylation in the sunitinib resistant tumors. In contrast, axitinib treatment was effective in inhibiting angiogenesis and tumor growth in both models, with its anti-tumor effect significantly increased by the combined treatment with crizotinib, independently from c-met expression. Combination treatment also induced prolonged survival and significant tumor growth inhibition in the 786-O human RCC model. Overall, our results support the rationale for the clinical testing of combined VEGF and HGF/c-met pathway blockade in the treatment of ccRCC, both in first and second line setting.
    Molecular Cancer Therapeutics 11/2014; · 5.60 Impact Factor
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    ABSTRACT: A major barrier for cancer immunotherapy is the presence of suppressive cell populations in cancer patients, such as myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), which contribute to the immunosuppressive microenvironment that promotes tumor growth and metastasis. Tasquinimod is a novel antitumor agent that is currently at an advanced stage of clinical development for treatment of castration-resistant prostate cancer. A target of tasquinimod is the inflammatory protein S100A9, which has been demonstrated to affect the accumulation and function of tumor-suppressive myeloid cells. Here, we report that tasquinimod provided a significant enhancement to the antitumor effects of two different immunotherapeutics in mouse models of cancer: a tumor vaccine (SurVaxM) for prostate cancer and a tumor-targeted superantigen (TTS) for melanoma. In the combination strategies, tasquinimod inhibited distinct MDSC populations and TAMs of the M2-polarized phenotype (CD206+). CD11b+ myeloid cells isolated from tumors of treated mice expressed lower levels of arginase-1 and higher levels of inducible nitric oxide synthase (iNOS), and were less immunosuppressive ex vivo, which translated into a significantly reduced tumor-promoting capacity in vivo when these cells were co-injected with tumor cells. Tumor-specific CD8+ T cells were increased markedly in the circulation and in tumors. Furthermore, T-cell effector functions, including cell-mediated cytotoxicity and IFNγ production, were potentiated. Taken together, these data suggest that pharmacologic targeting of suppressive myeloid cells by tasquinimod induces therapeutic benefit and provide the rationale for clinical testing of tasquinimod in combination with cancer immunotherapies.
    Cancer immunology research. 11/2014;
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    ABSTRACT: Background: Various RCTs have shown improved outcomes with addition of aprepitant to standard antiemetic treatment (SAT) in preventing CINV. We conducted a meta­analysis to study the overall impact of ACR in CINV prevention in adults. Methods: We searched Pubmed and Ovid databases, and American Society of Clinical Oncology meetings abstracts for RCTs using ACR with SAT for CINV prevention in adult cancer patients (pts). Major study end points were complete response to treatment (CR; defined as no emesis and no use of rescue medications) in overall phase (OP; 0­120 hours of chemotherapy), acute phase (AP; 0­24 hours) and delayed phase (DP; 24­120 hours). Additionally, we assessed the control of nausea and toxicity profile (TP). Stouffer's Z­score method was used to calculate the overall effect. Results: 16 RCTs (5,547 pts) were included. 11 trials (3,314 pts) involved highly emetogenic chemotherapy (HEC) and 5 trials (2,233 pts) involved moderately emetogenic chemotherapy (MEC). ACR increased CR in OP from 47% to 63% (OR=0.52, CI=0.46 to 0.58; p<0.001), in AP from 73% to 81% (p<0.01), and in DP from 51% to 66% (p<0.001). Significant increase in nausea control was seen in DP (p=0.03) but not in OP or AP. Incidence of various toxicities was statistically similar in both groups except slightly higher rate of fatigue (p=0.02) and hiccups (p<0.001), and lower rate of neutropenia (p=0.02) in ACR. Conclusions: ACR is effective in CINV due to both HEC and MEC in adult cancer pts. ACR improves the control of emesis in all phases, and nausea in delayed phase only. With the exception of causing more fatigue & hiccups, and lesser neutropenia, overall TP of ACR is similar to SAT.
    World Congress on Cancer Science and therapy; 10/2014
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    ABSTRACT: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Progression to metastatic disease is the primary cause of mortality in men with prostate cancer (PCa). Mouse models which progress with spontaneous metastasis are limited. Such models would allow for extensive studies of molecular mechanisms of metastasis, and more definite pre-clinical therapy trials. Orthotopic murine models have been described; however a limiting biology of these models is their lack of an intact immune system. Within, we describe the development of an androgen sensitive and castrate resistant tractable orthotopic murine syngeneic (immune competent) model of prostate cancer. Both models develop primary tumors which spontaneously progress to metastatic disease in lymph tissue. These models will allow for more complete mechanistic and therapeutic studies in a short time period. INTRODUCTION Prostate cancer (PCa) is among the top three most prevalent cancers among males [1] and the second leading cause of cancer related deaths in men in the United States [2]. An estimated 233,000 new prostate cancer patients were diagnosed in 2014 with an estimated total of 29,480 deaths due to prostate cancer [2]. Recent advances of FDA approved therapies including Enzalutamide (MDV3100), Zytiga (Abiraterone Acetate) and Radium-223 have displayed potential in the clinic. Unfortunately, these new therapies only offer modest survival in patients with mCRPC, and novel therapies are still urgently required which achieve sustainable suppression of tumor growth. Mouse models are a powerful tool to conduct preclinical or 'proof of concept' therapeutic experiments to expedite results to clinical trial. Death from PCa does not occur because of formation of the primary tumor, but rather the progression to metastatic disease. This highlights the primary concern for PCa patients is the successful treatment of metastatic tumors. a recent meeting held by the Prostate Cancer Foundation which addressed issues hampering the translation of bench to bedside discoveries resulting from research generated in animal models [3]. Concerns raised from this meeting included a lack of understanding of the molecular events that define tumorigensis and a lack of tools for studying tumor-host interactions [3]. Current transgenic mouse models of PCa very rarely reflect molecular features of prostate cancer initiation and progression that correlate with human disease. Also, development of castrate resistant or metastatic disease is limited. Experimental mouse models of metastatic PCa involve tail-vein or intracardiac injections, which generates an artificial metastatic environment. Further, these models do not accurately capture true progression of metastatic PCa, as tumors have not undergone a natural 'metastatic evolution' process, which includes escape of the primary tumor and microenvironment and ability to nest and grow at distal sites. Also, experimental models of metastatic PCa often involve human cell lines or tissue, meaning there is not a true representation of the immune system, which is a critical component of the
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    ABSTRACT: Background This phase I study evaluated the pharmacokinetics and pharmacodynamics of CEP-11981, an oral vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, in patients with advanced, relapsed, or refractory solid tumors. Methods Oral CEP-11981 dose escalations followed a modified Fibonacci sequence (from 3.0 to 4.2, 5.9, 11.8, 19.7, 29.6, 41.4, 55.0, 73.0, 97.4, and 126.6 mg/m(2)). The maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), tumor response, and safety were evaluated. Results CEP-11981 was tolerated at doses between 3.0 and 97.4 mg/m(2). The MTD of CEP-11981 was determined to be 97.4 mg/m(2), with DLTs observed at the 126.6 mg/m(2) dose. The DLTs were grade 4 neutropenia in 1 patient and grade 3 T-wave inversion with chest heaviness and fatigue in 1 patient. All 3 events resolved on stopping CEP-11981. The most frequently reported adverse events of any grade were fatigue, nausea, diarrhea, decreased appetite, abdominal pain, back pain, vomiting, constipation, headache, dizziness, and dyspnea. Treatment-related grade 3/4 neutropenia was observed in the highest-dose cohorts (2 patients at 97.4 mg/m(2) and 1 patient at 126.6 mg/m(2)), indicating some off-target inhibition. VEGF inhibition was greatest in the higher-dose groups. Although no patient experienced complete or partial response, 44 % patients achieved stable disease when measured at ≥ 6 weeks, which occurred more frequently in cohorts receiving ≥ 73.0 mg/m(2). Conclusions In patients with recurrent or refractory solid tumors, disease stabilization was achieved. Despite acceptable tolerability of CEP-11981 at the MTD, further development by the sponsor has ceased.
    Investigational New Drugs 08/2014; · 3.50 Impact Factor
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    ABSTRACT: Histone deacetylase (HDAC) inhibitors are immunomodulatory, and demonstrate antitumor activity in various tumor models including malignant melanoma.
    Journal of Dermatological Science 05/2014; · 3.52 Impact Factor
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    ABSTRACT: To present our experience of high-dose interleukin-2 (HDIL-2) in a high-volume National Cancer Institute-designated center for patients with metastatic renal cell carcinoma (mRCC). Patients with mRCC who received HDIL-2 monotherapy as a first- or second-line therapy during 2004-2011 were identified. Demographics, pathologic variables, renal function, time until the start of HDIL-2 therapy, number of cycles (1-3), responses (complete response, partial response, stable disease, and progressive disease), and primary renal cell carcinoma treatment were analyzed. Progression-free survival and overall survival (OS) were determined. Of 906 patients in the kidney cancer database, 91 patients with mRCC were treated with HDIL-2 and 18 patients (20.5%) underwent prior cytoreductive nephrectomy. Median age was 51 years, and 73.9% were men. Median follow-up was 45 months. Pretreatment renal function impairment led to more treatment cycles (2-3) than in those with adequate initial kidney function (92.3% vs 50.6%, respectively; P = .002). Lower tumor stage correlated with a better response (P = .023) and with longer time from diagnosis to initiation of HDIL-2 (P = .011). Complications included hypotension (67.4%), renal impairment (63%), impaired liver function (42.4%), and thrombocytopenia (31.5%). Four patients (4.5%) had a complete response, 10 (11.4%) had a partial response, and 28 (31.8%) had a stable disease. Median progression-free survival and OS were 8.6 and 35.5 months, respectively. The estimated 2-year OS rate was 60.6%. Incorporating HDIL-2 therapy in the treatment strategies for mRCC added to the patients' survival in this series. HDIL-2 therapy is well tolerated in patients with pre-existing renal impairment with no long-term renal toxicity.
    Urology 05/2014; 83(5):1129-34. · 2.42 Impact Factor
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    ABSTRACT: Background: Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma, is characterized VEGF driven tumor vascularization. However, in patients treated with anti-VEGF therapies inevitably tumor progression occurs, likely driven by up-regulation of alternative pro-angiogenic pathways including angiopoietins and c-MET. We hypothesize that angiopoietin inhibition in conjunction with c-MET inhibition will have anti-tumor effect on RCC and may reduce the development of resistance to anti-VEGF therapies. In the current study we utilized the dual angiopoietin inhibitor AMG 386 and a novel c-MET inhibitor in murine models of RCC, and assessed the preclinical impact of this strategy. Methods: Seven week old female Balb/c mice were injected with 250,000 RENCA cells (luciferase expressing), one week later these mice were randomized, using bioluminescence imaging into two treatment groups: vehicle or Amgen 386 (5.6mg/kg/day, twice a week, subQ injection). Body weight measurements, tumor growth rate, and end point tumor weight measurements were used to evaluate possible toxicity and the progression of RENCA tumors. Four weeks of treatment culminated in collection of tumor tissues for immunohistochemistry analysis of Ki67 and CD31. In addition we have ongoing studies utilizing patient derived xenografts (PDX) of ccRCC developed in our lab. Results: In the RENCA model AMG 386 induced a significant decrease of tumor weight by 44.0 percent (p = 0.0123). In addition, histological analysis of tumor sections revealed a high proportion of necrosis and decreased blood vessel density. Studies with sunitinib sensitive and sunitinib resistant PDXs treated with AMG 386 showed no significant decrease in end point tumor size. Finally, a second PDX treated with AMG 386 showed a reduction in the end point tumor weight, although this reduction was not significant. Conclusions: Our preliminary results suggest that AMG 386 as a single agent is inhibiting tumor growth in an orthotopic renal cell carcinoma model. Additional studies, utilizing AMG 386 in combination with a selective c-MET inhibitor, in patient derived xenograft models have shown a slight reduction in tumor size and vascularization as well as a significant reduction in the metastases to the lungs. This indicates a potential use for combination therapy in treating patients whose ccRCC harbor VEGF resistance and similarities to our PDX and murine renal cell model.
    American Association for Cancer Research Annual Meeting 2014, San Diego, California; 04/2014
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    ABSTRACT: These NCCN Guidelines Insights highlight treatment recommendations and updates specific to the management of patients with advanced non-clear cell carcinoma included in the 2014 version of the NCCN Clinical Practice Guidelines in Oncology for Kidney Cancer.
    Journal of the National Comprehensive Cancer Network: JNCCN 02/2014; 12(2):175-82. · 5.11 Impact Factor
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    ABSTRACT: First line treatment of patients with castrate resistant prostate cancer (CRPC) primarily involves administration of docetaxel chemotherapy. Unfortunately, resistance to docetaxel therapy is an ultimate occurrence. Alterations in androgen receptor (AR) expression and signaling are associated mechanisms underlying resistance to docetaxel treatment in CRPC. Heat shock protein 90 (Hsp90) is a molecular chaperone, which regulates the activation, maturation and stability of critical signaling proteins involved in prostate cancer, including the AR. This knowledge and recent advances in compound design and development have highlighted Hsp90 as an attractive therapeutic target for the treatment of CRPC. We recently reported the development of a MYC-CaP castrate resistant (MYC-CaP/CR) transplant tumor model, which expresses amplified wild type AR. Within, we report that a second generation Hsp90 inhibitor, NVP-AUY922, inhibits cell growth and significantly induces cell death in MYC-CaP/CR and Pten-CaP/cE2 cell lines. NVP-AUY922 induced proteasome degradation of AR, though interestingly does not require loss of AR protein to inhibit AR transcriptional activity. Further, NVP-AUY922 increased docetaxel toxicity in MYC-CaP/CR and Pten-CaP/cE2 cell lines in vitro. Finally, NVP-AUY922/docetaxel combination therapy in mice bearing MYC-CaP/CR tumors resulted in greater anti-tumor activity compared to single treatment. This study demonstrates that NVP-AUY922 elicits potent activity towards AR signaling and augments chemotherapy response in a mouse model of CRPC, providing rationale for the continued clinical development of Hsp90 inhibitors in clinical trials for treatment of CRPC patients.
    PLoS ONE 01/2014; 9(7):e103680. · 3.53 Impact Factor
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    ABSTRACT: Introduction Drug development and clinical decision making for patients with metastatic prostate cancer (PC) have been hindered by a lack of quantitative methods of assessing changes in bony disease burden that are associated with overall survival (OS). Bone scan index (BSI), a quantitative imaging biomarker of bone tumor burden, is prognostic in men with metastatic PC. We evaluated an automated method for BSI calculation for the association between BSI over time with clinical outcomes in a randomized double-blind trial of tasquinimod (TASQ) in men with metastatic castration-resistant PC (mCRPC). Methods Bone scans collected during central review from the TASQ trial were analyzed retrospectively using EXINIboneBSI, an automated software package for BSI calculation. Associations between BSI and other prognostic biomarkers, progression-free survival, OS, and treatment were evaluated over time. Results Of 201 men (57 TASQ and 28 placebo), 85 contributed scans at baseline and week 12 of sufficient quality. Baseline BSI correlated with prostate-specific antigen and alkaline phosphatase levels and was associated with OS in univariate (hazard ratio [HR] = 1.42, P = 0.013) and multivariate (HR = 1.64, P<0.001) analyses. BSI worsening at 12 weeks was prognostic for progression-free survival (HR = 2.14 per BSI doubling, P<0.001) and OS (HR = 1.58, P = 0.033) in multivariate analyses including baseline BSI and TASQ treatment. TASQ delayed BSI progression. Conclusions BSI and BSI changes over time were independently associated with OS in men with mCRPC. A delay in objective radiographic bone scan progression with TASQ is suggested; prospective evaluation of BSI progression and response criteria in phase 3 trials of men with mCRPC is warranted.
    Urologic Oncology: Seminars and Original Investigations. 01/2014;
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    ABSTRACT: Castrate-resistant prostate cancer (CRPC) is a disease where survival is poor and treatment is challenging. Over the past 3 years, significant advances in the field have been made with US Food and Drug Administration approval of new drugs for patients with CRPC. However, despite the presence of new approved drugs such as enzalutamide, abiraterone, sipuleucel-T, cabazitaxel, and alpharadin, there is still an unmet need for novel agents with different mechanisms of action to target CRPC. Based on earlier studies demonstrating therapeutic potential of a quinoline-3-carboxamide agent roquinimex as an anticancer drug, efforts were directed to identify other useful members in this class. Tasquinimod is a second-generation quinoline-3-carboxamide agent that is currently in final stages of clinical development as a treatment for CRPC. The preclinical studies of tasquinimod have formed the basis for its success as an antiangiogenic and immunomodulatory agent in this disease. Tasquinimod is an orally available agent that has shown efficacy and favorable safety profile as deduced by the results of Phase I and II clinical trials of this drug in prostate cancer. The place of tasquinimod in the treatment of CRPC patients is currently under examination in an ongoing Phase III clinical trial. In this review, we will discuss tasquinimod, starting from its discovery and current knowledge on potential mechanisms of action to its clinical potential in CRPC.
    OncoTargets and Therapy 01/2014; 7:223-234. · 2.07 Impact Factor
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    ABSTRACT: Objective To present our experience of high-dose interleukin-2 (HDIL-2) in a high-volume National Cancer Institute–designated center for patients with metastatic renal cell carcinoma (mRCC). Methods Patients with mRCC who received HDIL-2 monotherapy as a first- or second-line therapy during 2004-2011 were identified. Demographics, pathologic variables, renal function, time until the start of HDIL-2 therapy, number of cycles (1-3), responses (complete response, partial response, stable disease, and progressive disease), and primary renal cell carcinoma treatment were analyzed. Progression-free survival and overall survival (OS) were determined. Results Of 906 patients in the kidney cancer database, 91 patients with mRCC were treated with HDIL-2 and 18 patients (20.5%) underwent prior cytoreductive nephrectomy. Median age was 51 years, and 73.9% were men. Median follow-up was 45 months. Pretreatment renal function impairment led to more treatment cycles (2-3) than in those with adequate initial kidney function (92.3% vs 50.6%, respectively; P = .002). Lower tumor stage correlated with a better response (P = .023) and with longer time from diagnosis to initiation of HDIL-2 (P = .011). Complications included hypotension (67.4%), renal impairment (63%), impaired liver function (42.4%), and thrombocytopenia (31.5%). Four patients (4.5%) had a complete response, 10 (11.4%) had a partial response, and 28 (31.8%) had a stable disease. Median progression-free survival and OS were 8.6 and 35.5 months, respectively. The estimated 2-year OS rate was 60.6%. Conclusion Incorporating HDIL-2 therapy in the treatment strategies for mRCC added to the patients' survival in this series. HDIL-2 therapy is well tolerated in patients with pre-existing renal impairment with no long-term renal toxicity.
    Urology 01/2014; 83(5):1129–1134. · 2.42 Impact Factor
  • Journal of visualized experiments : JoVE. 01/2014;
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    ABSTRACT: The Notch ligand Delta-like 4 (Dll4) is highly expressed in vascular endothelium and has been shown to play a pivotal role in regulating tumor angiogenesis. Blockade of the Dll4-Notch pathway in preclinical cancer models has been associated with non-productive angiogenesis and reduced tumor growth. Given the cross-talk between the vascular endothelial growth factor (VEGF) and Delta-Notch pathways in tumor angiogenesis, we examined the activity of a function-blocking Dll4 antibody, REGN1035, alone and in combination with anti-VEGF therapy in renal cell carcinoma (RCC).
    PLoS ONE 01/2014; 9(11):e112371. · 3.53 Impact Factor
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    ABSTRACT: Obesity, smoking, hypertension, and diabetes are risk factors for renal cell carcinoma development. Their presence has been associated with a worse outcome in various cancers. We sought to determine their association with outcome of sunitinib treatment in metastatic renal cell carcinoma (mRCC).Methods.An international multicenter retrospective study of sunitinib-treated mRCC patients was performed. Multivariate analyses were performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors.Results.Between 2004 and 2013, 278 mRCC patients were treated with sunitinib: 59 were active smokers, 67 were obese, 73 were diabetic, and 165 had pretreatment hypertension. Median progression-free survival (PFS) was 9 months, and overall survival (OS) was 22 months. Factors associated with PFS were smoking status (past and active smokers: hazard ratio [HR]: 1.17, p = .39; never smokers: HR: 2.94, p < .0001), non-clear cell histology (HR: 1.62, p = .011), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 3.51, p < .0001), use of angiotensin system inhibitors (HR: 0.63, p = .01), sunitinib dose reduction or treatment interruption (HR: 0.72, p = .045), and Heng risk (good and intermediate risk: HR: 1.07, p = .77; poor risk: HR: 1.87, p = .046). Factors associated with OS were smoking status (past and active smokers: HR: 1.25, p = .29; never smokers: HR: 2.7, p < .0001), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 2.95, p < .0001), and sunitinib-induced hypertension (HR: 0.57, p = .002).Conclusion.Active smoking may negatively affect the PFS and OS of sunitinib-treated mRCC. Clinicians should consider advising patients to quit smoking at initiation of sunitinib treatment for mRCC.
    The Oncologist 12/2013; · 4.10 Impact Factor
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    ABSTRACT: Purpose: Data from epidemiological and experimental studies suggest that dietary protein intake may play a role in inhibiting prostate and breast cancer by modulating the IGF/AKT/mTOR pathway. In this study we investigated the effects of diets with different protein content or quality on prostate and breast cancer. Experimental Design: To test our hypothesis we assessed the inhibitory effect of protein diet restriction on prostate and breast cancer growth, serum PSA and IGF-1 concentrations, mTOR activity and epigenetic markers, by using human xenograft cancer models. Results: Our results showed a 70% inhibition of tumor growth in the castrate-resistant LuCaP23.1 prostate cancer model and a 56% inhibition in the WHIM16 breast cancer model fed with a 7% protein diet when compared to an isocaloric 21% protein diet. Inhibition of tumor growth correlated, in the LuCaP23.1 model, with decreased serum PSA and IGF-1 levels, down-regulation of mTORC1 activity, decreased cell proliferation as indicated by Ki67 staining, and reduction in epigenetic markers of prostate cancer progression, including the histone methyltransferase EZH2 and the associated histone mark H3K27me3. In addition, we observed that modifications of dietary protein quality, independently of protein quantity, decreased tumor growth. A diet containing 20% plant protein inhibited tumor weight by 37% as compared to a 20% animal dairy protein diet. Conclusions: Our findings suggest that a reduction in dietary protein intake is highly effective in inhibiting tumor growth in human xenograft prostate and breast cancer models, possibly through the inhibition of the IGF/AKT/mTOR pathway and epigenetic modifications.
    Oncotarget 11/2013; · 6.64 Impact Factor
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    ABSTRACT: Tasquinimod (Active Biotech) is an oral immunomodulatory, anti-angiogenic, and anti-metastatic agent that delayed metastatic disease progression in a randomized placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). Here, we report long-term survival with biomarker correlates from this trial.EXPERIMENTAL DESIGN: Two hundred and one (134 tasquinimod and 67 placebo) men with mCRPC were evaluated. Forty-one men randomized to placebo crossed over to tasquinimod. Survival data were collected with a median follow-up time of 37 months. Exploratory biomarker studies at baseline and over time were collected to evaluate potential mechanism-based correlates with tasquinimod efficacy including progression-free survival (PFS) and overall survival (OS).RESULTS: With 111 mortality events, median OS was 33.4 months for tasquinimod versus 30.4 months for placebo overall, and 34.2 versus 27.1 months in men with bone metastases (n = 136), respectively. Multivariable analysis demonstrated an adjusted HR of 0.52 [95% confidence interval (CI), 0.35-0.78; P = 0.001] for PFS and 0.64 (95% CI, 0.42-0.97; P = 0.034) for OS, favoring tasquinimod. Time-to-symptomatic progression was improved with tasquinimod (P = 0.039, HR = 0.42). Toxicities tended to be mild in nature and improved over time. Biomarker analyses suggested a favorable impact on bone alkaline phosphatase and lactate dehydrogenase (LDH) over time and a transient induction of inflammatory biomarkers, VEGF-A, and thrombospondin-1 levels with tasquinimod. Baseline levels of thrombospondin-1 less than the median were predictive of treatment benefit.CONCLUSIONS: The survival observed in this trial of men with minimally symptomatic mCRPC suggests that the prolongation in PFS with tasquinimod may lead to a survival advantage in this setting, particularly among men with skeletal metastases, and has a favorable risk:benefit ratio. Clin Cancer Res; 1-11. ©2013 AACR.
    Clinical Cancer Research 11/2013; · 7.84 Impact Factor
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    ABSTRACT: Recent studies have demonstrated that in clear cell renal cell carcinoma (ccRCC) several chromatin remodeling enzymes are genetically inactivated. Although, growing evidence in cancer models has demonstrated the importance of epigenetic changes, currently only changes in DNA methylation can be accurately determined from clinical samples. To address this limitation, we have applied formaldehyde-assisted isolation of regulatory elements (FAIREs) combined with next-generation sequencing (FAIRE-seq) to identify specific changes in chromatin accessibility in clinical samples of ccRCC. We modified the FAIRE procedure to allow us to examine chromatin accessibility for small samples of solid tumors. Our FAIRE results were compared with DNA-methylation analysis and show how chromatin accessibility decreases at many sites where DNA-methylation remains unchanged. In addition, our FAIRE-seq analysis allowed us to identify regulatory elements associated with both normal and tumor tissue. We have identified decreases in chromatin accessibility at key ccRCC-linked genes, including PBRM1, SETD2 and MLL2. Overall, our results demonstrate the power of examining multiple aspects of the epigenome.Oncogene advance online publication, 4 November 2013; doi:10.1038/onc.2013.455.
    Oncogene 11/2013; · 8.56 Impact Factor

Publication Stats

3k Citations
648.31 Total Impact Points

Institutions

  • 2009–2014
    • Roswell Park Cancer Institute
      • • Department of Medical Oncology
      • • Department of Urology
      Buffalo, New York, United States
    • VU University Medical Center
      Amsterdamo, North Holland, Netherlands
    • Karmanos Cancer Institute
      Detroit, Michigan, United States
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
  • 2013
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2012
    • Tel Aviv University
      Tell Afif, Tel Aviv, Israel
  • 2011
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Angeles, California, United States
  • 2010
    • University of Wisconsin–Madison
      Madison, Wisconsin, United States
    • Università degli Studi di Torino
      • Dipartimento di Scienze Mediche
      Torino, Piedmont, Italy
  • 2006–2010
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
  • 2008
    • University Health Network
      Toronto, Ontario, Canada
  • 2001–2004
    • Johns Hopkins University
      Baltimore, Maryland, United States