Waukesha, WI, United States
Waukesha, WI, United States

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Hoang T.,University of Wisconsin - Madison | Campbell T.C.,University of Wisconsin - Madison | Zhang C.,University of Wisconsin - Madison | Kim K.,University of Wisconsin - Madison | And 12 more authors.
Investigational New Drugs | Year: 2014

Introduction: The primary objective of this phase II trial was to evaluate the efficacy and tolerability of vorinostat and bortezomib as third-line therapy in advanced non-small cell lung cancer (NSCLC) patients. Methods: Eligibility criteria included recurrent/metastatic NSCLC, having received 2 prior systemic regimens, and performance status 0-2. Patients took vorinostat 400 mg PO daily days 1-14 and bortezomib 1.3 mg/m2 IV day 1, 4, 8 and 11 in a 21-day cycle. Primary endpoint was 3-month progression free survival (3m-PFS), with a goal of at least 40% of patients being free of progression at that time point. This study followed a two-stage minimax design. Results: Eighteen patients were enrolled in the first stage. All patients had two prior lines of treatment. Patients received a median of two treatment cycles (range: 1-6) on study. There were no anti-tumor responses; stable disease was observed in 5 patients (27.8%). Median PFS was 1.5 months, 3m-PFS rate 11.1%, and median overall survival 4.7 months. The most common grade 3/4 toxicities were thrombocytopenia and fatigue. Two patients who had baseline taxane-related grade 1 peripheral neuropathy developed grade 3 neuropathy. The study was closed at its first interim analysis for lack of efficacy. Conclusions: Bortezomib and vorinostat displayed minimal anti-tumor activity as third-line therapy in NSCLC. We do not recommend this regimen for further investigation in unselected patients. © Springer Science+Business Media 2013.


Jima D.D.,Duke University | Zhang J.,Duke University | Jacobs C.,Duke University | Richards K.L.,University of North Carolina at Chapel Hill | And 31 more authors.
Blood | Year: 2010

A role for microRNA (miRNA) has been recognized in nearly every biologic system examined thus far. A complete delineation of their role must be preceded by the identification of all miRNAs present in any system. We elucidated the complete small RNA transcriptome of normal and malignant B cells through deep sequencing of 31 normal and malignant human B-cell samples that comprise the spectrum of B-cell differentiation and common malignant phenotypes. We identified the expression of 333 known miRNAs, which is more than twice the number previously recognized in any tissue type. We further identified the expression of 286 candidate novel miRNAs in normal and malignant B cells. These miRNAs were validated at a high rate (92%) using quantitative polymerase chain reaction, and we demonstrated their application in the distinction of clinically relevant subgroups of lymphoma. We further demonstrated that a novel miRNA cluster, previously annotated as a hypothetical gene LOC100130622, contains 6 novel miRNAs that regulate the transforming growth factor-β pathway. Thus, our work suggests that more than a third of the miRNAs present in most cellular types are currently unknown and that these miRNAs may regulate important cellular functions.


Westin J.R.,University of Houston | Thompson M.A.,ProHealth Care Regional Cancer Center | Cataldo V.D.,Louisiana State University | Fayad L.E.,University of Houston | And 15 more authors.
Clinical Lymphoma, Myeloma and Leukemia | Year: 2013

Background: Patients with lymphoma are at risk of development of bone mineral density (BMD) loss from therapy with high-dose corticosteroids and alkylating agents. Zoledronic acid (ZA), a bisphosphonate, may prevent this complication of therapy. We evaluated the effect of ZA on the change in BMD and surrogate biomarkers in patients with lymphoma receiving initial chemotherapy. Patients and Methods: Our phase III trial randomized 74 patients with newly diagnosed lymphoma and a baseline BMD of ≥ -2.0 to receive oral calcium and vitamin D daily with or without ZA at enrollment and at 6 months after enrollment. BMD was evaluated at baseline and 1 year after enrollment. Secondary biomarker endpoints were collected at baseline and at 3, 6, 9, and 12 months after enrollment. Results: Forty-three percent of patients had baseline osteopenia. Fifty-three patients were evaluable for response: 24 received ZA and had stable BMD during the observation period, whereas 29 patients in the control group had decreased BMD (P <.05 at lumbar spine and bilateral femoral neck). Twenty-one randomized patients were not evaluable for response because of lymphoma progression or death, withdrawn consent/incomplete testing, or ineligibility. Bone biomarkers were higher in the control group at all intervals after treatment (P <.001). No fractures or intervention-related toxicities were observed during this trial. Conclusions: Newly diagnosed patients with lymphoma are at risk of low BMD, which may worsen with therapy. Treatment with ZA effectively stabilizes BMD and prevents bone loss. Our data suggest that BMD testing and prophylaxis should be considered as an early intervention for a preventable problem. © 2013 Elsevier Inc.


Chang J.,University of Wisconsin - Madison | Seo S.,University of Wisconsin - Madison | Kim K.,University of Wisconsin - Madison | Werndli J.,University of Wisconsin - Madison | And 6 more authors.
Clinical Lymphoma, Myeloma and Leukemia | Year: 2010

Purpose: Human recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) may potentiate rituximab activity by upregulating CD20 expression and activating effector cells necessary for antibody-dependent cellular cytotoxicity. GM-CSF was combined with standard rituximab + CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) chemotherapy (R-CHOP) in the treatment of elderly patients with de novo diffuse large B-cell lymphoma (DLBCL). Patients and Methods: Thirty-eight patients over the age of 60 years with newly diagnosed DLBCL were treated with R-CHOP every 21 days for 6-8 cycles and GM-CSF 250 μg/m2 per day on days 3-10. Patients were evaluated for response after cycles 4, 6, and 8. The primary endpoint was the rate of complete response, and secondary endpoints were progression-free survival (PFS), event-free survival, and overall survival (OS). Results: Thirty-eight patients were enrolled, with a median age of 72 years, and 29% of patients having high-risk disease (International Prognostic Index [IPI] score ≥ 4). A complete or unconfirmed complete response (CR) was achieved in 53% of patients. After a median follow-up of 51.1 months, the 3-year PFS and OS were 78% and 84%. Twenty-one percent of patients discontinued protocol treatment because of chemotherapy-related toxicity and 16% because of GM-CSF toxicity. Dose intensity for planned chemotherapy cycles was 81.1%. Conclusion: These data suggest that survival outcomes may be modestly improved when GM-CSF is combined with R-CHOP in the treatment of elderly DLBCL. GM-CSF had toxicity precluding planned administration in 16% of patients, which may limit usefulness of this agent. Further investigation of GM-CSF in combination with rituximab-containing chemotherapy is warranted.


Lipner M.B.,University of North Carolina at Chapel Hill | Marayati R.,University of North Carolina at Chapel Hill | Deng Y.,University of North Carolina at Chapel Hill | Wang X.,University of North Carolina at Chapel Hill | And 3 more authors.
PLoS ONE | Year: 2016

There is currently tremendous interest in developing anti-cancer therapeutics targeting cell signaling pathways important for both cancer cell metabolism and growth. Several epidemiological studies have shown that diabetic patients taking metformin have a decreased incidence of pancreatic cancer. This has prompted efforts to evaluate metformin, a drug with negligible toxicity, as a therapeutic modality in pancreatic cancer. Preclinical studies in cell line xenografts and one study in patient-derived xenograft (PDX) models were promising, while recently published clinical trials showed no benefit to adding metformin to combination therapy regimens for locally advanced and metastatic pancreatic cancer. PDX models in which patient tumors are directly engrafted into immunocompromised mice have been shown to be excellent preclinical models for biomarker discovery and therapeutic development. We evaluated the response of four PDX tumor lines to metformin treatment and found that all four of our PDX lines were resistant to metformin. We found that the mechanisms of resistance may occur through lack of sustained activation of adenosine monophosphateactivated protein kinase (AMPK) or downstream reactivation of the mammalian target of rapamycin (mTOR). Moreover, combined treatment with metformin and mTOR inhibitors failed to improve responses in cell lines, which further indicates that metformin alone or in combination with mTOR inhibitors will be ineffective in patients, and that resistance to metformin may occur through multiple pathways. Further studies are required to better understand these mechanisms of resistance and inform potential combination therapies with metformin and existing or novel therapeutics. © 2016 Lipner et al. 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.

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