Needham, MA, United States
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Rasool N.,U.S. National Cancer Institute | LaRochelle W.,Curagen Corporation | Zhong H.,Curagen Corporation | Ara G.,Curagen Corporation | And 2 more authors.
Clinical Cancer Research | Year: 2010

Purpose: Ovarian cancer recurrence with the development of paclitaxel resistance is an obstacle to long-term survival. We showed that secretory leukocyte protease inhibitor (SLPI) is a survival factor for ovarian cancer. We hypothesize that SLPI may antagonize paclitaxel injury. Experimental Design: Differential SLPI induction in response to paclitaxel and in response to stable forced expression of SLPI was shown in A2780-1A9 cells and their paclitaxel-resistant sublines, PTX10 and PTX22, and confirmed with HEY-A8 cells. SLPI-mediated survival was reduced by the MAP/extracellular signal-regulated kinase (ERK) kinase inhibitor, U0126, and a humanized neutralizing monoclonal anti-SLPI antibody, CR012. OVCAR3 xenographs tested the role of CR012 in vivo. Results: SLPI expression was lower in A2780-1A9 ovarian cancer cells than in PTX10 and PTX22, and SLPI was induced by paclitaxel exposure. Stable SLPI expression yielded a proliferation advantage (P = 0.01); expression of and response to SLPI in OVCAR3 cells were abrogated by exposure to CR012. SLPI reduced the paclitaxel susceptibility of 1A9 and HEY-A8 cells (P ≤ 0.05), and SLPI expression did not increase the resistance of PTX10 and PTX22 cells. Both paclitaxel and SLPI overexpression induced ERK activation. Inhibition of MAP/ERK kinase with U0126 increased paclitaxel injury and overcame SLPI-mediated cell protection. It did not reinstate PTX10 sensitivity to paclitaxel, which was associated with AKT activation. Significant inhibition of OVCAR3 xenograft growth was observed with CR012 and paclitaxel, over single agents (P ≤ 0.001). Conclusions: A two-pronged approach confirmed that SLPI overcomes paclitaxel in part through activation of ERK1/2. These results credential SLPI as a molecular target for ovarian cancer and suggest CR012 as a tool for proof of concept. ©2010 AACR.

Dizon D.S.,Brown University | Damstrup L.,TopoTarget A S | Finkler N.J.,Florida Hospital Cancer Institute | Lassen U.,Copenhagen University | And 6 more authors.
International Journal of Gynecological Cancer | Year: 2012

Background: Preclinical data show that belinostat (Bel) is synergistic with carboplatin and paclitaxel in ovarian cancer. To further evaluate the clinical activity of belinostat, carboplatin, and paclitaxel (BelCaP), a phase 1b/2 study was performed, with an exploratory phase 2 expansion planned specifically for women with recurrent epithelial ovarian cancer (EOC). Methods: Thirty-five women were treated on the phase 2 expansion cohort. BelCap was given as follows: belinostat, 1000 mg/m 2 daily for 5 days with carboplatin, AUC 5; and paclitaxel, 175 mg/m 2 given on day 3 of a 21-day cycle. The primary end point was overall response rate (ORR), using a Simon 2 stage design. Results: The median age was 60 years (range, 39-80 years), and patients had received a median of 3 prior regimens (range, 1-4). Fifty-four percent had received more than two prior platinum-based combinations, sixteen patients (46%) had primary platinum-resistant disease, whereas 19 patients (54%) recurred within 6 months of their most recent platinum treatment. The median number of cycles of BelCaP administered was 6 (range, 1-23). Three patients had a complete response, and 12 had a partial response, for an ORR of 43% (95% confidence interval, 26%Y61%). When stratified by primary platinum status, the ORR was 44% among resistant patients and 63% among sensitive patients. The most common drugrelated adverse events related to BelCaP were nausea (83%), fatigue (74%), vomiting (63%), alopecia (57%), and diarrhea (37%). With a median follow-up of 4 months (range, 0-23.3 months), 6-month progression-free survival is 48% (95% confidence interval, 31%Y66%). Median overall survival was not reached during study follow-up. Conclusions: Belinostat, carboplatin, and paclitaxel combinedwas reasonablywell tolerated and demonstrated clinical benefit in heavily-pretreated patients with EOC. The addition of belinostat to this platinum-based regimen represents a novel approach to EOC therapy and warrants further exploration. Copyright © 2012 by IGCS and ESGO.

Rose A.A.N.,McGill University | Grosset A.-A.,University of Montréal | Grosset A.-A.,INRS Institute Armand Frappier | Dong Z.,McGill University | And 9 more authors.
Clinical Cancer Research | Year: 2010

Purpose: Although the murine orthologue of glycoprotein nonmetastatic B (GPNMB), Osteoactivin, promotes breast cancer metastasis in an in vivo mouse model, its importance in human breast cancer is unknown. We have examined the significance of GPNMB expression as a prognostic indicator of recurrence and assessed its potential as a novel therapeutic target in breast cancer. Experimental Design: The clinical significance of GPNMB expression in breast cancer was addressed by analyzing GPNMB levels in several published gene expression data sets and two independent tissue microarrays derived from human breast tumors. GPNMB-expressing human breast cancer cell lines were further used to validate a toxin-conjugated anti-GPNMB antibody as a novel therapeutic agent. Results: GPNMB expression correlates with shorter recurrence times and reduced overall survival of breast cancer patients. Epithelial-specific GPNMB staining is an independent prognostic indicator for breast cancer recurrence. GPNMB is highly expressed in basal and triple-negative breast cancers and is associated with increased risk of recurrence within this subtype. GPNMB expression confers a more migratory and invasive phenotype on breast cancer cells and sensitizes them to killing by CDX-011 (glembatumumab vedotin), a GPNMB-targeted antibody-drug conjugate. Conclusions: GPNMB expression is associated with the basal/triple-negative subtype and is a prognostic marker of poor outcome in patients with breast cancer. CDX-011 (glembatumumab vedotin) is a promising new targeted therapy for patients with metastatic triple-negative breast cancers, a patient population that currently lacks targeted-therapy options. ©2010 AACR.

Williams M.D.,515 Holcombe Blvd. | Esmaeli B.,Section of Ophthalmology | Soheili A.,Section of Ophthalmology | Simantov R.,Curagen Corporation | And 3 more authors.
Melanoma Research | Year: 2010

Uveal melanoma is an aggressive disease without effective adjuvant therapy for metastases. Despite genomic differences between cutaneous and uveal melanomas, therapies based on shared biological factors could be effective against both tumor types. High expression of glycoprotein-NMB (GPNMB) in cutaneous melanomas led to the development of CDX-011 (glembatumumab vedotin), a fully human monoclonal antibody against the extracellular domain of GPNMB conjugated to the cytotoxic microtubule toxin monomethylauristatin E. Ongoing phase II trials suggest that CDX-011 has activity against advanced cutaneous melanomas. To determine the potential role of CDX-011 in uveal melanomas, we studied their GPNMB expression. Paraffin-embedded tissues from 22 uveal melanomas treated by enucleation from 2004-2007 at one institution were evaluated immunohistochemically for expression of GPNMB using biotinylated CDX-011 (unconjugated) antibody. Melanoma cells were evaluated for percentage and intensity of expression. Spectral imaging was used in one case with high melanin content. Clinical data were reviewed. Twelve women and 10 men with a median age of 58.7 years (range: 28-83 years) were included. Eighteen of 21 tumors evaluated immunohistochemically (85.7%) expressed GPNMB in 10-90% of tumor cells with variable intensity (5 tumors, 1+; 11, 2+; and 2, 3+). Eleven of 18 tumors (61.1%) expressed GPNMB in≥50% of cells. Spectral imaging showed diffuse CDX-011 (unconjugated) reactivity in the remaining case. Uveal melanoma, like cutaneous melanoma, commonly expresses GPNMB. Ongoing clinical trials of CDX-011 should be extended to patients with metastatic uveal melanoma to determine potential efficacy in this subset of patients with melanoma. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Topo Target UK Ltd and Curagen Corporation | Date: 2014-11-26

The present invention pertains to a method for treating cancer, such as lung cancer, multiple myeloma, lymphoma, and epithelial ovarian cancer, comprising the administration to a patient in need thereof a first amount or dose of a histone deacetylase (HDAC) inhibitor, such as PXD-101, and a second amount or dose of another chemotherapeutic agent, such as dexamethasone or 5-fluorouracil, or an epidermal growth factor receptor (EGFR) inhibitor, such as Tarceva, wherein the first and second amounts or doses together comprise a therapeutically effective amount.

The invention described herein is related to antibodies directed to the antigen TIM-1 and uses of such antibodies for the treatment of cancer (e.g., renal and ovarian cancer). In particular, there are provided fully human monoclonal antibodies directed to the antigen TIM-1. Isolated polynucleotide sequences encoding, and amino acid sequences comprising, heavy and light chain immunoglobulin molecules, particularly sequences corresponding to contiguous heavy and light chain sequences spanning the framework regions (FRs) and/or complementarity determining regions (CDRs), specifically from FR1 though FR4 or CDR1 through CDR3, are provided. Hybridomas or other cell lines expressing such immunoglobulin molecules and monoclonal antibodies are also provided.

TopoTarget UK Ltd and Curagen Corporation | Date: 2014-08-07

The present invention relates generally to methods for treating cancer. In one respect, the present invention relates to a method of treating a hematological cancer (e.g., multiple myeloma, leukemia, lymphoma) comprising administering to a patient in need thereof a therapeutically effective amount of a histone deacetylase inhibitor, for example, a histone deacetylase (HDAC) inhibitor as described herein, for example, PXD-101. In another respect, the present invention relates to a method of treating cancer (e.g., solid tumour cancer, e.g., rectal cancer, colon cancer, ovarian cancer, hematological cancer, e.g., multiple myeloma, leukemia, lymphoma) comprising administering to a patient in need thereof, a first amount of a histone deacetylase (HDAC) inhibitor, for example, a histone deacetylase inhibitor as described herein, for example, PXD-101, and a second amount of another chemotherapeutic agent, for example, another chemotherapeutic agent selected from: an antibody against VEGF, AVASTIN (bevacizumab), an antibody against CD20, rituximab, bortezomib, thalidomide, dexamethasone, vincristine, doxorubicin, and melphalan, wherein the first and second amounts together comprise a therapeutically effective amount.

Curagen Corporation and Abgenix Inc. | Date: 2011-04-06

The present invention provides fully human lonoclonal antibodies that specifically bind to GPNMB, and uses thereof. Nucleotide sequences encoding, and amino acid sequences comprising, heavy and light chain immunoglobulin molecules, particularly sequences corresponding to contiguous heavy and light chain sequences spanning the framework regions and/or complementarity determining regions (CDRs) are provided. The present invention also provides immunoconjugates comprising anti-GPNMB antibodies and methods of using such immunoconjugates. the present invention futher provides bispecific antibodies comprising an anti-GPNMB antibody component and an anti-CD3 component, and methods of using such bispecific antibodies.

PubMed | Curagen Corporation
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

6656 Background: Mucositis is a painful side effect of many transplant conditioning regimens. A new class of drugs in the fibroblast growth factor family is being investigated for ameliorating or preventing oral mucositis (OM). CG53135-05, recombinant human fibroblast growth factor-20 (rhFGF-20) purified from E. coli, promotes epithelial and mesenchymal cell proliferation in vitro and is being investigated to reduce the incidence or duration of severe OM following HDCT and PBSCT.A phase I trial was conducted to evaluate safety, tolerability and pharmacokinetics (PK) of CG53135-05. Patients (pts.) with hematologic malignancies undergoing HDCT and autologous PBSCT were enrolled. CG53135-05 was administered as single dose IV infusion over 15 min 24h after stem cell infusion. Evaluation of safety and PK was assessed for up to 30 days post dosing. Pts were scored daily for presence of OM using both the WHO and OMAS grading scales.30 patients (ages 25-75) treated with escalating doses of study drug, including (no. of pts): 0.03 mg/kg (10), 0.1 mg/kg (10), 0.2 mg/kg (8), and 0.33 mg/kg (2). Pts had multiple myeloma (n=16), non-Hodgkins lymphoma (n=12), acute myelogenous leukemia (n=1), or desmoplasmic round cell tumor (n=1). In general, CG53135-05 was well tolerated with no significant side effects up to a dose of 0.33 mg/kg. At that dose, 2 pts experienced infusional reactions with no further pts treated at that dose level. Pharmacokinetics were measured at all dose levels. Preliminary results confirmed dose dependent plasma exposure. Among the 30 pts who completed the study, 10 pts experienced no OM (including 5 Mel 200 pts), 13 pts experienced only WHO Grade 1 (n=7) or Grade 2 (n=6) OM, while 7 pts experienced severe Grade 3 or 4 OM. 2 pts experiencing Grade 4 OM required TPN.CG53135-05 is well tolerated in autologous stem cell transplant patients at doses up to 0.33 mg/kg. 23/30 pts did not develop severe (WHO Grades 3-4) mucositis following HDCT. A larger Phase II clinical trial has been initiated to evaluate the efficacy of CG53135-05 in preventing HDCT induced OM. [Table: see text].

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