Weill Cornell Cancer Center

New York City, NY, United States

Weill Cornell Cancer Center

New York City, NY, United States
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Darshan M.S.,Cornell University | Loftus M.S.,Cornell University | Thadani-Mulero M.,Cornell University | Levy B.P.,Cornell University | And 14 more authors.
Cancer Research | Year: 2011

Prostate cancer progression requires active androgen receptor (AR) signaling which occurs following translocation of AR from the cytoplasm to the nucleus. Chemotherapy with taxanes improves survival in patients with castrate resistant prostate cancer (CRPC). Taxanes induce microtubule stabilization, mitotic arrest, and apoptotic cell death, but recent data suggest that taxanes can also affect AR signaling. Here, we report that taxanes inhibit ligand-induced AR nuclear translocation and downstream transcriptional activation of AR target genes such as prostate-specific antigen. AR nuclear translocation was not inhibited in cells with acquired b-tubulin mutations that prevent taxane-induced microtubule stabilization, confirming a role for microtubules in AR trafficking. Upon ligand activation, AR associated with the minus-end-microtubule motor dynein, thereby trafficking on microtubules to translocate to the nucleus. Analysis of circulating tumor cells (CTC) isolated from the peripheral blood of CRPC patients receiving taxane chemotherapy revealed a significant correlation between AR cytoplasmic sequestration and clinical response to therapy. These results indicate that taxanes act in CRPC patients at least in part by inhibiting AR nuclear transport and signaling. Further, they suggest that monitoring AR subcellular localization in the CTCs of CRPC patients might predict clinical responses to taxane chemotherapy. ©2011 AACR.


Subbaramaiah K.,Weill Cornell Cancer Center | Howe L.R.,New York Medical College | Bhardwaj P.,Weill Cornell Cancer Center | Du B.,Weill Cornell Cancer Center | And 9 more authors.
Cancer Prevention Research | Year: 2011

Elevated circulating estrogen levels are associated with increased risk of breast cancer in obese post-menopausal women. Following menopause, the biosynthesis of estrogens through CYP19 (aromatase)-mediated metabolism of androgen precursors occurs primarily in adipose tissue, and the resulting estrogens are then secreted into the systemic circulation. The potential links between obesity, inflammation, and aromatase expression are unknown. In both dietary and genetic models of obesity, we observed necrotic adipocytes surrounded by macrophages forming crown-like structures (CLS) in the mammary glands and visceral fat. The presence of CLS was associated with activation of NF-κB and increased levels of proinflammatory mediators (TNF-α, IL-1β, Cox-2), which were paralleled by elevated levels of aromatase expression and activity in the mammary gland and visceral fat of obese mice. Analyses of the stromal-vascular and adipocyte fractions of the mammary gland suggested that macrophage-derived proinflammatory mediators induced aromatase and estrogen-dependent gene expression (PR, pS2) in adipocytes. Saturated fatty acids, which have been linked to obesity-related inflammation, stimulated NF-κB activity in macrophages leading to increased levels of TNF-α, IL-1β, and Cox-2, each of which contributed to the induction of aromatase in preadipocytes. The discovery of the obesity → inflammation → aromatase axis in the mammary gland and visceral fat and its association with CLS may provide insight into mechanisms underlying the increased risk of hormone receptor-positive breast cancer in obese postmenopausal women, the reduced efficacy of aromatase inhibitors in the treatment of breast cancer in these women, and their generally worse outcomes. The presence of CLS may be a biomarker of increased breast cancer risk or poor prognosis. ©2011 AACR.


Ricard M.J.,New York Medical College | Gudas L.J.,New York Medical College | Gudas L.J.,Weill Cornell Cancer Center
Journal of Biological Chemistry | Year: 2013

Background:How to differentiate embryonic stem cells into specific neuronal types is a key question. Results:Lack of Cyp26a1 results in increased ALDH1a2 and Hoxc6, markers of lateral motor column identity. Conclusion:The cytochrome P450 enzyme Cyp26a1 plays a critical role in specifying motor neuron columnar subtypes. Significance:Blocking Cyp26a1 has therapeutic potential in regenerative medicine, neurodegenerative diseases, and cancer therapies. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.


Tagawa S.T.,New York Medical College | Tagawa S.T.,Weill Cornell Cancer Center | Milowsky M.I.,New York Medical College | Milowsky M.I.,Sloan Kettering Cancer Center | And 19 more authors.
Clinical Cancer Research | Year: 2013

Purpose: To assess the efficacy of a single infusion of radiolabeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 (lutetium-177; 177Lu) by prostate-specific antigen (PSA) decline, measurable disease response, and survival. Experimental Design: In this dual-center phase II study, two cohorts with progressive metastatic castration-resistant prostate cancer received one dose of 177Lu-J591 (15 patients at 65 mCi/m2, 17 at 70 mCi/m2) with radionuclide imaging. Expansion cohort (n = 15) received 70 mCi/m2 to verify response rate and examine biomarkers. Results: Forty-seven patients who progressed after hormonal therapies (55.3% also received prior chemotherapy) received 177Lu-J591. A total of 10.6% experienced ≥50% decline in PSA, 36.2% experienced ≥30% decline, and 59.6% experienced any PSA decline following their single treatment. One of 12 with measurable disease experienced a partial radiographic response (8 with stable disease). Sites of prostate cancer metastases were targeted in 44 of 47 (93.6%) as determined by planar imaging. All experienced reversible hematologic toxicity, with grade 4 thrombocytopenia occurring in 46.8% (29.8% received platelet transfusions) without significant hemorrhage. A total of 25.5% experienced grade 4 neutropenia, with one episode of febrile neutropenia. The phase Imaximumtolerated dose (70mCi/m2) resulted in more30%PSA declines (46.9% vs. 13.3%, P = 0.048) and longer survival (21.8 vs. 11.9 months, P = 0.03), but also more grade 4 hematologic toxicity and platelet transfusions. No serious nonhematologic toxicity occurred. Those with poor PSMA imaging were less likely to respond. Conclusion: A single dose of 177Lu-J591 was well tolerated with reversible myelosuppression. Accurate tumor targeting and PSA responses were seen with evidence of dose response. Imaging biomarkers seem promising. © 2013 American Association for Cancer Research.


Thadani-Mulero M.,New York Medical College | Nanus D.M.,New York Medical College | Nanus D.M.,Weill Cornell Cancer Center | Giannakakou P.,New York Medical College | Giannakakou P.,Weill Cornell Cancer Center
Cancer Research | Year: 2012

Recent studies have shown that the microtubule-stabilizing drug paclitaxel, which is commonly used for the treatment of prostate cancer, inhibits signaling from the androgen receptor by inhibiting its nuclear accumulation downstream of microtubule stabilization. This mechanism is independent of paclitaxel-induced mitotic arrest and could provide an alternative mechanism of drug action that can explain its clinical activity. In this review, we highlight the importance of signaling and trafficking pathways that depend on intact and dynamic microtubules, and, as such, they represent downstream targets of microtubule inhibitors. We showcase prostate cancer, which is driven by the activity of the androgen receptor, as recent reports have revealed a connection between the microtubule-dependent trafficking of the androgen receptor and the clinical efficacy of taxanes. Identification and further elucidation of microtubule-dependent tumor-speci fic pathways will help us better understand the molecular basis of clinical taxane resistance as well as to identify individual patients more likely to respond to treatment. ©2012 AACR.


Kosuri S.,New York Medical College | Akhtar N.H.,New York Medical College | Smith M.,New York Medical College | Osborne J.R.,New York Medical College | And 3 more authors.
Advances in Urology | Year: 2012

Despite local therapy with curative intent, approximately 30 of men suffer from biochemical relapse. Though some of these PSA relapses are not life threatening, many men eventually progress to metastatic disease and die of prostate cancer. Local therapy is an option for some men, but many have progression of disease following local salvage attempts. One significant issue in this setting is the lack of reliable imaging biomarkers to guide the use of local salvage therapy, as the likely reason for a low cure rate is the presence of undetected micrometastatic disease outside of the prostate/prostate bed. Androgen deprivation therapy is a cornerstone of therapy in the salvage setting. While subsets may benefit in terms of delay in time to metastatic disease and/or death, research is ongoing to improve salvage systemic therapy. Prostate-specific membrane antigen (PSMA) is highly overexpressed by the majority of prostate cancers. While initial methods of exploiting PSMA's high and selective expression were suboptimal, additional work in both imaging and therapeutics is progressing. Salvage therapy and imaging modalities in this setting are briefly reviewed, and the rationale for PSMA-based systemic salvage radioimmunotherapy is described. © 2012 Satyajit Kosuri et al.


Subbaramaiah K.,Weill Cornell Cancer Center | Howe L.R.,New York Medical College | Zhou X.K.,New York Medical College | Yang P.,University of Texas M. D. Anderson Cancer Center | And 3 more authors.
Cancer Prevention Research | Year: 2012

Estrogen synthesis is catalyzed by cytochrome P450 aromatase, which is encoded by the CYP19 gene. In obese postmenopausal women, increased aromatase activity in white adipose tissue is believed to contribute to hormone-dependent breast cancer. Prostaglandin E2 (PGE2) stimulates the cAMP→protein kinase A (PKA) pathway leading to increased CYP19 transcription and elevated aromatase activity in inflamed white adipose tissue. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) plays a major role in the catabolism of PGE2. Here, we investigated the mechanism by which pioglitazone, a ligand of the nuclear receptor PPARγ suppressed aromatase expression. Treatment of human preadipocytes with pioglitazone suppressed Snail, a repressive transcription factor, resulting in elevated levels of 15-PGDH and reduced levels of PGE2 in the culture medium. Pioglitazone also inhibited cAMP→PKA signaling leading to reduced interaction between phosphorylated cAMP responsive element-binding protein, p300, and CYP19 I.3/II promoter. BRCA1, a repressor of CYP19 transcription, was induced by pioglitazone. Consistent with these in vitro findings, treatment of mice with pioglitazone activated PPARg , induced 15-PGDH and BRCA1 while suppressing aromatase levels in the mammary gland. Collectively, these results indicate that the activation of PPARγ induces BRCA1 and suppresses the PGE2→cAMP→PKA axis leading to reduced levels of aromatase. PPARγ agonists may have a role in reducing the risk of hormone-dependent breast cancer in obese postmenopausal women. ©2012 AACR.


Osborne J.R.,New York Medical College | Osborne J.R.,Weill Cornell Cancer Center | Akhtar N.H.,New York Medical College | Vallabhajosula S.,New York Medical College | And 5 more authors.
Urologic Oncology: Seminars and Original Investigations | Year: 2013

Prostate cancer (CaP) is the most common noncutaneous malignancy affecting men in North America. Despite significant efforts, conventional imaging of CaP does not contribute to patient management as much as imaging performed for other common cancers. Given the lack of specificity in conventional imaging techniques, one possible solution is to screen for CaP-specific antigenic targets and generate agents able to specifically bind. Prostate-specific membrane antigen (PSMA) is overexpressed in CaP tissue, with low levels of expression in the small intestine, renal tubular cells, and salivary gland. The first clinical agent for targeting PSMA was 111In-capromab, involving an antibody recognizing the internal domain of PSMA. The second- and third-generation humanized PSMA binding antibodies have the potential to overcome some of the limitations inherent to capromab penditide (i.e., inability to bind to live CaP cells). One example is the humanized monoclonal antibody J591 (Hu mAb J591) that was developed primarily for therapeutic purposes but also has interesting imaging characteristics, including the identification of bone metastases in CaP. The major disadvantage of use of mAb for imaging is slow target recognition and background clearance in an appropriate time frame for diagnostic imaging. Urea-based compounds, such as small molecule inhibitors may also present promising agents for CaP imaging with single-photon emission computed tomography (SPECT) and positron emission tomography (PET). Two such small-molecule inhibitors targeting PSMA, MIP-1072, and MIP-1095 have exhibited high affinity for PSMA. The uptake of 123I-MIP-1072 and 123I-MIP-1095 in CaP xenografts have imaged successfully with favorable properties amenable to human trials. While advances in conventional imaging will continue, Ab and small molecule imaging exemplified by PSMA targeting have the greatest potential to improve diagnostic sensitivity and specificity. © 2013 Elsevier Inc.


PubMed | Weill Cornell Cancer Center, Cornell College and Cornell University
Type: | Journal: Cancer research | Year: 2017

The complexity of cancer signaling networks limits the efficacy of most single-agent treatments and brings about challenges in identifying effective combinatorial therapies. In this study, we used chronic active B cell receptor (BCR) signaling in diffuse large B cell lymphoma (DLBCL) as a model system to establish a computational framework to optimize combinatorial therapy in silico. We constructed a detailed kinetic model of the BCR signaling network, which captured the known complex crosstalk between the NFB, ERK, and AKT pathways and multiple feedback loops. Combining this signaling model with a data-derived tumor growth model, we predicted viability responses of many single drugs and drug combinations in agreement with experimental data. Under this framework, we exhaustively predicted and ranked the efficacy and synergism of all possible combinatorial inhibitions of eleven currently targetable kinases in the BCR signaling network. Ultimately, our work establishes a detailed kinetic model of the core BCR signaling network and provides the means to explore the large space of possible drug combinations.Using chronic active B cell receptor (BCR) signaling in diffuse large B cell lymphoma (DLBCL) as a model system, we developed a kinetic-modeling based computational framework for predicting effective combination therapy in silico. By integrative modeling of signal transduction, drug kinetics and tumor growth, we were able to directly predict drug-induced cell viability responses at various dosages, which were in agreement with published cell line experimental data. We implemented computational screening methods that identified potent and synergistic combinations in silico and validated our independent predictions in vitro.


Jiang Y.,Weill Cornell Cancer Center | Dominguez P.M.,Weill Cornell Cancer Center | Melnick A.M.,Weill Cornell Cancer Center
Current Opinion in Hematology | Year: 2016

Purpose of review Perturbation of the epigenome is emerging as a central driving force in the pathogenesis of diffuse large B-cell lymphomas (DLBCL) and follicular lymphoma. The purpose of this review is to explain how alteration of different layers of the epigenome contributes to the biology and clinical features of these tumors. Recent findings Key new findings implicate DNA methylation heterogeneity as a core feature of DLBCL. Epigenetic diversity is linked to unfavorable clinical outcomes, clonal selection at relapse, and is driven at least in part because of the actions of activation-induced cytosine deaminase, which is a unique feature of B-cell lymphomas. Somatic mutations in histone modifier genes drive lymphomagenesis through the establishment of aberrant gene-specific histone modification signatures. For example, EZH2 somatic mutations drive silencing of bivalent gene promoters through histone 3 lysine 27 trimethylation, whereas KMT2D (MLL2) mutations disrupt specific sets of enhancers through depletion of histone 3 lysine 4 mono and dimethylation (H3K4me1/me2). Summary Appreciation of the epigenome in determining lymphoma clonal heterogeneity and in driving lymphoma phenotypes through altered promoter and enhancer histone modification profiles is leading to a paradigm shift in how we understand and design therapies for DLBCL and follicular lymphoma. © 2016 Wolters Kluwer Health, Inc.

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