Carla Heise

University of California, San Francisco, San Francisco, California, United States

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Publications (22)133.01 Total impact

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    ABSTRACT: nab-Paclitaxel plus gemcitabine was superior to gemcitabine alone for patients with metastatic pancreatic cancer (MPC) in the phase III MPACT trial. This study evaluated the association of Secreted Protein Acidic and Rich in Cysteine (SPARC) levels with efficacy as an exploratory endpoint. Patients with previously untreated MPC (N = 861) received nab-paclitaxel plus gemcitabine or gemcitabine alone. Baseline SPARC level was measured in the tumor stroma and epithelia (archival biopsies) and plasma. Experiments were performed in PC mouse models in which SPARC was intact or deleted. SPARC was measured in the tumor stroma of 256 patients (30%), the tumor epithelia of 301 patients (35%), and plasma of 343 patients (40%). Stroma-evaluable samples were from metastases (71%), the pancreas (11%), or of unidentifiable origin (insufficient tissue to determine; 17%). For all patients, stromal SPARC level (high [n = 71] vs. low [n = 185]) was not associated with overall survival (OS; hazard ratio 1.019; P = 0.903); multivariate analysis confirmed this lack of association. There was no association between stromal SPARC level and OS in either treatment arm. Neither tumor epithelial SPARC nor plasma SPARC were associated with OS. Results from a SPARC knockout mouse model treated with nab-paclitaxel plus gemcitabine revealed no correlation between SPARC expression and tumor progression or treatment efficacy. SPARC levels were not associated with efficacy in patients with MPC. This exploratory analysis does not support making treatment decisions regarding nab-paclitaxel plus gemcitabine or gemcitabine alone in MPC based on SPARC expression. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 07/2015; DOI:10.1158/1078-0432.CCR-14-3222 · 8.72 Impact Factor
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    ABSTRACT: A series of bicyclic pyrazole carboxamides was synthesized and tested for inhibitory activity against the class III deacetylase sirtuin enzymes. Moderate to low micromolar inhibitory activities were obtained against SIRT1 and SIRT2. These bicyclic pyrazole compounds represent a new class of sirtuin inhibitors with a preference for SIRT1 over SIRT2. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Bioorganic & Medicinal Chemistry Letters 04/2015; 25(12). DOI:10.1016/j.bmcl.2015.04.068 · 2.42 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):LB-94-LB-94. DOI:10.1158/1538-7445.AM2014-LB-94 · 9.33 Impact Factor
  • Annals of Oncology 06/2014; 25(suppl 2):ii106-ii106. DOI:10.1093/annonc/mdu193.4 · 7.04 Impact Factor
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    ABSTRACT: Sotatercept (ACE-011), a recombinant human fusion protein containing the extracellular domain of the human Activin receptor IIA, binds to and inhibits activin and other members of the transforming growth factor -β (TGF-β) superfamily. Administration of sotatercept led to a rapid and sustained increase in red blood cell (RBC) count and haemoglobin (Hb) in healthy volunteers (phase I clinical trials), but the mechanism is not fully understood. Mice treated with RAP-011 (murine ortholog of ACE-011) respond with a rapid (within 24 h) increase in haematocrit, Hb, and RBC count. These effects are accompanied by an equally rapid stimulation of late-stage erythroid precursors in the bone marrow (BM). RAP-011 also induces a significant increase in erythroid burst-forming units and erythropoietin, which could contribute to additional, sustained effects on RBC production. Further in vitro co-culture studies demonstrate that BM accessory cells are required for RAP-011 effects. To better understand which TGF-β family ligand(s) mediate RAP-011 effects, we evaluated the impact of several of these ligands on erythroid differentiation. Our data suggest that RAP-011 may act to rescue growth differentiation factor 11/Activin A-induced inhibition of late-stage erythropoiesis. These data define the mechanism of action of a novel agent that regulates RBC differentiation and provide the rationale to develop sotatercept for the treatment of anaemia and ineffective erythropoiesis.
    British Journal of Haematology 03/2014; 165(6). DOI:10.1111/bjh.12838 · 4.71 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):5666-5666. DOI:10.1158/1538-7445.AM2013-5666 · 9.33 Impact Factor
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    ABSTRACT: Durable responses with lenalidomide monotherapy have been reported in patients with non-Hodgkin lymphoma. In relapsed/refractory diffuse large B-cell lymphoma (DLBCL), higher responses were observed in the activated B-cell-like (ABC) subtype than in the germinal centre B-cell-like subtype. Herein, the molecular mechanisms involved in the differential efficacy of lenalidomide in DLBCL subtypes were investigated. Using DLBCL cell lines, lenalidomide treatment was found to preferentially suppress proliferation of ABC-DLBCL cells in vitro and delay tumour growth in a human tumour xenograft model, with minimal effect on non-ABC-DLBCL cells. This tumouricidal effect was associated with downregulation of interferon regulatory factor 4 (IRF4), a hallmark of ABC-DLBCL cells. IRF4 inhibition by lenalidomide induced downregulation of B-cell receptor (BCR)-dependent NF-κB. Whereas IRF4-specific small, interfering RNA mimicked the effects of lenalidomide reducing NF-κB activation, IRF4 overexpression enhanced NF-κB activation and conferred resistance to lenalidomide. These findings indicate the crucial role of IRF4 inhibition in lenalidomide efficacy in ABC cells. Furthermore, lenalidomide-induced IRF4 downregulation required the expression of cereblon, a molecular target of lenalidomide. Taken together, these findings suggest that lenalidomide has direct antitumour activity against DLBCL cells, preferentially ABC-DLBCL cells, by blocking IRF4 expression and the BCR-NF-κB signalling pathway in a cereblon-dependent manner.
    British Journal of Haematology 12/2012; 160(4). DOI:10.1111/bjh.12172 · 4.71 Impact Factor
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    ABSTRACT: We present data from a phase II study investigating a novel treatment strategy for relapsed/refractory mantle cell lymphoma (MCL). Twenty-six patients received lenalidomide 25 mg/d (days 1-21 of a 28-d cycle) for up to 6 cycles followed by low-dose maintenance lenalidomide (15 mg) in responding patients. Eight patients achieved complete or partial response to give an overall response rate of 31% with median response duration of 22·2 months [95% confidence interval (CI) 0·0-53·6] and median progression-free survival (PFS) of 3·9 months (95% CI 0·0-11·1). An additional six patients (23%) achieved stable disease. Eleven patients received maintenance with median PFS of 14·6 months (95% CI 7·3-21·9). Correlative studies showed that peripheral T and Natural Killer (NK) cells increased in responding patients by 40-60% over the first 6 cycles with an initial dip in NK cells suggestive of tumour infiltration. Peripheral regulatory T cells were increased in MCL patients (P = 0·001) and expanded further following lenalidomide. Sequential plasma analysis showed increased IL12 p40 and IL7 alongside decreased MMP9, IL10, and adiponectin. Finally, a significant correlation (P = 0·02) between gender and response suggested that female MCL patients were more sensitive to lenalidomide than males. In summary, we confirm the activity, safety and immunomodulatory properties of lenalidomide in MCL and highlight its potential as a low-dose maintenance agent.
    British Journal of Haematology 08/2012; 159(2):154-63. DOI:10.1111/bjh.12008 · 4.71 Impact Factor
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    ABSTRACT: Multi-drug resistance and cumulative cardiotoxicity are major limitations for the clinical use of anthracyclines. Here, we evaluated and compared the cross-resistance of amrubicin, a third-generation synthetic anthracycline and potent topoisomerase (topo)-II inhibitor with little or no observed cardiotoxicity to other anthracyclines and the topo-II inhibitor etoposide in drug-resistant tumor models in order to elucidate its potential mechanisms of action. Amrubicin activity was assessed in multi-drug-resistant cell lines and human tumor explants using cytotoxicity assays, confocal microscopy, fluorescence time-lapse imaging, flow cytometry, immunoblotting, and gene expression profiling techniques. We demonstrate that both doxorubicin-resistant tumor cell lines and several drug-resistant human ovarian and breast tumor explants retain sensitivity to amrubicin. In addition, we observed similar levels of amrubicin uptake and accumulation in doxorubicin-sensitive versus doxorubicin-resistant cell lines. Although amrubicin is a weak P-glycoprotein substrate, transport and retention of amrubicin were not solely modulated by P-glycoprotein in the resistant cell lines overexpressing drug efflux pumps. The cellular retention of amrubicin is likely to be a result of rapid influx due to its high intrinsic permeability and lipophilic properties, and this may explain why amrubicin overcomes pleiotropic drug resistance. Consistent with drug accumulation studies, amrubicin induced DNA damage, G(2)-M cell cycle arrest, and apoptosis in both doxorubicin-sensitive and doxorubicin-resistant lines. Using gene expression profiling studies, several classes of genes were significantly and uniquely regulated following amrubicin, but not doxorubicin or etoposide, treatment. Amrubicin appears to have a distinct mode of action that overcomes typical anthracycline resistance mechanisms. Therefore, amrubicin may be useful in the treatment of anthracycline-refractory or anthracycline-resistant tumors.
    Cancer Chemotherapy and Pharmacology 11/2011; 69(4):965-76. DOI:10.1007/s00280-011-1782-x · 2.77 Impact Factor
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    ABSTRACT: Histone deacetylase inhibitors are a group of recently developed compounds that modulate cell growth and survival. We evaluated the effects of the histone deacetylase inhibitor MGCD0103 on growth of pancreatic carcinoma models following single agent treatment and in combination with gemcitabine. MGCD0103 inhibited tumor cell growth and acted synergistically with gemcitabine to enhance its cytotoxic effects. Gene expression analysis identified the cell cycle pathway as one of the most highly modulated gene groups. Our data suggest that MGCD0103 + gemcitabine might be an effective treatment for gemcitabine-refractory pancreatic cancer.
    Cancer Science 03/2011; 102(6):1201-7. DOI:10.1111/j.1349-7006.2011.01921.x · 3.52 Impact Factor
  • Cancer Research 01/2011; 70(8 Supplement):LB-59-LB-59. DOI:10.1158/1538-7445.AM10-LB-59 · 9.33 Impact Factor
  • Carla Heise · Troy Carter · Peter Schafer · Rajesh Chopra
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    ABSTRACT: Lenalidomide has demonstrated clinical activity in myelodysplastic syndromes, particularly in patients with a deletion in the long arm of chromosome 5 (del[5q] abnormality). It has a direct effect on the del(5q) clone, which may contribute to its ability to induce cytogenetic responses. Lenalidomide also stimulates erythropoiesis, leading to erythroid responses in certain patients. Other effects include immunomodulation, anti-inflammatory effects and angiogenesis inhibition. New findings indicate that lenalidomide modulates key genes located within the del(5q) region, including tumor suppressor genes, and regulators of the actin cytoskeleton and cell membrane. Its effects on cytoskeleton regulation may explain its direct antitumor and immunomodulatory effects. This article provides an overview of the known effects of lenalidomide and new insights into its activity in del(5q) myelodysplastic syndromes.
    Expert Review of Anti-infective Therapy 10/2010; 10(10):1663-72. DOI:10.1586/era.10.135 · 2.25 Impact Factor
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    ABSTRACT: Inhibition of histone deacetylase 6 (HDAC6)-dependent aggresome function by pan HDAC inhibitors was recently reported to be a key mechanism underlying the synergistic activity between proteasome inhibitors and HDAC inhibitors in a variety of tumour types. Because these combinations induce significant thrombocytopenia in vivo, we examined whether less toxic, isotype-selective HDAC inhibitors may still synergize with proteasome inhibitors, and if so, by what mechanisms. Here, we showed that the class I HDAC inhibitor, MGCD0103, has a potent antiproliferative activity in Hodgkin lymphoma (HL) cell lines. Furthermore, MGCD0103 induced tumour necrosis factor α (TNF-α) expression and secretion, which was associated with nuclear factor (NF)-κB activation. Selective inhibition of TNF-α expression by short interfering mRNA, or inhibition of MGCD0103-induced NF-kB activation by proteasome inhibitors enhanced MGCD0103-induced cell death. Thus, our results demonstrate that MGCD0103 may synergize with proteasome inhibitors by HDAC6-independent mechanisms, providing mechanistic rationale for exploring this potentially less toxic combination for the treatment of lymphoma.
    British Journal of Haematology 09/2010; 151(4):387-96. DOI:10.1111/j.1365-2141.2010.08342.x · 4.71 Impact Factor
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    ABSTRACT: The cytidine nucleoside analogs azacitidine (AZA) and decitabine (DAC) are used for the treatment of patients with myelodysplastic syndromes and acute myeloid leukemia (AML). Few non-clinical studies have directly compared the mechanisms of action of these agents in a head-to-head fashion, and the agents are often viewed as mechanistically similar DNA hypomethylating agents. To better understand the similarities and differences in mechanisms of these drugs, we compared their in vitro effects on several end points in human AML cell lines. Both drugs effected DNA methyltransferase 1 depletion, DNA hypomethylation, and DNA damage induction, with DAC showing equivalent activity at concentrations 2- to 10-fold lower than AZA. At concentrations above 1 microM, AZA had a greater effect than DAC on reducing cell viability. Both drugs increased the sub-G1 fraction and apoptosis markers, with AZA decreasing all cell cycle phases and DAC causing an increase in G2-M. Total protein synthesis was reduced only by AZA, and drug-modulated gene expression profiles were largely non-overlapping. These data demonstrate shared mechanisms of action of AZA and DAC on DNA-mediated markers of activity, but distinctly different effects in their actions on cell viability, protein synthesis, cell cycle, and gene expression. The differential effects of AZA may be mediated by RNA incorporation, as the distribution of AZA in nucleic acid of KG-1a cells was 65:35, RNA:DNA.
    PLoS ONE 02/2010; 5(2):e9001. DOI:10.1371/journal.pone.0009001 · 3.23 Impact Factor
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    ABSTRACT: The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRbeta with IC(50) values <0.1 microM. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.
    Journal of Medicinal Chemistry 12/2008; 52(2):278-92. DOI:10.1021/jm800790t · 5.45 Impact Factor
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    ABSTRACT: Recombinant interleukin-2 (rIL-2) is a pleiotropic cytokine that activates select immune effector cell responses associated with antitumor activity, including antibody-dependent cellular cytotoxicity (ADCC). Rituximab is an anti-CD20 monoclonal antibody that activates ADCC in non-Hodgkin lymphoma (NHL). The ability of rIL-2 to augment rituximab-dependent tumor responses was investigated. The efficacy of rIL-2 in combination with rituximab was evaluated in 2 NHL tumor xenograft models: the CD20hi, rituximab-sensitive, low-grade Daudi model and the CD20lo, aggressive, rituximab-resistant Namalwa model. Combination of rIL-2 plus rituximab was synergistic in a rituximab-sensitive Daudi tumor model, as evidenced by significant tumor regressions and increased time to tumor progression, compared with rIL-2 and rituximab single agents. In contrast, rituximab-resistant Namalwa tumors were responsive to single-agent rIL-2 and showed an increased response when combined with rituximab. Using in vitro killing assays, rIL-2 was shown to enhance activity of rituximab by activating ADCC and lymphokine-activated killer activity. Additionally, the activity of rIL-2 plus rituximab F(ab')2 was similar to that of rIL-2 alone, indicating a critical role for immunoglobulin G1 Fc-FcgammaR-effector responses in mediating ADCC. Antiproliferative and apoptotic tumor responses, along with an influx of immune effector cells, were observed by immunohistochemistry. Collectively, the data suggest that rIL-2 mediates potent tumoricidal activity against NHL tumors, in part, through activation and trafficking of monocytes and natural killer cells to tumors. These data support the mechanistic and therapeutic rationale for combination of rIL-2 with rituximab in NHL clinical trials and for single-agent rIL-2 in rituximab-resistant NHL patients.
    Journla of Immunotherapy 02/2007; 30(1):64-74. DOI:10.1097/01.cji.0000211315.21116.07 · 4.01 Impact Factor
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    ABSTRACT: Overexpression of fibroblast growth factor receptor 3 (FGFR3) is a hallmark of t(4;14) multiple myeloma (MM). To dissect the mechanism of FGFR3 oncogenesis in MM, we used 3 FGFR selective kinase inhibitors-CHIR258, PD173074, and SU5402-and FGFR3-specific siRNA to modulate FGFR3 activity. Conversely, the ligand FGF was used to stimulate FGFR3 function in human MM cells. The transcriptional response to FGFR3 modification was recorded, and gene expression changes common to all 5 modifiers were documented. Ten genes were commonly regulated. Macrophage inflammatory protein-1 alpha (MIP-1alpha) was the single most differentially altered gene. MIP-1 alpha promoter function, gene expression, and protein secretion were each down-regulated following inhibition of FGFR3 signaling. Down-regulation of MIP-1 alpha was not, however, observed following FGFR3 inhibition in MM cells with RAS mutations implicating RAS-MAPK in MIP-1 alpha regulation. As confirmation, inhibition of ERK1 also down-regulated MIP-1 alpha in FGFR3 inhibitor-resistant cells harboring RAS mutations. MIP-1 alpha is implicated in the survival and proliferation of MM cells and the pathogenesis of MM bone disease. Our observation is the first to directly link an initiating IgH translocation not only to MM-cell growth and survival but also to the disease-associated bone disease.
    Blood 12/2006; 108(10):3465-71. DOI:10.1182/blood-2006-04-017087 · 10.45 Impact Factor
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    ABSTRACT: The ectopically expressed and deregulated fibroblast growth factor receptor 3 (FGFR3) results from a t(4;14) chromosomal translocation that occurs in approximately 15% of multiple myeloma (MM) patients and confers a particularly poor prognosis. This study assesses the antimyeloma activity of CHIR-258, a small-molecule inhibitor of multiple receptor tyrosine kinases that is currently in phase I trials, in a newly developed FGFR3-driven preclinical MM animal model. We developed an orthotopic MM model in mice using a luciferase-expressing human KMS-11-luc line that expresses mutant FGFR3 (Y373C). The antimyeloma activity of CHIR-258 was evaluated at doses that inhibited FGFR3 signaling in vivo in this FGFR3-driven animal model. Noninvasive bioluminescence imaging detected MM lesions in nearly all mice injected with KMS-11-luc cells, which were mainly localized in the spine, skull, and pelvis, resulting in frequent development of paralysis. Daily oral administration of CHIR-258 at doses that inhibited FGFR3 signaling in KMS-11-luc tumors in vivo resulted in a significant inhibition of KMS-11-luc tumor growth, which translated into a significant improvement in animal survival. Our data provide a relevant preclinical basis for clinical trials of CHIR-258 in FGFR3-positive MM patients.
    Clinical Cancer Research 09/2006; 12(16):4908-15. DOI:10.1158/1078-0432.CCR-06-0957 · 8.72 Impact Factor
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    ABSTRACT: 3-Benzimidazol-2-yl-1H-indazole analogs were developed as inhibitors of receptor tyrosine kinases (RTK). The synthesis and SAR of this series is reported.
    Bioorganic & Medicinal Chemistry Letters 08/2006; 16(13):3595-9. DOI:10.1016/j.bmcl.2006.03.069 · 2.42 Impact Factor
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    ABSTRACT: Fms-like tyrosine kinase 3 (FLT3) encodes a receptor tyrosine kinase (RTK) for which activating mutations have been identified in a proportion of acute myelogenous leukemia (AML) patients and associated with poor clinical prognosis. Given the relevance of FLT3 mutations in AML, we investigated the activity of CHIR-258, an orally active, multitargeted small molecule, with potent activity against FLT3 kinase and class III, IV, and V RTKs involved in endothelial and tumor cell proliferation in AML models. CHIR-258 was tested on two human leukemic cell lines in vitro and in vivo with differing FLT3 mutational status [MV4;11 cells express FLT3 internal tandem duplications (ITD) versus RS4;11 cells with wild-type (WT) FLT3]. Antiproliferative activity of CHIR-258 against MV4;11 was approximately 24-fold greater compared with RS4;11, indicating more potent inhibition against cells with constitutively activated FLT3 ITD. Dose-dependent down modulation of receptor phosphorylation and downstream signaling [signal transducer and activator of transcription 5 (STAT5) and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase] in MV4;11 cells with CHIR-258 confirmed the molecular mechanism of action. Target modulation of phospho-FLT3, phospho-STAT5, and phospho-ERK in MV4;11 tumors was achieved at biologically active doses of CHIR-258. Tumor regressions and eradication of AML cells from the bone marrow were shown in s.c. and bone marrow engraftment leukemic xenograft models. Tumor responses were characterized by decreased cellular proliferation and positive immunohistochemical staining for active caspase-3 and cleaved poly(ADP-ribose) polymerase, suggesting cell death was mediated in part via apoptosis. Our data indicate that CHIR-258 may be an effective therapy in FLT3-associated AML and warrants clinical trials.
    Clinical Cancer Research 08/2005; 11(14):5281-91. DOI:10.1158/1078-0432.CCR-05-0358 · 8.72 Impact Factor

Publication Stats

685 Citations
133.01 Total Impact Points


  • 2011
    • University of California, San Francisco
      San Francisco, California, United States
  • 2008
    • Novartis Institutes for BioMedical Research
      Cambridge, Massachusetts, United States
  • 2006
    • University of Toronto
      Toronto, Ontario, Canada
  • 2005
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada