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While early detection of breast cancer (BC) has improved prognoses, there is an urgent need to improve outcomes for patients with distant metastatic disease. Higher expression of the Notch ligand JAG1 in primary BC tumors is strongly associated with lymph node metastasis and patient mortality, but causality is unclear. We show that JAG1 expression is higher in patients’ metastatic BC cells colonizing lymph nodes than in primary tumors, suggesting that tumor cells with high JAG1 are preferentially able to metastasize to lymph nodes. JAG1 expression is higher in a derivative of BC line MDA-MB-231 selected for tropism to lymph nodes (MDA231-LN) than in the parental line or derivatives with other tropisms. To determine the mechanism(s) of JAG1-mediated metastasis, we generated clonal JAG1 knockout cell lines from MDA231-LN cells with corresponding JAG1 rescue lines. We investigated the role of JAG1 in spontaneous metastasis under clinically relevant conditions by orthotopically implanting JAG1 knockout and expressing cells, resecting the primary tumor, and following long-term metastatic spread in a mouse model. Quantification of tumor cells in blood showed that survival, metastatic burden, and JAG1 expression did not correlate with the number of circulating tumor cells. Conversely, JAG1 expression drove an increase in lymph node and body-wide metastatic burden and a trend toward decreased survival. In this model metastatic cells were abundant throughout lymph vessels, suggesting lymphatics are the primarily route of dissemination. Preliminary transcriptional analysis suggests that JAG1 alters interactions with lymphatic endothelial cells (LEC), potentially via VEGF signaling, leading us to examine downstream events in co-cultures of LEC with lymphatically invasive BC lines. Deciphering tumor-lymphatic endothelial signaling events may open new avenues to target BC metastasis. Citation Format: Benjamin Gordon, Bhairavi Swaminathan, LA Naiche, Jan Kitajewski. Jagged-1 promotes breast cancer metastasis through the lymphatic system [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-10.

Endothelial Notch signaling is critical for tumor angiogenesis and growth. Inhibition of Notch1 or its ligand, Dll4, can induce tumor vessel hypersprouting, which interferes with perfusion and reduces tumor development. Unfortunately, blocking Notch1 in endothelial cells of normal tissue can lead to tissue hypoxia and vascular neoplasms. Notch4, another member of the Notch family, is upregulated and increased in the endothelium of certain tumor types compared to normal vasculature. Reducing Notch4, unlike Notch1, causes reduction in developmental and tumor angiogenesis. Using a newly developed anti-Notch4 antibody, E7011, we assessed the effects on Notch4 inhibition on developmental retinal angiogenesis. E7011 treatment did not alter capillary density within the vascular plexus or endothelial tip cell number, but did decrease radial outgrowth and vein diameter, supporting the hypothesis that Notch4 functions as a pro-angiogenic signal. These findings suggest that the targeting of Notch4 could interfere with tumor angiogenesis and offer a novel therapeutic avenue. To establish the role of Notch4 within the tumor microenvironment, we analyzed its expression in both human and murine tumor samples. Immunofluorescent staining revealed a range of Notch4 expression in both tumor cells and endothelium in human triple negative breast cancers. Several murine syngeneic tumors examined expressed Notch4 primarily in the endothelium with only rare tumor expression. We treated orthotopically implanted Py8119 murine breast carcinomas and B16F10 melanomas with E7011, which significantly reduced tumor size compared to IgG treated controls, indicating that suppression of Notch4 is anti-tumorigenic. To determine mechanistically how E7011 delays tumor growth, we performed single cell RNA sequencing on E7011 and control treated Py8119 tumors. Surprisingly, we found that while Notch4 transcripts were present only in endothelial cells, E7011 administration dramatically altered macrophage and monocyte populations within the tumor. Taken together, these findings indicate that inhibition of tumor endothelial Notch4 by E7011 can regulate the presence of immune cells within the tumor microenvironment and improve tumor control. Citation Format: Jason Eng, L.A. Naiche, Bhairavi Swaminathan, Yu Kato, Krishna Thakkar, Rahul Vadakath, James Herts, Rajyasree Emmadi, Junji Matsui, Jan Kitajewski. Targeting Notch4 with a novel neutralizing antibody inhibits tumor growth and alters immune cell populations within the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 247.

Notch signaling is activated by ligands Delta-like 4 (Dll4) and Jagged1 in the tumor microenvironment to promote tumor angiogenesis and perfusion. Notch activation is associated with poor outcomes in several cancers, particularly triple negative breast cancer (TNBC), and affects both tumor angiogenesis and metastasis. The development of therapeutics targeting angiogenesis, such as the Notch pathway, has again attracted attention. Previous approaches to globally inhibit the Notch pathway or block Dll4/Notch1 activation, such as γ-secretase inhibitors (GSI), have raised safety concerns due to gastrointestinal toxicity due to accumulation of secretory goblet cells in the intestine. Similarly, anti-Dll4 therapy resulted in pathological changes in the liver as well as severe vascular neoplasms when evaluated using preclinical animal models. Development of new approaches for targeting the Notch pathway remains a critical clinical problem currently unaddressed. Our lab has previously developed ligand-specific inhibitors of Notch signaling, called Notch decoys, which are comprised of Fc fusions to specific EGF-like repeats of the Notch1 extracellular domain. These Notch decoys bind ligand non-productively and interfere with ligand function. Jagged-specific Notch1 decoys inhibit angiogenesis in vitro and significantly impair tumor growth, tumor angiogenesis, and perfusion without apparent toxicity in mouse models of TNBC. However, this previous work utilized Notch decoys produced via viral expression vectors, which preclude dosage control and limit clinical applicability. We have developed a new generation of Notch “mini” decoys that contain fewer EGF-like repeats. These mini decoys show improved secretion characteristics and can be purified as active proteins in clinically relevant quantities. Using a variety of binding assays, we observed that these Notch mini decoys demonstrate strong but distinct binding to Notch ligands Dll4 and Jagged1 and block Notch signaling when evaluated in cultured cells. Our newly generated Notch decoys can now be sufficiently purified for use in a dose-dependent manner to test the therapeutic role of Notch inhibition on tumor angiogenesis using preclinical animal models. Citation Format: Timothy Sargis, Seock-Won Youn, Hyun Lee, L.A. Naiche, Jan Kitajewski. Notch decoys as potential anti-angiogenic biotherapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3207.

Expression of the Notch family of receptors are often upregulated in pancreatic ductal adenocarcinoma (PDAC), however, the functional impacts of the Notch signaling network on pancreatic tumorigenesis remain unresolved. In this study, we focused on Notch4, which had not been investigated in PDAC. Leveraging the conventional Notch4 deficient mouse line and previously established genetically engineered mouse models (GEMM) for PDAC, we generated KC (LSL-KrasG12D;p48-Cre), N4−/−KC (Notch4−/−;LSL-KrasG12D;p48-Cre), PKC (p16flox/flox;LSL-KrasG12D;p48-Cre), and N4−/−PKC GEMMs (Notch4−/−; p16flox/lox;LSL-KrasG12D;p48-Cre). We performed caerulein treatment in both KC and N4−/−KC mice, and compared the development of acinar to ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) between them. The ADM/PanIN lesions were significantly smaller in the N4−/−KC than in the KC GEMM (p=0.01), suggesting that Notch4 deficiency attenuated early pancreatic tumorigenesis. This in vivo result was confirmed by in vitro ADM induction of the explant cultures of mouse pancreatic acinar cells. The number of ADM structures in the N4−/−KC acinar cultures was significantly lower than the KC acinar cultures (p Citation Format: Kiyoshi Saeki, Wanglong Qiu, Richard Friedman, Carrie Shawber, Jan Kitajewski, Jianhua Hu, Gloria H. Su. Inactivation of Notch4 attenuated pancreatic tumorigenesis in mice [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-073.

Though survival is improving for breast cancer patients, clinical outcomes remain poor for patients with aggressive molecular subtypes. Triple negative breast cancer (TNBC) is considered the most aggressive breast cancer subtype, and despite having a 90% five-year relative survival rate for localized disease, that number drops to as low as 11% for patients with distant TNBC metastasis. The poor clinical outcomes for TNBC patients are largely due to lack of clinically actionable molecular targets and pathways compared to other breast cancer subtypes. Given the lack of effective treatment strategies for advanced TNBC, there is an urgent and unmet need to understand the means through which tumor cells disseminate and metastasize to distant tissues in hopes of identifying new targets for therapeutic intervention. For tumor cells to metastasize, they acquire complex series of pathophysiological phenotypes, starting with invasion into surrounding tissue and intravasation into systemic lymphatic or blood vascular systems. Only a small fraction of tumor cells can survive in circulation, with a smaller fraction able to extravasate from vessels and establish distant metastases. While some cancer cells partially coopt the mechanisms that leukocytes use to extravasate, circulating TNBC cells also use distinct mechanisms to breach an endothelial barrier. However, the mechanism(s) of TNBC extravasation remains largely unknown, underlying the need to study further. High expression of Notch ligand JAGGED-1 (JAG1) is associated with increased metastasis and mortality in patients with breast cancer. While JAG1 enhances tumor angiogenesis and tumor growth, the means through which JAG1 promotes tumor cell dissemination is not clear. Our preliminary data supports a role for JAG1 as a key regulator of tumor cell interactions with the endothelium, controlling tumor cell adhesion, transendothelial migration (TEM), and transcription of critical paracrine-acting extravasation proteins, such as SPARC and ICAM1. Using both JAG-specific ligand traps as well as CRISPR/Cas9 mediated deletion of JAG1, we show that JAG1 promotes TEM in static transwell models, promotes primary tumor growth, and directs a tumor cell transcriptional program that upregulates cell surface interaction pathways distinct from global Notch inhibition. It is our central hypothesis that JAG1 promotes TNBC migration across the vascular endothelium, thereby allowing disseminated cancer cells to exit from circulation and enhancing TNBC metastasis. To define the JAG1-mediated elements of extravasation, we will examine five CRISPR/Cas9 JAG1 knockout lines in a cutting-edge flow system that recapitulates the vascular shear stress microenvironments where extravasation is thought to occur in vivo. We will evaluate multiple steps of extravasation including tumor cell binding, rolling, and TEM under various flow parameters. Moreover, we will study in vivo lung extravasation using a murine tail vein injection model and interrogate transcriptional candidates downstream of JAG1 as identified by our RNAseq data. Citation Format: Benjamin Gordon, Reyhaan A. Chaudhri, Tim Sargis, L.A. Naiche, Jan K. Kitajewski. JAGGED-1 as a novel metastatic extravasation promoter of triple negative breast cancer cells [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO015.

Endothelial Notch signaling is critical for tumor angiogenesis and growth. Inhibitors of Notch1 or its ligand Dll4 cause tumor vessel hypersprouting but interfere with vessel perfusion causing reduced tumor growth. Unfortunately, normal tissue vessels respond to these inhibitors causing tissue hypoxia or vascular neoplasms. Mice null for Notch4, unlike Notch1 mutants, exhibit reduced developmental and tumor angiogenesis. Notch4 expression is increased in the endothelium of some tumor types. These results suggest that specifically targeting Notch4 could reduce tumor angiogenesis with fewer effects on normal tissue and represents an unexplored therapeutic opportunity. We use a newly developed anti-Notch4 antibody, E7011, and show that in endothelial cells, inhibition of Notch4 signaling suppresses expression of a subset of canonical Notch target genes. Treatment with E7011 also suppresses expression of a unique set of genes not regulated by canonical Dll4-Notch1 signaling, which appear to be distinct Notch4 targets. We administered E7011 to neonatal mice to examine the effects on developmental retinal angiogenesis. A single dose of E7011 significantly reduced retinal vascular outgrowth, demonstrating that E7011 has anti-angiogenic activity in vivo. E7011 treatment did not alter capillary density within the vascular plexus or endothelial tip cell number, both of which are typically increased by loss of Notch1 signaling. Because the E7011 phenotype was markedly distinct from the Notch1 loss of function, we combined E7011 treatment with endothelial-specific loss of Notch1 (Notch1ECKO) to compare Notch1 to Notch4 function. E7011-treated Notch1ECKO retina showed a compound phenotype, exhibiting both the loss of vascular outgrowth characteristic of E7011/Notch4 and the hypersprouting characteristic of Notch1 loss of function. These results suggest that Notch1 and Notch4 have distinct roles in developmental angiogenesis, with Notch4 being a pro-angiogenic signaling pathway. We evaluated Notch4 expression in the breast cancer tumor microenvironment to determine if Notch4 functions in tumor vessels. Human triple negative breast cancer (TNBC) shows a range of expression of Notch4 in both tumor cells and tumor endothelium. The anti-angiogenic effects that we observe in the retina lead us to hypothesize that E7011 will show anti-tumor activity against tumors that induce Notch4 expression in neighboring endothelium, and that targeting endothelial Notch4 is a novel anti-angiogenic approach. Citation Format: L. A. Naiche, Bhairavi Swaminathan, Yu Kato, Sarita Das, Jason W. Eng, Qanber Raza, Krishna Thakkar, James H. Herts, Rajyasree Emmadi, Junji Matsui, Jan K. Kitajewski. A novel Notch4 neutralizing antibody inhibits angiogenesis and tumor growth via a distinct mechanism from endothelial Notch1 inhibition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1488.

Introduction: Gliomas are highly infiltrative tumors rendering complete resection impossible. As such, prognosis remains dismal. Recent studies have identified both proneural and mesenchymal cell populations. Crucially, recurring gliomas bear a mesenchymal phenotype. Understanding mechanisms driving mesenchymal transformation is important in developing tailored, more efficient therapeutic approaches. Methods: Using targeted biopsies from a mouse glioma model and human glioma databases, we applied bioinformatics and identified Notch as an additional master regulator (MR) protein driving mesenchymal transformation. To better understand the role of Notch, we overexpressed active forms of Notch1 (N1IC) or Notch3 (N3IC) in primary cells, orthotopic xenotransplants, and transgenic mouse models. We performed mouse survival studies and examined Notch-induced phenotypic alterations in tumor cells and the microenvironment using molecular and immunohistochemical approaches. Finally, we performed high-throughput drug and radiation screening studies to assess responses to treatment. Results: In silico analyses on RNAseq of biopsies from spatially distinct tumor regions in a mouse glioma model identified Notch as a highly active pathway in the cores of tumors undergoing mesenchymal transformation. Importantly, MR analysis of TCGA samples and single cell transcriptomic data identified the Notch pathway as a driver of proneural to mesenchymal transformation. Immunophenotyping and RNAseq profiling of human GBMs identified Notch receptors on tumor cells and Notch ligands on astrocytes and microglia suggesting potential microenvironment-mediated plasticity since Notch proteins are not frequently mutated in GBM. Overexpression of N1IC or N3IC in proneural cells induced mesenchymal transformation with slow proliferation and a highly invasive phenotype. Orthotransplantation of N3IC-expressing cells in mice led to slower growing tumors, perivascular invasion, increased recruitment of reactive phagocytes and slightly prolonged survival. A novel transgenic mouse model in which N1IC was overexpressed also led to prolonged survival compared to a control population. Importantly, high-throughput screening studies showed that N1IC and N3IC rendered tumor cells significantly more resistant to standard and targeted therapies, including irradiation and etoposide. Conclusions: Our study identifies Notch signaling as an important, likely microenvironment-driven pathway driving proneural to mesenchymal transformation in glioma. While Notch was shown to slow tumor growth and prolong survival, cells were more invasive and less sensitive to treatment. These findings suggest that Notch plays a role in the mesenchymal transformation and therapeutic resistance seen in post-treatment recurrence. Targeting Notch may therefore be important in improving therapeutic responses against glioma. Citation Format: Matei A. Banu, Athanassios Dovas, Henar Cuervo, Brianna Pereira, Aayushi Mahajan, Hongxu Ding, Mukesh Bansal, Sergey Pampou, Charles Karan, Andrea Califano, Peter A. Sims, Jan Kitajewski, Jeffrey N. Bruce, Peter Canoll. Notch is a master regulator of mesenchymal transformation and therapeutic resistance in glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5103.

Notch signaling is required for vascular development and tumor angiogenesis. Although inhibition of the Notch ligand Delta-like 4 can restrict tumor growth and disrupt neovasculature, the effect of inhibiting Notch receptor function on angiogenesis has yet to be defined. In this study, we generated a soluble form of the Notch1 receptor (Notch1 decoy) and assessed its effect on angiogenesis in vitro and in vivo. Notch1 decoy expression reduced signaling stimulated by the binding of three distinct Notch ligands to Notch1 and inhibited morphogenesis of endothelial cells overexpressing Notch4. Thus, Notch1 decoy functioned as an antagonist of ligand-dependent Notch signaling. In mice, Notch1 decoy also inhibited vascular endothelial growth factor–induced angiogenesis in skin, establishing a role for Notch receptor function in this process. We tested the effects of Notch1 decoy on tumor angiogenesis using two models: mouse mammary Mm5MT cells overexpressing fibroblast growth factor 4 (Mm5MT-FGF4) and NGP human neuroblastoma cells. Exogenously expressed FGF4 induced Notch ligand expression in Mm5MT cells and xenografts. Notch1 decoy expression did not affect tumorigenicity of Mm5MT-FGF4 cells in vitro but restricted Mm5MT-FGF4 xenograft growth in mice while markedly impairing neoangiogenesis. Similarly, Notch1 decoy expression did not affect NGP cells in vitro but disrupted vessels and decreased tumor viability in vivo. These results strongly suggest that Notch receptor signaling is required for tumor neoangiogenesis and provides a new target for tumor therapy. [Cancer Res 2008;68(12):4727–35]

The Notch signaling network is an evolutionarily conserved intercellular signaling pathway which regulates interactions between adjacent cells. The Notch family receptor and its signaling pathways are involved in the development of numerous tissues in multicellular organisms. Recent studies from our Acvr1bflox/flox;LSL-KrasG12D;Pdx1-Cre mice suggest that Notch4 plays an oncogenic role in dictating cell fate and contributes to pancreatic tumorigenesis, particularly in the development of pancreatic intraductal papillary mucious neoplasms (IPMNs). The perinuclear localization of the activated Notch4 (but not other Notch members) intracellular domain (ICD) in the apical cytoplasm of neoplastic cells appeared to be associated with the expansion of the IPMN lesions. The unique role of Notch4 signaling pathway in IPMN development was also confirmed by unbiased RNA-Seq analyses. The deletion of Notch4 in the p16flox/flox;LSL-KrasG12D;Pdx1-Cre mice prolonged survival, further supporting its oncogenic role in pancreatic tumorigenesis. Citation Format: Wanglong Qiu, David D. Suh, Natasha M. Tsay, Simona Chadi, Adam R. Chambers, Peter A. Sims, Carrie J. Shawber, Jan Kitajewski, Helen E. Remotti, Gloria H. Su.{Authors}. Notch4 acts as an oncogenic signal in pancreatic tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A51.

This study investigates how Notch3 signal activation affects ovarian cancer metastatic growth in order to provide insight into the mechanisms of ovarian cancer progression. Ovarian cancer is often detected at late stages after peritoneal metastasis, at which point prognosis is poor. TCGA defined the Notch signaling pathway as detectably altered in 22% of high-grade serous ovarian cancers, and NOTCH3 in particular is commonly overexpressed. Patients with NOTCH3-high recurrent tumors exhibit worse prognosis and decreased survival. NOTCH3 expression is correlated with resistance to platinum-based chemotherapy. To investigate the mechanisms by which Notch3 signaling functions to promote ovarian cancer, we performed experiments using the ID8 IP2 luciferase mouse ovarian surface epithelial line. This low-Notch3 expressing line was lentivirally infected with Notch3 intracellular domain (N3IC), an activated form of the Notch3 receptor. Increase in N3IC expression and Notch signal activation were confirmed with a dual luciferase reporter assay and via quantitative PCR for N3IC and downstream HES and HEY family targets. We then compared Notch3 activated ID8 IP2 cells to control cells using in vitro assays to evaluate growth properties of the cells, and in vivo intraperitoneal implants in NCR-nu/nu athymic mice to assess metastatic potential. In vitro N3IC and control cells were found to be morphologically similar, and assessment of N3IC cells demonstrated no significant effect on proliferation rate. Anchorage independent growth was also not significantly altered upon activation of Notch3. In addition, the effect of platinum therapy response was assessed in N3IC and control lines. When tested in a DIMSCAN cytotoxicity assay with cisplatinum doses raging from 2-16 μM, no significant difference in sensitivity to platinum treatment, as measured by IC50, was observed. In vivo, however, preliminary results indicate that activation of Notch3 signaling leads to acceleration of ascites accumulation and tumorigenesis. Ascites derived from mice with Notch3 activated tumors had a notably higher blood content indicating alteration of tumor vasculature. Finally, mice display a significant reduction in overall survival with Notch3 activation. We conclude that Notch3 signal activation in ID8 IP2 cells promotes metastatic growth in the peritoneum and ascites accumulation. Notch3 activation was associated with a decreased overall survival of tumor bearing mice. The growth properties of cultured ID8 IP2 cells were not noticeably altered due to Notch3 activation. We propose that Notch3 activation promotes increased tumorigenesis by influencing interaction between cancer cells and the host environment. Citation Format: Jessica Price, Nathaniel Jones, Jan Kitajewski. Notch3 signal activation promotes tumorigenesis in a mouse model of peritoneal epithelial ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4023. doi:10.1158/1538-7445.AM2015-4023

Purpose: Vascular endothelial growth factor (VEGF) inhibition is a validated cancer treatment. However, even in responsive tumors, acquired resistance is common. Notch proteins also function as key angiogenic effectors, and cross-regulate VEGF expression, raising the question of whether combined treatment would enhance tumor suppression. We hypothesized that dual VEGF/Notch blockade would inhibit tumor growth in experimental SY5Y neuroblastoma. Methods: SY5Y neuroblastoma cells were lentivirally transfected to express Notch1-decoy (N1D) or GFP (control). Proliferation was assessed in vitro under both hypoxia and normoxia using BrdU assays. To examine the effect of N1D on tumor growth, 10[6] cells were xenografted intrarenally in nude mice and treated with placebo or bevacizumab (BV) twice a week. Tumor progression was monitored by bioluminescence. Metastatic burden in target organs was quantified by bioluminescence and histology. Vascular disruption due to N1D and BV treatment was evaluated by immunostaining. IACUC approval was obtained for all experiments. Results: Expression of soluble N1D was confirmed by immunoblotting conditioned media. SY5Y+N1D cells proliferated more rapidly in hypoxia than control SY5Y+GFP cells (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2325. doi:1538-7445.AM2012-2325