bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 1548: Baseline serum levels of osteopontin and thrombospondin-1 predict shorter overall survival in primary resected non-small cell lung cancer
Authors: Rouanne Mathieu , Adam Julien , Goubar Aïcha , Robin Angélique , Ohana Caroline , Louvet Emilie , Cormier Jiemin , Mercier Olaf , Dorfmüller Peter , Fattal Soly , Thomas de Montpreville Vincent , Fadel Elie , Besse Benjamin , Olaussen Ken André , Auclair Christian , Soria Jean-Charles
Published: August 2015

Background: Osteopontin and thrombospondin-1 are extracellular matrix proteins secreted by both stromal and tumor cells. These proteins may play a key role in the tumor microenvironment for cancer development and metastasis. This study focused on the prognostic value of circulating osteopontin and thrombospondin-1 in primary resected NSCLC patients.

Methods: Between January and December of 2012, serums were collected from 171 patients prior to primary surgery and from age-matched cancer-free individuals (n = 20). At baseline, circulating osteopontin and thrombospondin-1 levels were measured by ELISA. Tissue protein expression in primary tumor samples was determined by immunohistochemical analysis.

Results: High levels of serum osteopontin and thrombospondin-1 levels were found in the cohort study. The difference between patients and healthy individuals was statistically significant (p<0.0001). Serum levels of osteopontin and thrombospondin-1 were independent prognostic factors of overall survival in multivariate analysis (HR 1.71, 95% CI 1.04-2.82, p = 0.04 for an increase in osteopontin of 50 ng/mL; HR 0.18, 95% CI 0.04-0.87, p = 0.03 for an increase in thrombospondin-1 of 10 ng/mL) similarly to their combination (HR is 1.31, 95% CI 1.03-1.67, p = 0.03 for an increase in osteopontin/thrombospondin-1 ratio of 6 ng/mL). Osteopontin and thrombospondin-1 levels were inversely correlated to survival rates.

Conclusions: Baseline osteopontin and thrombospondin-1 serum levels, and even more importantly their combination, can serve as strong independent prognostic factors to predict overall survival in primary resected NSCLC patients, and therefore reflect the aggressiveness of the tumor.

Citation Format: Mathieu Rouanne, Julien Adam, Aïcha Goubar, Angélique Robin, Caroline Ohana, Emilie Louvet, Jiemin Cormier, Olaf Mercier, Peter Dorfmüller, Soly Fattal, Vincent Thomas de Montpreville, Elie Fadel, Benjamin Besse, Ken André Olaussen, Christian Auclair, Jean-Charles Soria. Baseline serum levels of osteopontin and thrombospondin-1 predict shorter overall survival in primary resected non-small cell lung 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 1548. doi:10.1158/1538-7445.AM2015-1548
Abstract 155: LncRNA AK023948 promotes breast tumorigenesis by enhancing AKT phosphorylation
Authors: Koirala Pratirodh , MO Yin Yuan
Published: August 2015

The human genome expresses a large number of long non-coding RNAs (lncRNAs), however, little is known about their physiological functions or their role in cancer for the vast majority of these lncRNAs. In the present study, we identified a set of lncRNAs that were differentially expressed in breast cancer tissues as compared to normal tissue. Among them is AK023948 which is up-regulated in breast cancer tissue and in breast cancer cell lines. Ectopic expression of AK023948 in breast cancer MCF-7 cells promotes proliferation and anchorage independent cell growth along with activation of AKT phosphorylation. On the other hand, knockdown or knockout of AK023948 in MCF-7 cells reduces the proliferation of cells and phosphorylation of AKT. Furthermore, there is a positive correlation between AK023948 and pAKT expression in breast cancer tissue microarray. To determine the underlying mechanism of AK023948-mediated activation of AKT, we performed RNA precipitation assays using biotin-labeled AK023948 RNA probe, followed by PAGE analysis, and detected a unique protein band by silver staining. Mass spectrometry analysis identified it as ATP dependent RNA helicase A (RHA/DHX9) which was confirmed by Western blot and RNA immunoprecipitation (IP), respectively. Co-IP indicated that DHX9 interacts with p85PI3K regulatory subunit. Further characterization revealed that p85-DHX9 interaction is essential for stability of p85α and AKT phosphorylation. Together, these results suggest that AK023948 may function as an oncogenic lncRNA in breast cancer and thus, it may serve as a novel target for breast cancer therapy.

Citation Format: Pratirodh Koirala, Yin Yuan MO. LncRNA AK023948 promotes breast tumorigenesis by enhancing AKT phosphorylation. [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 155. doi:10.1158/1538-7445.AM2015-155
Abstract 1561: Detection of colorectal cancer-associated genetic and epigenetic alterations in urine of patients with CRC
Authors: Clemens Adam Winfield , Lin Selena , Jain Surbhi , Su Ying-Hsiu , Song Wei
Published: August 2015

Colorectal cancer (CRC) has been the second leading cause of cancer-related deaths due in part to a low compliance rate (<50%) of the current screening method, an invasive colonoscopy, resulting in failure of detecting cancer early in its curative stages. 20% of CRC cases are only detected once the cancer has spread to a distant site, drastically reducing the 5-year survival rate from 90% to 12%. In order to improve the success of early detection methods of CRC, we have focused on developing non-invasive, multi-biomarker detection assays designed to identify CRC-associated genetic alterations. We have previously demonstrated that urine contains circulation-derived low molecular weight (LMW) DNA (<300 bp), which suggests that LMW urine DNA could be used to detect CRC-associated genetic alterations. Using previously identified stool and serum-based biomarkers for CRC, we have developed a panel of potential CRC markers for early detection for use in a non-invasive urine DNA test. Our panel contains genetic mutations and epigenetic alterations of nine genes: mutations of KRAS codons 12/13 and BRAF V600E and aberrant hypermethylation of VIM, SEPT9, BMP3, NDRG4, CDKN2A, TFPI2, and MGMT. The proof-of-concept of a CRC urine DNA test was demonstrated in a small pilot study investigating mVIM as a biomarker for CRC in matched tissue-urine samples. This led to the development of a PCR-based approach to quantify these markers in a prevalidation study with blinded CRC samples to identify the specificity and sensitivity of these genetic mutations and epigenetic alterations. In a concordant study using this blinded CRC sample set, our panel of markers was used in an amplicon NGS-based study. Results from these two studies will be used to confirm the sensitivity and specificity of each marker for early detection of CRC.

Citation Format: Adam Winfield Clemens, Selena Lin, Surbhi Jain, Ying-Hsiu Su, Wei Song. Detection of colorectal cancer-associated genetic and epigenetic alterations in urine of patients with CRC. [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 1561. doi:10.1158/1538-7445.AM2015-1561
Abstract 157: LncRNA ANRIL indicates a potential prognostic biomarker in gastric cancer and promotes tumor growth by silencing of miR-99a/miR-449a
Authors: Xu Zhi , Chen Jinfei , Luk John M. , De Wei
Published: August 2015

Long noncoding RNAs are involved in several kinds of cancers. Here, we reported that ANRIL (CDKN2B-AS1), a 3.8-kb long noncoding RNA, recruiting and binding to PRC2, was generally upregulated in human gastric cancer (GC) tissues. In a cohort of 120 GC patients, the higher expression of ANRIL was significantly correlated with higher TNM stages (P = 0.041) and larger tumor sizes (P = 0.001). Multivariate analyses revealed that ANRIL expression served as an independent predictor for overall survival (OS) (P = 0.036). Further experiments revealed that the knockdown of ANRIL significantly repressed the proliferation of GC cell lines both in vitro and in vivo. We also showed that E2F1 could induce ANRIL and ANRIL-mediated growth promotion is partly due to epigenetic repression of miR-99a/miR-449a in Trans (controlling the targets_mTOR and CDK6/E2F1 pathway) by binding to PRC2, thus forming a positive feedback loop, continuing to promote GC cell proliferation. To our knowledge, this is the first report which showed that the role of ANRIL in the progression of GC and ANRIL could crosstalk with microRNAs in epigenetic level. Our results suggest that ANRIL, as a growth regulator, may serve as a potential prognostic biomarker and target for new therapies in human GC.

Citation Format: Zhi Xu, Jinfei Chen, John M. Luk, Wei De. LncRNA ANRIL indicates a potential prognostic biomarker in gastric cancer and promotes tumor growth by silencing of miR-99a/miR-449a. [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 157. doi:10.1158/1538-7445.AM2015-157
Abstract 1604: IMI CANCER-ID: Validation of novel blood-based biomarker technologies in clinical settings
Authors: Schlange Thomas , Krahn Thomas , Pleier Sabrina , Pantel Klaus , Terstappen Leon WMM , Baggiani Barbara
Published: August 2015

The Innovative Medicines Initiative (IMI) was launched in 2008 as a public-private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA). IMI aims to facilitate the collaboration of healthcare stakeholders such as academic and clinical researchers, pharmaceutical industry and small and medium-sized enterprises (SMEs) in Europe, in order to address key issues in drug development and patient access to innovative medicines.

Tumor heterogeneity and the dynamic changes at the molecular level during disease progression make longitudinal monitoring of malignant disease highly desirable in order to choose the best treatment options and to monitor treatment efficacy. As access to tumor tissue is often the limiting factor and historic samples are not predictive for the current state of the disease, liquid biopsies are explored to support personalized treatment of cancer patients. The CANCER-ID consortium was established in 2014 and aims to validate technologies for blood-based biomarkers such as Circulating Tumor Cells (CTCs), circulating tumor DNA (ctDNA) and microRNAs (miRNAs) to determine the absence/presence of drug targets and to assess the response to treatment. To prove broader applicability and clinical utility of the consortium's technologies and protocols, the validated assays will be deployed in controlled clinical studies (TRACERx, NCT01888601; NVALT17, NTR4410; SPECTAlung, NCT02214134; patients under SoC treatment) in 1) Non-Small Cell Lung Cancer (NSCLC) and 2) anti-Her2-resistant metastatic breast cancer (Her2RMBC). CANCER-ID is a unique network of experts in the fields of tumor biology, biomarker development, clinical sciences and bioinformatics with a total indicative budget of 14 Mio €. The consortium joins forces of 16 academic groups (ten large clinical trial sites), 6 EFPIA companies, 1 multi-national diagnostics company, 5 SMEs with advanced technologies for CTC isolation or for complex data analysis and big data handling, and two non-profit organizations. In order to fully exploit the synergies created by CANCER-ID, regulatory agencies and patient advocacy groups are involved and invited to participate in the IMI project.

Citation Format: Thomas Schlange, Thomas Krahn, Sabrina Pleier, Klaus Pantel, Leon WMM Terstappen, Barbara Baggiani. IMI CANCER-ID: Validation of novel blood-based biomarker technologies in clinical settings. [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 1604. doi:10.1158/1538-7445.AM2015-1604
Abstract 1623: Targeted therapy of Ewing's Sarcoma and childhood leukemia (ALL) by hybrid polymerized liposomal nanoparticles (HPLN)
Authors: Kang Hyunggyoo , Shahbazian Violette , Holly Ryan , Nagy Jon , Triche Timothy
Published: August 2015

Poor selectivity of the current cancer therapies causes a variety of side effects such as secondary cancers, heart or lung damage, infertility or chronic hepatitis. Therefore a reliable tumor specific therapy is urgently needed to treat cancer patients. It has been widely recognized that the recent chemotherapy could be far more effective if higher doses could be specifically delivered to the tumor and not to normal tissues. Targeted nanoparticles have shown the potential to deliver anticancer drugs to cancer cells selectively and thus to overcome unexpected cytotoxicity and limited efficacy of the chemotherapy caused by the unselective delivery to normal cells. However in addition to the selectivity the efficacy of the targeted nanoparticles depends upon two more requirements: immune evasion and timely release of contents in target cells. In spite of a lot of effort still the optimal formulation of nanoparticle for the actual translational applications was not established yet. PLN (Polymerized Liposomal Nanoparticles) can be synthesized to a variety of physiochemical properties including a broad range of composition and size. By refining the early formulations and after extensive testing, recently we could invent HPLN (Hybrid Polymerized Liposomal Nanoparticles) and demonstrate that this new type of polymeric nanoparticle overcomes many, if not most, of the deficiencies noted and has tremendous potential as an effective delivery vehicle for treating many types of cancer. In our study it was shown that the targeted HPLN with antibodies (antiCD99 or antiCD19) can inhibit the growth of Ewing's sarcoma and childhood leukemia (ALL) in a murine model. The antitumor effects were diminished pretty much by the removal of antibody or drug (Doxorubicin), which proves efficacy of the targeted HPLNs is specifically dependent upon the targeting antibody and drug. In addition, no abnormalities in liver and kidney function tests, complete blood counts or pathology of major organs are observed from tail-vein administrations. These data provide strong evidence for the safety and efficacy of this targeted HPLN delivery system of anticancer drugs to Ewing's sarcoma and childhood leukemia (ALL). In conclusion, our result showed a potential of targeted HPLN as a selective delivery vehicle of cytotoxic drugs to cancers. Hopefully this technology will be applied to treat many other different types of tumor cells in the future.

Citation Format: Hyunggyoo Kang, Violette Shahbazian, Ryan Holly, Jon Nagy, Timothy Triche. Targeted therapy of Ewing's Sarcoma and childhood leukemia (ALL) by hybrid polymerized liposomal nanoparticles (HPLN). [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 1623. doi:10.1158/1538-7445.AM2015-1623
Abstract 1632: Microsomal prostaglandin E synthase 1: a novel therapeutic target of neuroblastoma
Authors: Kock Anna , Larsson Karin , Joan Raouf , Korotkova Marina , Johnsen John-Inge , Jakobsson Per-Johan , Kogner Per
Published: August 2015

Background:

Tumor promoting inflammation is important for Neuroblastoma development and progression. We have previously shown that the inflammatory prostaglandin E2 (PGE2) acts as an autocrine survival factor in NB and that high expression of microsomal prostaglandin E synthase-1 (mPGES-1), essential for PGE2 synthesis, is coupled to poor clinical outcome in high risk NB. We have also shown that mPGES-1 promotes growth and survival of several malignancies.

In this study we investigate the impact of specific PGE2 targeting in NB by using a novel mPGES-1 inhibitor in vivo.

Methods: The in vivo effect of the mPGES-1 inhibitor on tumor growth was carried out using the MYCN driven transgenic mouse model that spontaneously develops an aggressive form of neuroblastoma (tg TH-MYCN model). Protein and mRNA expression of mPGES-1 and the COX enzymes in the tumors was determined by immunohistochemistry (IHC) and RT-qPCR.

Infiltration and polarization of macrophages in treated and nontreated tumors was assessed by IHC using the PAN-marker F4/80 and the M2 polarized macrophage marker CD206.

The effect of mPGES-1 inhibition on angiogenesis was determined by IHC by using the endothelial marker CD31.

Results: Expression of mPGES-1 and COX-1 could be detected in tumours from the tg TH-MYCN model. By treating the animals with the mPGES-1 inhibitor we could significantly delay the tumor growth with reduced tumor weights at sacrifice compared to tumors from untreated control animals.

To study the effect of inflammation we analyzed macrophage abundance and polarization in the treated and untreated tumors. There was no diffrence in the total level of macrophage infiltration while a significant decrese of M2 polarized macrophages was seen in the treated tumors.

Furthermore, mPGES-1 inhibition significantly reduced angiogenesis in the tumors.

Conclusion: Our results demonstrate that specific PGE2 inhibition by targeting mPGES-1 is a way of reducing NB growth.

Note: This abstract was not presented at the meeting.

Citation Format: Anna Kock, Karin Larsson, Raouf Joan, Marina Korotkova, John-Inge Johnsen, Per-Johan Jakobsson, Per Kogner. Microsomal prostaglandin E synthase 1: a novel therapeutic target of neuroblastoma. [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 1632. doi:10.1158/1538-7445.AM2015-1632
Abstract 1657: The role of Noxa/MCL-1 axis in solid tumors treated with DNA damaging agents
Authors: Nakajima Wataru , Sharma Kanika , Hicks Mark A. , Lee June Y. , Tanaka Nobuyuki , Harada Hisashi
Published: August 2015

DNA damaging agents, such as cisplatin and etoposide, are employed for the treatment of a wide array of solid tumors, but the prolonged use of chemotherapeutic drugs is limited by their toxicity and by the development of resistance. To overcome these major roadblocks to improved prognosis requires mechanism-based therapeutic strategies that maximize the antitumor effect of drugs while limiting their toxicities. These agents exert anticancer effects via multiple mechanisms, yet its most prominent mode of action involves the generation of DNA lesions followed by the activation of the DNA damage response and the induction of BCL-2 family-dependent mitochondrial apoptosis. Direct therapeutic targeting of the BCL-2 family in cancer is therefore conceptually appealing but has proved remarkably challenging. This is due, in part, to the difficulty in producing effective drugs and in achieving a satisfactory therapeutic index. Also important, but less appreciated in this regard, are the potentially complex, tissue-specific interactions among the BCL-2 family members observed in different tumor types.

We have found that the expression of pro-apoptotic Noxa and anti-apoptotic MCL-1 proteins of the BCL-2 family is a critical determinant of the sensitivity to DNA-damaging agents in solid tumors; (1) MCL-1 is a labile protein and its stability is regulated by phosphorylation followed by ubiquitination and proteasome-mediated degradation; (2) Noxa specifically binds to and recruits MCL-1 from the cytosol to the mitochondria. Translocation of MCL-1 initiates its phosphorylation and subsequent ubiquitination, which triggers proteasome-mediated degradation; (3) The Noxa-dependent phosphorylation sites are regulated by CDK2 and are different from those phosphorylated by CDK1 in response to paclitaxel treatment; (4) Noxa is transcriptionally induced by cisplatin or etoposide. Downregulation of Noxa by shRNA strongly inhibits cisplatin-induced apoptosis. These results suggest that the Noxa/MCL-1 axis plays a critical role in apoptosis induced by DNA damaging agents and targeting Noxa/MCL-1 could be an alternative strategy to overcome the resistance to these agents.

Citation Format: Wataru Nakajima, Kanika Sharma, Mark A. Hicks, June Y. Lee, Nobuyuki Tanaka, Hisashi Harada. The role of Noxa/MCL-1 axis in solid tumors treated with DNA damaging agents. [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 1657. doi:10.1158/1538-7445.AM2015-1657
Abstract 1674: HER3 inhibition potentiates anti-tumor effects of PI3K inhibitors in pre-clinical models of HNSCC
Authors: Davis Kara S. , Khan Nayel , Kemp Carolyn , Kulkarni Sucheta , Alvarado Diego , LaVallee Theresa , Grandis Jennifer R. , Duvvuri Umamaheswar
Published: August 2015

Background: The phosphoinositide 3-kinase (PI3K) pathway is thought to be the most frequently mutated oncogenic pathway in head and neck squamous cell carcinoma (HNSCC). This pathway is often further activated by deregulated receptors such as the epidermal growth factor receptor family. HER3 has a direct phosphorylation site with the regulatory subunit of PIK3CA, and is being investigated as a potential co-target to increase anti-tumor effects of PI3K inhibition. In this investigation, we use blocking antibodies against HER3 and its ligand, neuregulin β-1, (KTN3379) and PIK3CA (BYL719) to investigate the effect of HER3 in modulating response to PI3K inhibition.

Methods and Results: Treatment with neuregulin β-1 significantly increased phosphorylation of HER3, AKT, and S6 across HNSCC, regardless of baseline level of HER3 expression. HER3 inhibition (KTN3379) consistently abrogated these effects, and decreased baseline phosphorylation of HER3. Combined blockade of HER3 (KTN3379) and PI3K (BYL719) inhibits the growth of HNSCC cell lines more effectively than inhibition of a single receptor alone, in both cell proliferation and colony formation assays. Combined treatment decreases phosphorylation of AKT and S6 more effectively than inhibition with either drug in some HNSCC cell lines. Treatment with neuregulin β-1 diminishes the inhibitory effect of BYL719 on HNSCC cell growth. Furthermore, treatment of some HNSCC cell lines with BYL719 led to upregulation of the HER3 pathway in HNSCC cell lines by Western blotting analysis, suggesting a possible role of HER3 in PI3K resistance.

Conclusion: HER3 interacts with PI3KCA, and the PI3K pathway in multiple HNSCC cell lines, and combined blockade leads to pronounced effects in pre-clinical models of HNSCC. These findings suggest that HER3 blockade, may be efficacious when combined with PI3K pathway inhibition.

Citation Format: Kara S. Davis, Nayel Khan, Carolyn Kemp, Sucheta Kulkarni, Diego Alvarado, Theresa LaVallee, Jennifer R. Grandis, Umamaheswar Duvvuri. HER3 inhibition potentiates anti-tumor effects of PI3K inhibitors in pre-clinical models of HNSCC. [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 1674. doi:10.1158/1538-7445.AM2015-1674
Abstract 1676: An agonistic antibody to EphA2 exhibits anti-tumor effect to human melanoma
Authors: Kato Kazunori , Sakamoto Atsushi , Kojima Taro , Hasegawa Toshio , Ikeda Shigaku
Published: August 2015

EphA2 is a member of the Eph family of receptor tyrosine kinases and is highly expressed in aggressive human cancers, including melanoma. Recently, EphA2 has been found to be integral player in cancer formation and expected as a target for antibody therapy. In this study, we have investigated the therapeutic effect of various anti-EphA2 mAbs that were recently established in our laboratory. Cell surface expression of EphA2 on melanoma cell lines was analyzed by flow cytometry and therapeutic effects of anti-EphA2 mAbs were investigated using cell proliferation, cell migration, invasion and antibody-mediated drug cytotoxicity assays. We found that human melanoma cell lines expressed EphA2 on their surface, while normal dermal fibroblasts and melanocytes were negative for EphA2. Recombinant human protein of EphrinA1 (a natural ligand for EphA2) and anti-EphA2 mAbs could not suppress melanoma cell proliferation, however, one of agonistic anti-EphA2 mAb, termed SHM16, inhibited metastatic potential such as migration and invasive properties of human melanoma. In contrast, an antagonistic anti-EphA2 mAb, SHM17, had no effect on migration and invasive assay. In addition, drastic growth inhibition and cell cytotoxicity were found in targeted delivery of immunotoxin by SHM16. In conclusion, these findings indicate a promising role for EphA2 as a target for antibody treatment in melanoma and enhance the therapeutic effect as an agonistic antibody to EphA2.

Citation Format: Kazunori Kato, Atsushi Sakamoto, Taro Kojima, Toshio Hasegawa, Shigaku Ikeda. An agonistic antibody to EphA2 exhibits anti-tumor effect to human melanoma. [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 1676. doi:10.1158/1538-7445.AM2015-1676
Abstract 1681: Inhibition of tumor growth in vivo through neutralization of the interaction of MCAM with laminin alpha 4
Authors: Flanagan Ken , Li Lauri W. , Lorenzana Carlos , Tam Stephen J. , Liu Yue , Dolan Philip J. , Alexander Lana , Salmans Josh , Barbour Robin M. , Higaki Jeffrey N. , Nijjar Tarlochan , Zago Wagner , Yednock Ted A. , Kinney Gene
Published: August 2015

Melanoma cell adhesion molecule (MCAM/CD146) is highly expressed on a subset of many tumor types including melanoma and glioblastoma, and expression of MCAM correlates with enhanced cellular invasion, increased metastasis, and poor patient prognosis. The expression of MCAM on tumor cells confers unique migratory and adhesion capacity, which, if specifically targeted, could result in interruption of multiple biological processes required for tumor growth and spread. Although a role for MCAM in tumor progression has long been appreciated, the unidentified ligand for MCAM precluded the development of targeted approaches to inhibit extracellular interactions mediated by MCAM. Recently, we identified the MCAM ligand as laminin alpha 4. Laminin alpha 4 is present within the extracellular matrix of the tumor in addition to the vasculature throughout the body, providing an adhesive substrate for MCAM expressing tumor cells both within the tumor microenvironment and the blood vessels. The presence of laminin alpha 4 within the tumor and the vasculature may allow for a biological interaction by which MCAM mediated adhesion could be involved in both the homotypic aggregation required for tumor growth, in addition to the vascular adhesion required for the processes of metastasis and angiotropism. We generated monoclonal antibodies that bind to the epitope required for MCAM interactions with laminin alpha 4. Such antibodies entirely abrogate interactions of the tumor cell with laminin alpha 4 in vitro. Furthermore, we characterized the inhibition of tumor growth in vivo mediated by neutralization of MCAM/laminin alpha 4 interactions. Notably, tumor growth was delayed by blockade of MCAM, but required inhibition of both the MCAM expressed by the tumor, as well as vascular MCAM. We further characterize the unique pattern of MCAM expression on tumor cells within the perivascular extracellular matrix in human tumors, which suggest that these interactions are involved in human disease pathogenesis. Thus, antibodies neutralizing the interaction between MCAM and laminin alpha 4 have potential to inhibit a critical molecular interaction used by myriad tumor types.

Citation Format: Ken Flanagan, Lauri W. Li, Carlos Lorenzana, Stephen J. Tam, Yue Liu, Philip J. Dolan, Lana Alexander, Josh Salmans, Robin M. Barbour, Jeffrey N. Higaki, Tarlochan Nijjar, Wagner Zago, Ted A. Yednock, Gene Kinney. Inhibition of tumor growth in vivo through neutralization of the interaction of MCAM with laminin alpha 4. [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 1681. doi:10.1158/1538-7445.AM2015-1681
Abstract 1684: Preclinical anti-tumor efficacy of FGFR2-ADC BAY 1187982 in patient-derived gastric, breast and ovarian cancer models
Authors: Sommer Anette , Kopitz Charlotte , Schatz Christoph , Zierz Ruprecht , Schuhmacher Joachim , Wittemer-Rump Sabine , Prins Klaas , Braun Manuela , Reetz Frank , Kreft Bertolt , Huynh Hung T. , Ziegelbauer Karl
Published: August 2015

Antibody-drug conjugates (ADC) represent a promising therapeutic approach for treatment of cancer. We have developed a novel ADC directed against fibroblast growth factor receptor 2 (FGFR2). FGFR2 is overexpressed in several cancer indications, such as gastric, breast, and ovarian cancer and thus represents a potential therapeutic target for treatment of FGFR2-positive cancer patients with ADC-based therapy.

FGFR2-ADC consists of a fully human anti-FGFR2-Ab (BAY 1179470) conjugated via a stable linker to a novel auristatin cytotoxic agent licensed from Seattle Genetics. FGFR2-ADC exhibits low nM to sub-nM potency in vitro in a panel of FGFR2-positive cancer cells lines (SNU-16, MFM-223, NCI-H716) while being inactive against FGFR2-low or -negative cell lines (MDA-MB-231, HEK-293, BaF/3) and highly selective versus a control ADC.

FGFR2-ADC is highly efficacious in monotherapy and results in tumor growth inhibition in the gastric cancer xenograft model SNU-16 and tumor regression in the breast cancer xenograft model MFM-223. FGFR2-ADC induces tumor stasis in the colorectal cancer xenograft model NCI-H716 and regrown tumors are sensitive to a second treatment cycle of FGFR2-ADC.

FGFR2-ADC shows high efficacy in vivo in monotherapy in patient-derived (PDX) FGFR2-positive murine xenograft models, e.g. in the ovarian cancer model OV30-0511A. FGFR2-ADC is also efficacious in the gastric cancer PDX model GC10-0608 and the breast cancer model MAXF857.

The toxophore metabolite of FGFR2-ADC was more than 30-fold enriched in tumors versus other organs (liver, spleen, kidneys) in NCI-H716 tumor-bearing mice.

Based on the preclinical efficacy, PK and tolerability data, evaluation of FGFR2-ADC in cancer patients appears warranted. A Phase I study is planned.

Citation Format: Anette Sommer, Charlotte Kopitz, Christoph Schatz, Ruprecht Zierz, Joachim Schuhmacher, Sabine Wittemer-Rump, Klaas Prins, Manuela Braun, Frank Reetz, Bertolt Kreft, Hung T. Huynh, Karl Ziegelbauer. Preclinical anti-tumor efficacy of FGFR2-ADC BAY 1187982 in patient-derived gastric, breast and ovarian cancer models. [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 1684. doi:10.1158/1538-7445.AM2015-1684
Abstract 1693: ASN004, a novel 5T4-targeted Dolaflexin™ antibody drug conjugate, causes complete regression in multiple solid tumor models
Authors: Smith Roger A. , Damle Nitin K. , Reddy Sanjeeva P. , Yurkovetskiy Alex , Bodyak Natalya , Yin Mao , Gumerov Dmitry , Ter-Ovanesyan Elena , Qin Liu , Park Peter U. , Lowinger Timothy B. , Gupta Sandeep
Published: August 2015

ASN004 is an Antibody Drug Conjugate (ADC) that targets the 5T4 oncofetal antigen (trophoblast glycoprotein), which is highly expressed in a wide range of malignant tumors, while having very limited expression in normal tissues. ASN004 incorporates a novel single-chain homo-dimer antibody, Fleximer® linker technology (Mersana Therapeutics), and several cytotoxic dolastatin (auristatin) analog warheads per ADC molecule (drug/antibody ratio ∼15). ASN004 shows high affinity for the 5T4 antigen and for 5T4-expressing tumor cells. As well, ASN004 shows potent cytotoxicity that is selective for 5T4-expressing tumor cells. ASN004 provides strong tumor regression and tumor-free survivors in multiple tumor xenograft models, at well-tolerated doses as low as 0.3 mg/kg iv. Furthermore, ASN004 causes tumor regression when administered to xenografts bearing more advanced (500 mm3) tumors. Robust, potent efficacy for ASN004 has also been demonstrated in head-to-head comparison studies with relevant reference ADCs. A favorable pharmacokinetics profile was observed in rodents and primates. Dose-range finding exploratory toxicology studies have been completed in both pharmacological and non-pharmacological non-clinical species. Efforts toward IND-enabling safety studies with this promising new agent are in progress.

Citation Format: Roger A. Smith, Nitin K. Damle, Sanjeeva P. Reddy, Alex Yurkovetskiy, Natalya Bodyak, Mao Yin, Dmitry Gumerov, Elena Ter-Ovanesyan, Liu Qin, Peter U. Park, Timothy B. Lowinger, Sandeep Gupta. ASN004, a novel 5T4-targeted Dolaflexin™ antibody drug conjugate, causes complete regression in multiple solid tumor models. [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 1693. doi:10.1158/1538-7445.AM2015-1693
Abstract 1706: Whole exome sequencing of pre and post treatment diffuse large B cell lymphoma reveals the mutation spectrum of the relapse/refractory patient population
Authors: Greenawalt Danielle , Byth Kate , Lai Zhongwu , Johnson Justin , Ahmed Ambar , Dougherty Brian , Thress Kenneth , Zinda Michael , Liang Winnie S. , Carpten John , Fawell Stephen , Barrett J. Carl
Published: August 2015

Our current understanding of the mutation spectrum of relapse/refractory patients is limited. Several published studies describing the mutational landscape of Diffuse Large B cell Lymphoma (DLBCL) have focused, by design, on diagnostic (pre-treatment) biopsies alone, while re-biopsy of patients who are refractory to first line therapy or who relapse on treatment is not standard of care in DLBCL. We have performed whole exome sequencing on 47 post treatment DLBCL core needle biopsies, 8 with matched diagnostic biopsies. Samples were obtained during a phase II trial prior to the start of treatment with the BCR targeted agent fostamatinib (1,2). Patients had progressed following therapy with an anthracycline-based regimen such as R-CHOP and had a median of 3 prior therapies (range 1-8). We compared the whole exome somatic variant and copy number calls from the post treatment and matched pairs to 2 cohorts of primary DLBCL (n = 112) analyzed with the same mutation caller (3,4). The average mutation rate between the pre and post treatment samples (n = 250, 282 respectively) and the paired diagnostic and post treatment biopsies were similar. However, we found that the mutation spectrum between the paired biopsies differed. Known DLBCL hotspot mutations such as MYD88 L265P remained consistent between pre and post treatment biopsies, however novel mutations in known DLBCL targets were found to emerge in the post treatment biopsies.

1. Veldman-Jones, M. et al. Reproducible, quantitative and flexible molecular sub-typing of clinical DLBCL samples using the NanoString nCounter system. Clin Cancer Res (2014)

2. Flinn I, B.N., Blum KA, et al. A Phase II Trial to Evaluate the Efficacy of Fostamatinib in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL). American Society of Hematology (San Francisco, 2014).

3. Zhang, J. et al. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A 110, 1398-403 (2013).

4. Pasqualucci, L. et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet 43, 830-7 (2011).

Citation Format: Danielle Greenawalt, Kate Byth, Zhongwu Lai, Justin Johnson, Ambar Ahmed, Brian Dougherty, Kenneth Thress, Michael Zinda, Winnie S. Liang, John Carpten, Stephen Fawell, J. Carl Barrett. Whole exome sequencing of pre and post treatment diffuse large B cell lymphoma reveals the mutation spectrum of the relapse/refractory patient population. [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 1706. doi:10.1158/1538-7445.AM2015-1706
Abstract 1720: HO-3867, a selective inhibitor of stat3, suppress ovarian tumor growth and metastasis in human tissue culture and in an orthotopic mouse model
Authors: Naidu Shan , Saini Uksha , ElNaggar Adam C. , Bid Hemant K. , Wanner Ross , Bixel Kristin , Suarez Adrian A. , Bolyard Chelsea , Kaur Balveen , Goodfellow Paul J. , Kuppusamy Periannan , Cohn David , Selvendiran Karuppaiyah
Published: August 2015

The lack of an efficient pre-clinical model predicting a drug's clinical response before it enters into clinical trials is a major reason behind the limited success or complete failure of most of the traditional anti-cancer compounds. In this study, we evaluate our novel, safe and selective STAT3 inhibitor HO-3867 for its anti-cancer efficacy/bio-availability using a pre-clinical relevant, orthotopic ovarian tumor model and ex-vivo human tumor tissue culture. Treatment with HO-3867 (100PPM) significantly suppressed ovarian tumor growth and metastasis when compared to the standard Cisplatin (4mg/kg). A substantial amount of HO-3867 was detected in the ovarian tumor tissues and quantified using EPR spectroscopy. Markers specific to cell proliferation (Ki-67, Cyclin D1), angiogenesis (VEGF and Kinase array) and apoptosis (caspase-3 activity) were significantly altered by treatment with HO-3867. In vivo histopathological evaluation of internal organs collected from treated tumor mice revealed no evidence of toxicity specific to HO-3867. Normal and malignant tissues were collected and TUNEL/8-OHdG staining revealed selective induction of apoptosis limited to neoplastic cells and concomitant increase in reactive oxygen species within the orthotopic tumor. Suppression of STAT3 and its downstream target proteins (cell proliferative, anti-apoptotic and angiogenic) was confirmed with proteomic array. HO-3867 treated samples had significantly reduced vessel formation (∼4 times) as compared to the untreated control as is evident by in vivo Matrigel assay. HO-3867 was also found to have cytotoxic effects in ex vivo culture of freshly collected human tumor samples, including patients with chemotherapy resistant form of the disease. Overall, these results highlight the clinical anti-cancer potential of HO-3867 using a relevant preclinical orthotopic ovarian tumor model, and provide a rationale for the inclusion of ex vivo patient tumor slice culture in oncologic drug development processes.

Citation Format: Shan Naidu, Uksha Saini, Adam C. ElNaggar, Hemant K. Bid, Ross Wanner, Kristin Bixel, Adrian A. Suarez, Chelsea Bolyard, Balveen Kaur, Paul J. Goodfellow, Periannan Kuppusamy, David Cohn, Karuppaiyah Selvendiran. HO-3867, a selective inhibitor of stat3, suppress ovarian tumor growth and metastasis in human tissue culture and in an orthotopic mouse model. [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 1720. doi:10.1158/1538-7445.AM2015-1720
Abstract 173: SOX4 interacts with EZH2 and HDAC3 to suppress microRNA-31 in invasive esophageal cancer cells
Authors: Koumangoye Rainelli B. , Andl Thomas , Taubenslag Kenneth J. , Zilberman Steven T. , Taylor Chase , Andl Claudia D.
Published: August 2015

Tumor metastasis is responsible for 90% of cancer-related deaths. A strong link between microRNA dysregulation and human cancers has recently been established. However, the molecular mechanisms through which microRNAs regulate metastasis and cancer progression remain unclear. We analyzed the reciprocal expression regulation of miR-31 and SOX4 in esophageal squamous and adenocarcinoma cell lines by qRT-PCR and Western Blotting using overexpression and shRNA knock-down approaches. Here we report that SOX4 promotes esophageal tumor cell proliferation and invasion by silencing miR-31 via activation and stabilization of a co-repressor complex with EZH2 and HDAC3. We demonstrate that miR-31 is significantly decreased in invasive esophageal cancer cells compared to non-invasive cell lines, while upregulation of miR-31 inhibits growth, migration and invasion of esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC) cell lines. miR-31, in turn, targets SOX4 for degradation by directly binding to its 3′-UTR. Additionally, miR-31 regulates EZH2 and HDAC3 indirectly. SOX4, EZH2 and HDAC3 levels inversely correlate with miR-31 expression in ESCC cell lines. Ectopic expression of miR-31 in ESCC and EAC cell lines leads to down regulation of SOX4, EZH2 and HDAC3. Conversely, pharmacologic and genetic inhibition of SOX4 and EZH2 restore miR-31 expression. We show that SOX4, EZH2 and HDAC3 form a co-repressor complex that binds to the miR-31 promoter, repressing miR-31 through an epigenetic mark by H3K27me3 and by histone acetylation. Clinically, when compared to normal adjacent tissues, esophageal tumor samples show upregulation of SOX4, EZH2, and HDAC3, and EZH2 expression is significantly increased in metastatic ESCC tissues. Thus, we identified a novel molecular mechanism by which the SOX4, EZH2 and miR-31 circuit promotes tumor progression and potential therapeutic targets for invasive esophageal carcinomas.

Citation Format: Rainelli B. Koumangoye, Thomas Andl, Kenneth J. Taubenslag, Steven T. Zilberman, Chase Taylor, Claudia D. Andl. SOX4 interacts with EZH2 and HDAC3 to suppress microRNA-31 in invasive esophageal cancer cells. [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 173. doi:10.1158/1538-7445.AM2015-173
Abstract 1741: GRP78 / BiP / HSPA5 expression and those of other chaperone proteins is rapidly degraded by OSU-03012 and Viagra exposure: Implications for anti-cancer and anti-pathogen therapies
Authors: Booth Laurence A. , Roberts Jane L. , Dent Paul
Published: August 2015

We examined the interaction between the non-coxib OSU-03012 with phosphodiesterase 5 (PDE5) inhibitors to determine the role of the chaperone GRP78/BiP/HSPA5 in the response of cells. Sildenafil (Viagra) interacted in a greater than additive fashion with OSU-03012 to kill tumor cells including stem-like and anoikis resistant cells. Treatment of cells with OSU-03012/sildenafil: abolished the expression of growth factor receptors and plasma membrane drug efflux pumps; and caused a more rapid degradation of GRP78 and of other important chaperone proteins e.g. HSP27, HSP40, HSP60, HSP70 and HSP90. Decreased expression of receptors and pumps was dependent upon enhanced PERK-eIF2 signaling and blocked by GRP78 over-expression. The combination of OSU-03012/sildenafil synergized with sorafenib to kill tumor cells. GRP78 is also a protein required for human virus reproduction. Pre-treatment of mammalian cells with OSU-03012/sildenafil reduced expression of the coxsakie and adenovirus receptor in parallel with also reducing the ability of a serotype 5 adenovirus or coxsakie virus B4 to infect and to reproduce. Similar data were obtained using Cytomegalovirus and Influenza viruses. OSU-03012/sildenafil decreased the expression of: NPC1 and TIM1; LAMP1; and NTCP1, receptors for Ebola / Hepatitis A, Lassa fever, and Hepatitis B viruses, respectively. Bacteria express a GRP78 homologue and phosphodiesterases, and treatment of multi-antibiotic resistant E. coli and N. gonorrhoeae with OSU-03012/PDE5 inhibitor combinations was bactericidal and restored antibiotic sensitivity. Thus modulation of GRP78 function may be of therapeutic use in multiple human pathologies.

Citation Format: Laurence A. Booth, Jane L. Roberts, Paul Dent. GRP78 / BiP / HSPA5 expression and those of other chaperone proteins is rapidly degraded by OSU-03012 and Viagra exposure: Implications for anti-cancer and anti-pathogen therapies. [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 1741. doi:10.1158/1538-7445.AM2015-1741
Abstract 1743: Pharmacological sequestration of Skp1 causes degradation of oncogenic E3 ligases and mitotic blockade
Authors: Zhou Guangbiao , Liu Yong-Qiang , Liu Jinsong
Published: August 2015

Skp1 is an essential adaptor protein of the Skp1-Cul1-F-box protein complex and is able to stabilize the conformation of some ubiquitin E3 ligases. However, the role Skp1 plays during tumorigenesis remains unclear and Skp1-targeting agent is lacking. Here we showed that Skp1 was overexpressed in 33/56 (58.9%) non-small cell lung cancers, and elevated Skp1 was associated with poor prognosis. By structure-based high-throughput virtual screening, we found some Skp1-targeting compounds including 6-O-angeloylplenolin (6-OAP). 6-OAP could bind to Skp1 at sites critical to Skp1-Skp2 interaction, leading to dissociation and proteolysis of oncogenic E3 ligases NIPA, Skp2, and β-TRCP. Consequently, substrates of these E3 ligases Cyclin B1, P27 and E-Cadherin accumulated within the cells and caused prometaphase arrest. 6-OAP exhibited potent anti-lung cancer activity in two murine models and showed low adverse effect. These results indicate that Skp1 is critical to lung cancer pathogenesis, and targeting Skp1 can inactivate crucial oncogenic E3 ligases and exhibits significant therapeutic potentials.

Citation Format: Guangbiao Zhou, Yong-Qiang Liu, Jinsong Liu. Pharmacological sequestration of Skp1 causes degradation of oncogenic E3 ligases and mitotic blockade. [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 1743. doi:10.1158/1538-7445.AM2015-1743
Abstract 1745: NPY1 receptor specific peptide-drug-conjugates as novel treatment for metastatic breast cancer
Authors: Weber Lutz , Rennert Robert
Published: August 2015

The NPY1 receptor is a known marker for breast cancer that was characterized first at the university hospital Bern by the group of Reubi. In healthy breast tissue the NPY2 receptor (NPY2R) can be found, expression of which is switched to the NPY1R in tumor tissues (Reubi et al., Cancer Res. 2001, 61, 4636-4641). Particularly high NPY1R densities were also found in tumor biopsies of patients suffering from Ewing's sarcoma, which is a rare, difficult to treat juvenile bone cancer (Körner et al., Clin. Cancer Res. 2008, 14, 5043-5049.). Our own results verify these literature reports, shown on a panel of patient biopsies where nearly 50% of the tumors strongly overexpress the NPY1R, whereas NPY2R could not be detected.

OntoChem has developed peptide-drug-conjugates (“CytoPep”) that are selective agonists of the NPY1 receptor. As drugs we have used tubulin binding cytolysins and maytansines. CytoPep shall be developed as novel approach to treat Ewing's sarcoma and NPY1R expressing breast cancer.

We will present data on in vitro and in vivo pharmacology of these PDCs. IN particular efficacy is directly correlated with NPY1R expression levels in cells. We will also demonstrate internalization studies, showing a fast and selective internalization into NPY1R expressing cells. These in vitro data will be compared with corresponding data from ADCs such as for example trastuzumab emtansine, that show a considerably slower internalization and efficacy.

Citation Format: Lutz Weber, Robert Rennert. NPY1 receptor specific peptide-drug-conjugates as novel treatment for metastatic breast 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 1745. doi:10.1158/1538-7445.AM2015-1745