bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-308: Monoubiquitination is critical for Otub1 to suppress UbcH5 and stabilize p53
Authors: Li Yuhunag , Sun Xiao-Xin , Elferich Johannes , Shinde Ujwal , David Larry , Dai Mushui
Published: May 2015

Otub1 regulates p53 stability and activity via non-canonical inhibition of the MDM2 cognate ubiquitin (Ub)-conjugating enzyme (E2) UbcH5. However, it is not clear how this activity of Otub1 is regulated in cells. Here we report that Otub1 is monoubiquitinated by UbcH5 in cells and in vitro, primarily at lysine 59 and 109 residues. This monoubiquitination in turn contributes to the activity of Otub1 to suppress UbcH5. The lysine-free Otub1 mutant (Otub1K0) fails to be monoubiquitinated and is unable to suppress the Ub-conjugating activity of UbcH5 in vitro and the MDM2-mediated p53 ubiquitination in cells. Consistently, this mutant is unable to stabilize p53, induce apoptosis, and suppress cell growth. Overexpression of Otub1K0 inhibits DNA-damage induced apoptosis. Adding either Lys 59 or Lys 109 back to the Otub1K0 mutant restored the monoubiquitination of Otub1 and its function to stabilize and activate p53. We further show that UbcH5 preferentially binds to the monoubiquitinated Otub1 via Ub interaction with its backside donor Ub-interacting surface, suggesting that this binding interferes with the self-assembly of Ub-charged UbcH5 (UbcH5∼Ub) conjugates, which is critical for the Ub transfer. Thus, our data reveal novel insights into the Otub1 inhibition of E2 wherein monoubiquitination promotes the interaction of Otub1 with and its function to suppress UbcH5.

Citation Format: Yuhunag Li, Xiao-Xin Sun, Johannes Elferich, Ujwal Shinde, Larry David, Mushui Dai. Monoubiquitination is critical for Otub1 to suppress UbcH5 and stabilize p53. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-308. doi:10.1158/1538-7445.AM2014-LB-308
Abstract LB-31: Castration induces upregulation of intratumoral androgen biosynthesis and androgen receptor expression in orthotopic VCaP human prostate cancer xenograft model
Authors: Knuuttila Matias , Yatkin Emrah , Kallio Jenny , Savolainen Saija , Laajala Teemu Daniel , Aittokallio Tero , Oksala Riikka , Häkkinen Merja , Keski-Rahkonen Pekka , Auriola Seppo , Poutanen Matti , Mäkelä Sari
Published: May 2015

Androgens are key factors involved in the development and progression of prostate cancer (PCa), and the growth of PCa can be suppressed by androgen deprivation therapy (ADT). In a significant proportion of men receiving ADT, PCa progresses to castration-resistant prostate cancer (CRPC), which is a major challenge in the development of efficient therapies. The aim of the study was to characterize the cellular and molecular changes in tumors after ADT (castration), by using orthotopic VCaP human prostate cancer xenograft model. VCaP cells were inoculated in the dorsolateral prostate of immunodeficient mice, and tumor growth was followed by weekly serum PSA measurements. Mice with recurrent tumors after castration were randomized to treatment groups. Serum PSA concentrations showed significant correlation with the tumor volume, confirming that PSA is a reliable indicator of the tumor volume in the orthotopic VCaP xenograft model. Tumor and serum samples were collected and concentrations of androgens were measured by LC-MS/MS. Castration-resistant tumors retained their intratumoral androgen (androstenedione, testosterone, 5α-dihydrotestosterone) concentrations at levels similar to those in tumors growing in intact hosts. Accordingly, castration induced upregulation of enzymes involved in androgen biosynthesis (CYP17A1, AKR1C3 and HSD17B6), as well as expression of full-length androgen receptor (AR) and AR splice variants (AR-V1 and AR-V7). Furthermore, AR target gene expression was maintained in castration-resistant xenografts. AR antagonists, MDV3100 and ARN-509, suppressed the PSA production of castration-resistant tumors, confirming their androgen-dependency. In conclusion, we demonstrated that VCaP xenograft model exhibits the key characteristics of clinical CRPC, thus providing a valuable tool to identify druggable targets and for testing therapeutic strategies targeting AR signaling in CRPC.

Citation Format: Matias Knuuttila, Emrah Yatkin, Jenny Kallio, Saija Savolainen, Teemu Daniel Laajala, Tero Aittokallio, Riikka Oksala, Merja Häkkinen, Pekka Keski-Rahkonen, Seppo Auriola, Matti Poutanen, Sari Mäkelä. Castration induces upregulation of intratumoral androgen biosynthesis and androgen receptor expression in orthotopic VCaP human prostate cancer xenograft model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-31. doi:10.1158/1538-7445.AM2014-LB-31
Abstract LB-320: Systemic tumor-stroma interactions are prognostic indicators of breast tumor invasiveness
Authors: Bainer Russell , Frankenberger Casey , Rabe Daniel , Saleh Sadiq , Park Morag , Chada Kiran , Gilad Yoav , Rosner Marsha
Published: May 2015

Tumor invasiveness dysregulates homeostatic processes within tissues, driving both tumor and stroma cells to locally proliferate while also disrupting tissue boundaries and recruiting cells from distal sites to promote metastatic dissemination. Here, we use an RNA sequencing approach in mouse models of invasive and noninvasive breast cancer to directly test whether the transcriptional changes that occur as invasive tumors disrupt their microenvironment can be used to predict tumor subtype and patient outcomes. We find that tumor and stroma gene expression levels are largely synchronized within the tumor microenvironment, but that the expression levels of a subset of genes with high prognostic potential are strongly negatively correlated and may reflect opposing responses of tumor and normal stroma cells to tissue disruption. We clinically validate these observations in multiple human breast tumor gene expression datasets and demonstrate that stromal transcript levels enable superior classification of breast cancer subtypes relative to those expression changes observed between invasive and noninvasive tumor tissue. We show that local stromal remodelling is partially driven by differential recruitment of macrophages to invasive tumor sites by CCL5, and that invasion-specific gene expression changes that are prognostic for metastasis-free survival in human patients are detectable in stromal tissues far from the primary lesion. Our data indicate that dysregulation of tissue homeostasis by invasive tumors generates transcriptional changes both within the tumor microenvironment and in peripheral tissues that have significant diagnostic and prognostic potential and could facilitate novel patient therapeutic strategies.

Citation Format: Russell Bainer, Casey Frankenberger, Daniel Rabe, Sadiq Saleh, Morag Park, Kiran Chada, Yoav Gilad, Marsha Rosner. Systemic tumor-stroma interactions are prognostic indicators of breast tumor invasiveness. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-320. doi:10.1158/1538-7445.AM2014-LB-320
Abstract LB-33: Establishment and application of patient-derived xenograft models for translational research of personalized cancer therapeutics
Authors: Park Hyeji , Ju Eun Jin , Choi Jinhyang , Park Seok Soon , Park Jaesook , Lee Jae Hee , Shin Seol Hwa , Jeong Seong-Yun , Song Si Yeol , Choi Eun Kyung
Published: May 2015

Although there have been world-wide huge efforts in the field of cancer research to overcome cancer, the therapeutic influence is not satisfactory level yet, because of the diversity and complexity of cancers. The lack of preclinical models for translational research reliably predicting clinical activity of novel therapeutics is another obstacle in cancer research. Xenotransplantation of human cancer cell line into immunodeficient mice is very useful for studying human cancer therapy. However, these animal models have been limited to reflect a practical consideration of clinic and genetic diversity of patients. The creation of patient-derived xenografts (PDX) that carry partial or complete human physiological systems has been certainly accepted as a helpful tool to overcome these obstacles.

We have established total 339 cases in total (lung 79 cases, liver 109 cases, stomach 106 cases and colon 45 cases) up to date, and they were analyzed for the gene mutations by “Onco map” method, in order to compare to the original patient-tumor. As a result of cytogenetically homology comparison and finger printing, PDX tumors represent the same characteristics of the original PD tumors. These PDX models have been practically used for the translational research for personalized cancer therapeutics. This study represents new technologies for translational research platform of personalized cancer therapeutics. Additionally, these translational research platform promise the new access in many other studies such as a drug efficacy test, target discovery and co-clinical study.

Citation Format: Hyeji Park, Eun Jin Ju, Jinhyang Choi, Seok Soon Park, Jaesook Park, Jae Hee Lee, Seol Hwa Shin, Seong-Yun Jeong, Si Yeol Song, Eun Kyung Choi. Establishment and application of patient-derived xenograft models for translational research of personalized cancer therapeutics. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-33. doi:10.1158/1538-7445.AM2014-LB-33
Abstract LB-35: Living biobank of cancer organoids for drug development and screening
Authors: Vries Robert G.J. , Clevers Hans
Published: May 2015

Future cancer therapy will rely on treatment with drugs that are specific for individual tumours and patients. However, predicting clinical responses from genomic data remains highly challenging. Recently, systematic screens utilizing large panels of tumor cell lines have been used to correlate drug sensitivity with tumor genotype to identify predictive genomic markers of drug response. However, tumour cell lines have several drawbacks including being of limited genetic diversity; pre-clinical models that are more representative of the ‘natural’ mutational diversity of cancer are urgently required.

The Clevers lab recently developed methods for long-term culture of human primary tissues and cancers (‘organoids’). By establishing a large collection of tumour-specific organoids, the genetic spectrum of tumours can be captured as a pre-clinical model. This will allow stratification of tumours based on their genomic footprint and drug sensitivity, and may reveal correlations between drug sensitivity and this footprint. We have now established the organoid technology and the first biobank of Colon, Pancreas, and Lung primary carcinomas and metastasis. Importantly, whole genome sequencing of the initial tumour material and long term cultures demonstrate that, similar to healthy organoids, also tumour organoids are stable. The first screens with sets of drugs that are clinically available shows that the organoids respond as would be predicted by their sequence analysis, such as KRAS mutant organoids not responding to the EGFR inhibitor Cetuximab. We do however find patient specific differences which points to a promising role for organoids in drug development, patient stratification and possibly diagnosis. Finally, genetic analysis has indicated that we are efficiently generating organoids of the full range of genetic alterations previously identified in patients for these tumour types, including specific genotypes that are poorly or not represented in any other in vitro model at the moment.

Citation Format: Robert G.J. Vries, Hans Clevers. Living biobank of cancer organoids for drug development and screening. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-35. doi:10.1158/1538-7445.AM2014-LB-35
Abstract LB-5: Ultraviolet radiation inhibits murine mammary carcinogenesis at an early stage
Authors: Makarova Anastasia M. , Wang Grace , Libove Eileen , Khaimskiy Yefim , Epstein Ervin H.
Published: May 2015

Epidemiological studies of geographical variations in breast cancer mortality rates have found increased death rates at higher latitudes in USA and other countries. This breast cancer latitudinal gradient is hypothesized to be mediated by ultraviolet radiation (UVR) - produced vitamin D3. We have tested the effects of UVR in the well-described C3(1)/Tag transgenic mouse and have demonstrated that UVR started at age 6w and continued throughout the life of the mouse inhibits mammary carcinogenesis. Thus UVR prolongs palpable tumor - free survival (15±0.9 vs. 18±1.1 w; p=0.023) and delays the time of death (22±0.9 vs. 25±1.1 w; p=0.028).

To differentiate between an inhibitory effect of UVR on the processes leading to initial histologic changes vs. an effect on the later stage of progression from microscopic to palpable tumors we assessed the anti-carcinogenic effects of UVR given at different time points and for different intervals. UVR was given thrice weekly at 350mJ/cm2 per treatment to FVBN/J C3(1)-Tag females. Treatment groups: (1) No UVR, (2) UVR age 6 w until end of the study, (3) UVR age 6 w until the 1st palpable tumor, (4) UVR 1st palpable tumor until the end of the study, (5) UVR age 12 w (a time when histologic changes are present but no tumor has become palpable) until the 1st palpable tumor. Results: (1) UVR significantly delayed the onset of the first palpable tumor when started at age 6 w (12 days delay, p=0.005, two-tailed t-test) but not when started at age 12 w. (2) UVR started after the 1st tumor became palpable did not reverse already-existing histological changes and did not prolong overall survival, thus confirming that UVR's effects occur at an early, pre-palpable stage of carcinogenesis. (3) UVR was sufficient to delay the first palpable tumor and to prolong overall survival (21±1.0 vs. 23±0.9 w; p=0.002, compared to untreated group) even at short-term exposure from age 6 w until the 1st palpable tumor. Furthermore, UVR reduces the percentage of glands with DCIS changes appreciable histologically by 82, 55, 66, 20 and 19% at ages 9, 11, 13, 14 and 15 weeks). Thus UVR is able to delay the appearance of early stages of breast carcinogenesis but is unable to reverse already-present histologic changes and their progression to more advanced cancer.

Garland, F. C. et all. Prev Med 1990, 19, 614-22.; Green, J. E. et all. Oncogene 2000, 19, 1020-7.

Citation Format: Anastasia M. Makarova, Grace Wang, Eileen Libove, Yefim Khaimskiy, Ervin H. Epstein. Ultraviolet radiation inhibits murine mammary carcinogenesis at an early stage. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-5. doi:10.1158/1538-7445.AM2014-LB-5
Abstract LB-50: TRIM3, the human homolog of Drosophila Brat, is a tumor suppressor that regulates asymmetric cell division (ACD) in glioblastoma stem cells
Authors: Mukherjee Subhas , Chen Gang , Anand Monika , Kong Jun , Tucker-Burden Carol , Rong Yuan , Rahman Fahmia , Moreno Carlos , Meir Erwin Van , Hadjipanayis Constantinos , Brat Daniel
Published: May 2015

Cancer stem cells, capable of self-renewal and multipotent differentiation, influence tumor behavior through a complex balance of symmetric and asymmetric cell divisions. Mechanisms regulating the dynamics of stem cell and their progeny in human cancer are poorly understood. In Drosophila, mutation of brain tumor (brat) leads to loss of normal asymmetric cell division by developing neural cells and results in a massively enlarged brain composed of neuroblasts with neoplastic properties. Brat promotes asymmetric cell division and directs neural differentiation at least partially through its suppression on Myc. We identified TRIM3 (11p15.5) as a human ortholog of Drosophila brat and demonstrate its regulation of asymmetric cell division and stem cell properties of glioblastoma (GBM), a highly malignant human brain tumor. TRIM3 gene expression is markedly reduced in human GBM samples, neurosphere cultures and cell lines and its reconstitution impairs growth properties in vitro and in vivo. TRIM3 expression attenuates stem-like qualities of primary GBM cultures, including neurosphere formation and the expression of stem cell markers CD133, Nestin and Nanog. In GBM stem cells, TRIM3 expression leads to a greater percentage dividing asymmetrically rather than symmetrically. As with Brat in Drosophila, TRIM3 suppresses c-Myc expression and activity in human glioma cell lines. We also demonstrate a strong regulation of Musashi-Notch signaling by TRIM3 in GBM neurospheres and neural stem cells that may better explain its effect on stem cell dynamics. We conclude that TRIM3 acts as a tumor suppressor in GBM by restoring asymmetric cell division.

Citation Format: Subhas Mukherjee, Gang Chen, Monika Anand, Jun Kong, Carol Tucker-Burden, Yuan Rong, Fahmia Rahman, Carlos Moreno, Erwin Van Meir, Constantinos Hadjipanayis, Daniel Brat. TRIM3, the human homolog of Drosophila Brat, is a tumor suppressor that regulates asymmetric cell division (ACD) in glioblastoma stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-50. doi:10.1158/1538-7445.AM2014-LB-50
Abstract LB-63: Cell ground state dictates cancer susceptibility across organs
Authors: Zhu Liqin , Poppleton Helen , Neale Geoffrey , Onar-Thomas Arzu , Pounds Stanley , Bahrami Armita , Utley Sarah , Wang Kasper S. , Lopez-Terrada Dolores H. , Ellison David W. , Gilbertson Richard J.
Published: May 2015

Cancers are distributed unevenly across the body, suggesting that cell context dictates susceptibility to transformation. To test this hypothesis, we mapped cellular susceptibility to tumor initiation across all organs in adult mice. Ten combinations of potent oncogenic mutations, including activating mutations of Kras, Notch1, Ctnnb1 and deletions of tumor suppressors Tp53,Pten and Cdkn2a, were targeted by conditional recombination into Prom1+ (CD133+) cells in the organs of >800 Prom1-Cre/+ mice. Life time clinical surveillance, necropsy and gene expression profiling of over 250 animals, across all genotypes, identified extensive tumor formation that was biased to certain organs including small intestine, stomach, liver, skin, prostate and uterus. Extensive histology and cross-species genomics confirmed these tumors recapitulated >250 tissue-matched human cancers. Detailed mapping of the number and proliferative activity of Prom1+ cells in organs demonstrated that these variables did not dictate cancer incidence. Rather, parallel, life-long linage tracing of Prom1+ populations showed that the capacity of these cells to repair and regenerate their host organ is directly correlated with their tumorigenic capacity. Only Prom1+ cells capable of long-term tissue renewal generated cancers; quiescent and differentiated Prom1+ cells rarely formed tumors regardless of targeted oncogenic mutation. The repair/regeneration capacity of Prom1+ populations also dictated developmental and damage-response patterns of tumorigenesis. Normally quiescent and tumor-resistant Prom1+ cells in the adult liver became highly regenerative upon liver damage, dramatically increasing their tumorigenic capacity. Conversely, Prom1+ cells are highly proliferative in the neonatal liver - driving the development of this organ - and were highly susceptible to transformation without inducing liver damage. Remarkably, neonatal Prom1+ cells formed hepatoblastoma, the pediatric form of liver cancer. Our large-scale, comprehensive mapping of tumor susceptibility shows that cell ground-state, and specifically the capacity to repair and regenerate organs, is a common determinant of cancer susceptibility across all major organs.

Citation Format: Liqin Zhu, Helen Poppleton, Geoffrey Neale, Arzu Onar-Thomas, Stanley Pounds, Armita Bahrami, Sarah Utley, Kasper S. Wang, Dolores H. Lopez-Terrada, David W. Ellison, Richard J. Gilbertson. Cell ground state dictates cancer susceptibility across organs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-63. doi:10.1158/1538-7445.AM2014-LB-63
Abstract LB-65: Bevacizumab fate in glioblastoma: Mechanism of internalization by endothelial cells and glioma stem cells
Authors: Muller-Greven Gaelle M. , Carlin Cathleen , Rich Jeremy , Hamerlik Petra , Gladson Candece L.
Published: May 2015

Antiangiogenic therapy shows great promise for treatment of cancer. Bevacizumab is a humanized mAb that blocks VEGF-A, thereby inhibiting angiogenesis. It has received FDA approval for patients with recurrent glioblastoma (GBM); however, greater than 30% of patients are non-responsive and the underlying mechanism for the lack of response is not known. It has been assumed that Bevacizumab solely targets circulating VEGF-A; however, VEGF-A found in the tumor could also be an important target for Bevacizumab that impacts the response of patients. We hypothesized that Bevacizumab is transcytosed across brain endothelial cells (ECs), gains access to the perivascular niche containing glioma stem cells (GSCs), and that differences in GSC endocytosis of Bevacizumab and either recycling or degradation determine a patients response. We found that Bevacizumab is internalized by normal and tumor-isolated brain ECs in a time-dependent manner that is partially inhibited by amiloride and stimulated by EGF, suggesting Bevacizumab enters the cells by an endocytic pathway such as macropinocytosis. In a standard transcytosis assay, we showed that brain ECs transcytose 62% of Bevacizumab from the upper chamber to the lower chamber over two-hours. We also found that GSCs internalize Bevacizumab in a manner resembling macropinocytosis and that it is partially co-localized with LAMP1, suggesting Bevacizumab is partly targeted for degradation. Furthermore, in an orthotopic xenograft model of GBM administered Bevacizumab, we found that Bevacizumab was localized to the perivascular space, found within perivascular GBM tumor cells, and that a gradient of Bevacizumab was detected with less observed at further distances from vessels. Ongoing experiments will determine the endocytic compartment(s) containing Bevacizumab in GSCs and its trafficking. Understanding the mechanism of internalization and trafficking of Bevacizumab in GBM tumors and in isolated GSCs from different molecular subtypes will likely help us understand who will be responsive to Bevacizumab, and perhaps who will be responsive to therapy with other mAbs.

Citation Format: Gaelle M. Muller-Greven, Cathleen Carlin, Jeremy Rich, Petra Hamerlik, Candece L. Gladson. Bevacizumab fate in glioblastoma: Mechanism of internalization by endothelial cells and glioma stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-65. doi:10.1158/1538-7445.AM2014-LB-65
Abstract LB-73: SOX9 regulates EGFR/ERBB signaling in pancreatic cancer
Authors: Pinho Andreia V. , Grimont Adrien , Cowley Mark J. , Augereau Cecile , Mawson Amanda , Giry-Laterriere Marc , Steen Geraldine Van den , Waddell Nicola , Pajic Marina , Sempoux Christine ,   Australian Pancreatic Cancer Genome Initiative, Wu Jianmin , Grimmond Sean M. , Biankin Andrew V. , Lemaigre Frederic P. , Jacquemin Patrick , Rooman Ilse
Published: May 2015

The transcription factor SOX9 has recently been shown to have a role in the ontogenesis of pancreatic ductal adenocarcinoma (PDAC) through metaplastic changes in pancreatic acinar cells. Nevertheless, the mechanisms through which SOX9 operates remain to be explored.

We analyzed genomic and transcriptomic data from a cohort of surgically resected cases of PDAC (n=90) from the Australian Pancreatic cancer Genome Initiative (APGI). Genetic aberrations (mutation and copy number changes) in the SOX9 gene were found in 15% of patient tumors. Protein expression analysis revealed that most PDAC samples strongly express SOX9 protein and differential SOX9 expression correlates with patient survival. SOX9 gene expression was higher in the classical PDAC subtype, which relates with better patient outcome and increased response to epidermal growth factor receptor (EGFR)-directed therapy.

In patient tumors, we found that SOX9 expression correlates with expression of EGFR signaling pathway genes, including ErbB2. Analysis of patient-derived xenografts confirmed strong correlation of SOX9 and ErbB2 expression and manipulation of human tumor cell lines demonstrated that Sox9 regulates the expression of ErbB2.

We extended these findings by using a mouse model lacking pancreatic Sox9 expression where we found reduced expression of Egfr/ErbB signaling components. Sox9-deficient pancreatic acinar cells failed to generate PDAC precursor lesions and did not respond to EGF, indicating that Sox9 is required for Egfr/ErbB signaling pathway activity.

In conclusion, by using an integrative approach that combines human and mouse models data, we discovered a new function of SOX9 in the regulation of EGFR/ERBB signaling throughout pancreatic tumorigenesis. This provides a novel mechanistic insight of potential therapeutic significance for pancreatic cancer patients.

Citation Format: Andreia V. Pinho, Adrien Grimont, Mark J. Cowley, Cecile Augereau, Amanda Mawson, Marc Giry-Laterriere, Geraldine Van den Steen, Nicola Waddell, Marina Pajic, Christine Sempoux, Australian Pancreatic Cancer Genome Initiative, Jianmin Wu, Sean M. Grimmond, Andrew V. Biankin, Frederic P. Lemaigre, Patrick Jacquemin, Ilse Rooman. SOX9 regulates EGFR/ERBB signaling in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-73. doi:10.1158/1538-7445.AM2014-LB-73
Abstract LB-8: Design and development of a novel series of HDAC6-selective inhibitors for the treatment of cancer
Authors: Shuttleworth Stephen J.
Published: May 2015

Inhibition of the zinc-dependent histone deacetylase (HDAC) family of enzymes has been pursued as a clinical strategy in cancer for over a decade. HDACs regulate the expression and activity of numerous proteins involved in both cancer initiation and cancer progression; by removal of acetyl groups from histones, HDACs create a non-permissive chromatin conformation that prevents the transcription of genes that encode proteins involved in tumorigenesis. The current landscape of HDAC-targeting therapeutics has, however, been dominated by pan-inhibitors that regulate the activity of most, if not all, of the HDAC family members which, through dysregulation of expression of a myriad of genes, has led to agents with undesirable toxicities and narrow therapeutic margins. Recently, however, attention has begun to turn to the role of specific HDAC isoforms in tumorigenesis and, in turn, the development of more selective therapeutics. HDAC6 has emerged as a particularly interesting target as it plays an essential role in aggresomal protein degradation: specifically, HDAC6 binds polyubiquitinated misfolded proteins and recruits misfolded protein cargo to dynein motors for transport to aggresomes. Cells deficient in HDAC6 fail to clear these misfolded protein aggregates from the cytoplasm, cannot form aggresomes properly, and are hypersensitive to the accumulation of misfolded proteins, which leads to activation of apoptosis. This presentation will outline the design and development of a new class of highly-potent, selective and orally-active HDAC6 inhibitors with the potential in the treatment of multiple tumor types. Uniquely, this series of compounds has been designed such that selectivity levels for HDAC6 over other isoforms can be finely regulated, enabling the investigation of preferred levels of HDAC6 specificity for therapy.

Citation Format: Stephen J. Shuttleworth. Design and development of a novel series of HDAC6-selective inhibitors for the treatment of cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-8. doi:10.1158/1538-7445.AM2014-LB-8
Abstract LB-86: Dependent and independent tumor suppression function of ARF and p53 in murine BCC carcinogenesis in Ptch1+/- mice
Authors: Wang Grace Y. , Wood Carla , Hu Hiroe , Dolorito John , Libove Eileen , Eptein Ervin H.
Published: May 2015

Basal cell carcinoma (BCC), the most commonly diagnosed human cancer, is driven by aberrant activation of hedgehog (HH) signaling. In addition, we have found that p53 is a potent inhibitor of HH-driven BCC carcinogenesis - ablation of p53 in Ptch1+/- K14CreER2 p53fl/fl (PF mice) dramatically accelerates BCC formation with a shorter tumor latency and a 10 fold increase of tumor burden. To begin to determine how p53 is activated in this Ptch1+/- murine BCC model, we investigated the role of p19ARF in translating oncogene-induced stress (OIS) into p53 activation.

We bred Ptch1+/- mice with ARFGFP/GFP to generate Ptch1+/- ARFGFP/GFP (ARF mice), lacking functional ARF. In addition, we crossed ARF mice and PF mice to generate ARF/p53 double deletion mice (DD mice), treated ARF, PF and DD mice as well as Ptch1+/- (ARF+/+, p53+/+) with IR at mouse age 8w, and quantified BCC formation. .As assessed in age 5m skin biopsies, PF and DD mice had a significantly higher microscopic BCC tumor burden than did ARF and Ptch1+/- mice. There was no significant difference between PF and DD or between ARF and Ptch1+/-. ARF and PF mice developed visible BCC starting at 5-6 m. By contrast, DD mice had visible BCCs as early as age 4m, a statistically different age of onset. Consistent with our previous findings, Ptch1+/- mice did not form any visible BCCs until age 9 m or later. These data indicate that loss of functional ARF or of p53 promotes malignant conversion of microscopic BCCs to visible BCCs. However, only loss of p53, but not loss of ARF, enhances tumor initiation. To gain further insights in the molecular mechanisms differentiating these tumors, we examined the whole genome expression analysis by RNA-seq.

Taken together, our findings suggest that both ARF-dependent and -independent activation of p53 is involved in BCC carcinogenesis. ARF-mediated p53 activation, presumably via the OIS pathway, appears to be crucial in regulating malignant transformation of BCC, while ARF-independent p53 activation inhibits tumor initiation.

Citation Format: Grace Y. Wang, Carla Wood, Hiroe Hu, John Dolorito, Eileen Libove, Ervin H. Eptein. Dependent and independent tumor suppression function of ARF and p53 in murine BCC carcinogenesis in Ptch1+/- mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-86. doi:10.1158/1538-7445.AM2014-LB-86
Abstract LB-97: A novel anticancer bispecific antibody targeting VEGF and Dll4 inhibits tumor progression in lung and gastric cancer xenograft models
Authors: You Weon-Kyoo , Lee Dongheon , Choi Yu Bin , Kang Kyung Jae , Kim Dong In , Ahn Jin-Hyung , Jung Jinwon , Sung Eun-Sil , Goo Jun Seo , Jang Hyun Sook , Moon Kyung Duk , Lee Sang Hooon
Published: May 2015

Several angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signaling pathway have been used for cancer treatment. However, VEGF inhibitors alone can promote tumor invasion and metastasis by increase of intratumoral hypoxia in some preclinical models. Emerging reports regarding angiogenesis suggest Delta-like-ligand 4 (Dll4) is a promising target to augment the effects of VEGF inhibitors. Dll4 blockade inhibits tumor progression by increasing nonproductive angiogenesis whereas VEGF blockade inhibits tumor progression by decreasing angiogenesis. To evaluate the effect by inhibiting both VEGF and Dll4 on tumor angiogenesis, we have developed HD105, a novel bispecific antibody targeting VEGF and Dll4, as the format of VEGF-binding IgG linked with Dll4-binding single-chain Fv. The bispecific antibody showed potent binding affinity against VEGF (KD: 3.4 x 10-12 M) and Dll4 (KD: 4.2 x 10-8 M), which are comparable with KD values of anti-VEGF antibody (9.8 x 10-10 M) and Dll4 single targeting antibody (5.5 x 10-9 M). The HD105 bispecific antibody also inhibited interaction of Dll4 and its receptor, Notch 1 (IC50: 1 nM ± 0.2). By using in vitro cell-based assays, the HD105 effectively blocked Dll4 as well as VEGF signaling pathways in endothelial cells, resulting in downregulation of Notch intracellular domain (NICD) and VEGFR-2/extracellular-signal-regulated kinase (ERK) phosphorylation. In addition, the HD105 more efficiently inhibited tumor progression than each single-targeting antibody in A549 human lung cancer and SCH human gastric cancer xenograft models. In conclusion, the novel bispecific antibody could be potentially developed as a clinically more efficacious therapeutic antibody.

Citation Format: Weon-Kyoo You, Dongheon Lee, Yu Bin Choi, Kyung Jae Kang, Dong In Kim, Jin-Hyung Ahn, Jinwon Jung, Eun-Sil Sung, Jun Seo Goo, Hyun Sook Jang, Kyung Duk Moon, Sang Hooon Lee. A novel anticancer bispecific antibody targeting VEGF and Dll4 inhibits tumor progression in lung and gastric cancer xenograft models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-97. doi:10.1158/1538-7445.AM2014-LB-97
Abstract PL03-01: Evolutionary dynamics of cancer in response to targeted therapy
Authors: Nowak Martin
Published: May 2015

Cancer is an evolutionary process. Cancer initiation and progression are caused by somatic mutation and selection of dividing cells. The mathematical theory of evolution can therefore provide quantitative insights into human cancer. I will discuss the role of chromosomal instability (CIN) and the accumulation of drivers and passengers in growing tumors. I will study success and failure of targeted therapy including combination of different drugs and evolution of resistance. A simple conclusion is that combination treatment can succeed, if the cancer requires at least two point mutations to gain resistance. From the perspective of preventing resistance, simultaneous therapy is highly recommended whereas sequential therapy is a recipe for almost certain treatment failure.

Further Reading

1. Bozic et al (2010). Accumulation of driver and passenger mutations during tumor progression. Proc Natl Acad Sci USA 107: 18545-18550.

2. Diaz et al (2012) The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486: 537-540.

3. Bozic et al (2013). Evolutionary dynamics of cancer in response to targeted combination therapy. eLife 2: e00747.

Citation Format: Martin Nowak. Evolutionary dynamics of cancer in response to targeted therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr PL03-01. doi:10.1158/1538-7445.AM2014-PL03-01
Abstract SY02-04: Overlapping mechanisms in CNS development and gliomagenesis
Authors: Rowitch David H.
Published: May 2015

Glioblastoma multiforme (GBM) is a lethal brain cancer resistant to therapy in part because of its highly invasive nature. GBMs are a highly vascular tumor with heterogeneous histological features, but they are generally considered to derive from glial lineage progenitors. We have defined Olig2, a bHLH transcription factor, as a critical determinant of oligodendrocyte progenitor identity during development. Olig2 is expressed in human GBMs, raising the possibility of similar features between oligodendrocyte progenitors and glioma-propagating cells, a concept is supported by expression profiling and mouse models. This talk will review functions for OPCs during development, including proliferation, migration into adult parenchymal tissue and angiogenesis. As such, there are provocative similarities between normal OPCs and progenitors for GBM.

Citation Format: David H. Rowitch. Overlapping mechanisms in CNS development and gliomagenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY02-04. doi:10.1158/1538-7445.AM2014-SY02-04
Abstract SY04-03: Gut microbiome-driven exposure to anti-inflammatory dietary bioactives in humans
Authors: Lampe Johanna Wyss
Published: May 2015

Chronic, low-grade systemic inflammation is hypothesized to be a risk factor for carcinogenesis. In humans, dietary patterns, foods, and dietary constituents are associated with concentrations of circulating inflammation biomarkers (e.g., CRP, IL-6, IL-18, and TNF-α); meat-based or “Western” diet patterns have been positively associated with inflammation markers, whereas vegetable- and fruit-based or “healthy” diet patterns have been inversely associated. The gut microbiome may contribute to chronic inflammation in part through its interaction with host diet. Diet influences amounts and types of gut microbes, and gut microbial metabolism of dietary constituents produces compounds that can be protective or harmful to the host. We have shown that differences in gut microbial metabolism and diversity of the microbial community among individuals accounts for some of the variation in human exposure to phytochemicals. Components of diet also serve as substrates for certain groups of bacteria, such that changes in diet can result in a gut microbial community with greater or lesser inflammatory potential. Our findings suggest that a greater understanding of diet-gut microbiome interactions may inform future cancer-prevention strategies.

Citation Format: Johanna Wyss Lampe. Gut microbiome-driven exposure to anti-inflammatory dietary bioactives in humans. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY04-03. doi:10.1158/1538-7445.AM2014-SY04-03
Abstract SY10-01: Understanding metabolic heterogeneity in cancer
Authors: DeBerardinis Ralph J.
Published: May 2015

Metabolic reprogramming is considered to be a hallmark of malignancy and a consequence of the mutations that cause cancer. Classical components of metabolic reprogramming include enhancements of nutrient uptake, aerobic conversion of glucose to lactate, and biosynthesis of proteins, lipids and nucleic acids. These activities are believed to collaborate to support states of supra-physiological stress resistance and proliferative capacity. However, recent work, primarily performed in cancer cell lines, has revealed an unexpected heterogeneity of metabolic programs that can support cancer cell survival and growth. It is unclear how these heterogeneous metabolic programs are regulated by the oncogenotype, and more importantly, which of the myriad activities observed in culture are relevant to bona fide tumor metabolism in vivo. I will discuss approaches to address these challenges. First, I will discuss ongoing efforts to use systematic analysis of cancer cell lines to link metabolic phenotypes with oncogenotypes, and to identify chemotherapeutic sensitivities associated with particular metabolic preferences. Second, I will describe efforts to probe metabolism in living tumors using a combination of stable isotope tracing and complementary methods. Finally, I will discuss approaches to merge metabolomics with non-invasive imaging to understand the development and consequences of metabolic heterogeneity within individual tumors.

Citation Format: Ralph J. DeBerardinis. Understanding metabolic heterogeneity in cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY10-01. doi:10.1158/1538-7445.AM2014-SY10-01
Abstract SY13-03: Signal pathways in prostate cancer stem cells
Authors: Witte Owen N.
Published: May 2015

New therapeutic strategies are needed to treat prostate cancer as it progresses to the castration resistant stage following treatment with drugs to reduce androgen production or interfere with androgen receptor function. Genetic analyses of DNA alterations and RNA expression show that multiple pathways can be involved in this cancer progression. An understanding of the cellular components needed to initiate prostate cancer and sustain it during the process of metastasis may help to elucidate new pathways for therapy. We have developed techniques to transform mouse and human benign prostate epithelial basal stem cells and define them as one cell of origin which can respond to multiple stimuli to produce cancers which are capable of maturing to more differentiated cell types including luminal, squamous and neuroendocrine phenotypes. Different subtypes of cells with the properties of cancer stem cells capable of transplantation of the cancer phenotype have been defined. Current work is focusing on the activation of specific kinase driven pathways to provide new targets for therapy in metastatic prostate cancer. We previously demonstrated that castration resistant prostate cancer (CRPC) tissues exhibit increased tyrosine phosphorylation, suggesting that enhanced tyrosine kinase activity may contribute to advanced disease. To identify specific kinase activation patterns in metastatic CRPC, we utilized phospho-tyrosine peptide enrichment and quantitative mass spectrometry using tissue from CRPC patients obtained at rapid autopsy. Evaluation of these rare metastatic CRPC samples for tyrosine phosphorylation and kinases revealed activated SRC, EGFR, RET, ALK, and other targets. Importantly, these kinase activation patterns exhibited intrapatient similarity and interpatient heterogeneity implying clonal origins of these lesions. To evaluate the function of these kinases in metastatic CRPC, we are analyzing their role during specific steps of the metastatic cascade. We hope our approach will improve an understanding of the mechanistic role of kinase activation in prostate cancer and identify promising therapeutic strategies targeting non-mutated kinases for metastatic CRPC.

Citation Format: Owen N. Witte. Signal pathways in prostate cancer stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY13-03. doi:10.1158/1538-7445.AM2014-SY13-03
Abstract SY23-02: Nanotechnology and single cell proteomics as a diagnostic tool
Authors: Heath James R. , Wei Wei , Shin Young Shik , Xue Min , Zhou Jing , Sutherland Alex , Yu Jing
Published: May 2015

Single-cell functional proteomics assays can connect genomic information to biological function through the use of quantitative and multiplex protein measurements. Tools for single-cell proteomics have developed rapidly over the past 5 years, and are providing approaches for directly elucidating phospho-protein signaling networks in cancer cells, or for capturing high-resolution snapshots of immune system function in cancer patients participating therapies that involve immune system engineering and manipulation. We discuss advances in single cell proteomics platforms, with an emphasis the types of data that can be obtained, and how analysis of that data can provide deep insights into either designing therapies, or understanding patient responses to therapies. I will provide illustrative examples of how microchip-based single cell functional proteomics platforms are being applied to both fundamental biology and clinical studies.

Citation Format: James R. Heath, Wei Wei, Young Shik Shin, Min Xue, Jing Zhou, Alex Sutherland, Jing Yu. Nanotechnology and single cell proteomics as a diagnostic tool. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY23-02. doi:10.1158/1538-7445.AM2014-SY23-02
Abstract SY33-04: Tumor suppression by the DNA damage response
Authors: Petrini John
Published: May 2015

The DNA damage response (DDR) is activated by oncogenic stress, but the mechanisms by which this occurs and the particular DDR functions that constitute barriers to tumorigenesis remain unclear. We established a mouse model of sporadic oncogene-driven breast tumorigenesis in a variety of mutant mouse strains with specific DDR deficiencies to reveal a novel role for the Mre11 complex (comprised of Mre11, Nbs1, and Rad50) in the response to oncogene activation. We demonstrate that the Mre11-mediated DDR suppresses tumorigenesis by inducing a G2 arrest and a program of chromatin alteration that, when compromised, results in oncogene-induced mammary hyperplasias that progress to invasive and metastatic breast cancers. In contrast, we provide genetic evidence that the intra-S checkpoint and the DNA damage-induced apoptosis functions of the DDR are dispensable for tumor suppression. These findings provide novel insight into the mechanism of DDR engagement by activated oncogenes, and reveal the particular DDR functions that must be overcome during tumorigenesis. We further demonstrate that impairment of these Mre11-dependent functions promotes metastatic dissemination, particularly upon secondary inactivation of the Ink4a-p19Arf (CDKN2a) locus. These findings provide insight into the mechanism of DDR engagement by activated oncogenes, and reveal a novel genetic interaction between the DDR and Ink4a-p19Arf pathways in suppression of oncogene-driven tumorigenesis and metastasis.

Citation Format: John Petrini. Tumor suppression by the DNA damage response. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY33-04. doi:10.1158/1538-7445.AM2014-SY33-04