bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 5188: Combination of radiofrequency ablation and Sunitinib in the treatment of experimental hepatocellular cancer
Authors: Qi Xiaoqiang , Li Guangfu , Liu Dai , F Staveley-O’Carroll Kevin , Kimchi Eric
Published: July 2016

Radiofrequency Ablation (RFA) is one of current clinical option in the treatment of hepatocellular cancer (HCC); however, RFA monotherapy is often not curative as a consequence of tumor micro-metastases and recurrence. Thus, induction of systemic response with additive treatment is required. In the present study, we are exploring the combination of RFA and sunitinib, an FDA-approved multiple tyrosine kinase inhibitor, in the treatment of HCC. Using our established strategy a clinically relevant murine model of HCC is prepared which mimics human disease and reflect its typical features. The follow-up magnetic resonance imaging (MRI) is applied to monitor tumor progression until the cumulative tumor volume reaches 2000 mm3. Size-matched tumor-bearing mice are assigned into 3 groups and receive the following treatments: no treatment, RFA alone with our improved machine and optimized parameters, combination of sunitinib and RFA. The therapeutic efficacy is evaluated by measuring tumor volume with MRI every twice weeks. We demonstrate that tumors grow substantially in the mice without treatment. RFA alone effectively destroys tumors, but unable to prevent tumor recurrence and micro-metastasis. In contrast, > 50% size reduction in tumor size is detected in the combined group compared to that in control mice, even no detectable tumors are observed in some treated mice. In conclusion, combination of sunitinib and RFA powerfully suppress tumor growth and could be translate into clinic practice.

Citation Format: Xiaoqiang Qi, Guangfu Li, Dai Liu, Kevin F Staveley-O’Carroll, Eric Kimchi. Combination of radiofrequency ablation and Sunitinib in the treatment of experimental hepatocellular cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5188.
Abstract 5199: An in vivo reporter to quantitatively and temporally analyze the effects of CDK4/6 inhibitor-based therapies in melanoma
Authors: Teh Jessica L. , Purwin Timothy , Greenawalt Evan J. , Chervoneva Inna , Goldberg Allison , Davies Michael E. , Aplin Andrew
Published: July 2016

Aberrant cell cycle progression is a hallmark feature of cancer cells. Cyclin-dependent kinase 4 and 6 (CDK4/6) drive progression through the G1 stage of the cell cycle, at least in part, by inactivating the tumor suppressor, retinoblastoma (RB). CDK4/6 are targetable and the selective CDK4/6 inhibitor, palbociclib (IBRANCE/PD-0332991), was recently FDA approved for the treatment of estrogen receptor-positive, HER2-negative advanced breast cancer. In cutaneous melanoma, driver mutations in NRAS and BRAF signal to promote CDK4/6 activation suggesting that inhibitors such as palbociclib are likely to provide therapeutic benefit most likely in combination with BRAF and/or MEK inhibitors that are FDA-approved. However, the determinants of the response to CDK4/6 inhibitors alone and in combination with other targeted inhibitors are poorly defined. Furthermore, in vivo systems to quantitatively and temporally measure the efficacy of CDK4/6 inhibitors and determine the extent that CDK activity is reactivated during acquired resistance are lacking. Here, we describe the heterogeneous effects of CDK4/6 inhibitors, the expression of anti-apoptotic proteins that associate with response to CDK4/6 and MEK inhibitors, and the development of a luciferase-based reporter system to determine the effects of CDK4/6 inhibitors alone and in combination with MEK inhibitors in melanoma xenografts. These findings are likely to inform on-going and future clinical trials utilizing CDK4/6 inhibitors in cutaneous melanoma.

Citation Format: Jessica L. Teh, Timothy Purwin, Evan J. Greenawalt, Inna Chervoneva, Allison Goldberg, Michael E. Davies, Andrew Aplin. An in vivo reporter to quantitatively and temporally analyze the effects of CDK4/6 inhibitor-based therapies in melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5199.
Abstract 52: NF-kB promotes a Warburg metabolic profile in pediatric sarcomas
Authors: Ijiri Yuichi , Londhe Priya , London Cheryl , Houghton Peter J. , Guttridge Denis C.
Published: July 2016

In contrast to normal cells that use mitochondrial oxidative phosphorylation for ATP production in aerobic conditions, many cancer cells depend on glycolysis even in the presence of sufficient oxygen. This process is known as aerobic glycolysis or the Warburg effect. Recent reports have shown that both the classical and alternative signaling pathways of NF-κB play important roles in controlling the metabolic profile of cancer and normal cells, respectively. However, how these signaling pathways affect the metabolism of pediatric sarcomas has not yet been explored. Here, we show NF-κB activity undergoes a shift in signaling from an alternative to a classical pathway in the genesis of sarcoma subtypes, rhabdomyosarcoma and osteosarcoma. Inhibition of classical NF-κB in sarcoma cells restores alternative signaling, as well as an oxidative metabolic phenotype in vitro and in vivo. In contrast, forced expression of the alternative pathway in rhabdomyosarcoma or in osteosarcoma cells is unable to reverse NF-κB classical activity, suggesting that the activation of the classical pathway in sarcomagenesis dominates over alternative signaling. Furthermore, we observed that inhibition of NF-κB in sarcoma cells reduced the expression of the glycolytic gene, hexokinase 2 (HK2). Through chromatin immunoprecipitation (ChIP) assays, we show that HK2 is a direct NF-κB target. Moreover, deletion of HK2 by using shRNA shifts the metabolic profile in sarcoma cells away from a warburg effect. These findings demonstrate a crucial role for classical NF-κB in sarcomagenesis and suggest that NF-κB metabolically reprograms sarcoma cells by regulating HK2.

Citation Format: Yuichi Ijiri, Priya Londhe, Cheryl London, Peter J. Houghton, Denis C. Guttridge. NF-kB promotes a Warburg metabolic profile in pediatric sarcomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 52.
Abstract 5207: Comparison of subtype-specific incidence rates of lymphoid malignancies in Hong Kong and the United States
Authors: Rothman Nathaniel , Bassig Bryan A. , Au Wing-Yan , Mang Oscar , Ngan Roger , Morton Lindsay M. , K.M. Ip Dennis , Hu Wei , Zheng Tongzhang , Seow Wei Jie , Xu Jun , Lan Qing
Published: July 2016

Clinical studies of lymphoid malignancies (LMs) have suggested that the descriptive patterns of these neoplasms differ in East Asia compared to Western populations. However, there are very limited available data on population-based, subtype-specific incidence rates of LMs in the East Asian population, particularly in Chinese. Using data from the Hong Kong (HK) Cancer Registry and the United States (U.S.) Surveillance, Epidemiology, and End Results Program, we calculated and compared age-adjusted incidence rates of LM subtypes in HK to those in Whites and Asians living in the U.S. Overall and sex-specific rates were calculated for the period 2001-2010. In order to formally compare the incidence rates between HK and the U.S., standardized rate ratios (SRRs) were calculated comparing the age-adjusted rates of each subtype for U.S. Whites and U.S. Asians in the SEER 13 database to HK. The incidence of most subtypes was low in the HK population, with rates <1 case per 100,000 for all subtypes except for diffuse large B-cell lymphoma (3.26/100,000) and plasma cell neoplasms (1.99/100,000). Age-adjusted incidence rates of all evaluated B-cell subtypes were significantly higher in U.S. Whites compared to HK, with SRRs ranging from 1.6 (Burkitt lymphoma) to 9.1 (chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)). Rates in U.S. Asians were generally intermediate to those in U.S. Whites and HK, with SRRs for B-cell subtypes ranging from 1.0 (Burkitt) to 2.0 (CLL/SLL) comparing Asians in the U.S. to HK. For T or NK-cell subtypes, rates of extranodal NK/T-cell lymphoma were significantly lower in both U.S. Whites (SRR = 0.2) and U.S. Asians (SRR = 0.5) compared to HK. However, incidence rates of other evaluated T-cell subtypes were comparable or slightly higher in the U.S. population compared to HK. Our findings, which are based on data from population-based disease registries, provide new insight into the subtype-specific patterns of LMs in the Chinese population, and suggest the need for etiological studies of LMs in the East Asian population to elucidate the factors responsible for these differences in the geographic incidence patterns.

Citation Format: Nathaniel Rothman, Bryan A. Bassig, Wing-Yan Au, Oscar Mang, Roger Ngan, Lindsay M. Morton, Dennis K.M. Ip, Wei Hu, Tongzhang Zheng, Wei Jie Seow, Jun Xu, Qing Lan. Comparison of subtype-specific incidence rates of lymphoid malignancies in Hong Kong and the United States. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5207.
Abstract 521: c-MYC as a differentiating marker between angiosarcoma and atypical vascular lesion
Authors: Kak Ipshita , Sadikovic Bekim , Pare Guillaume , Corbett Tom , Popovic Snezana
Published: July 2016

Introduction: Angiosarcoma is a rare, aggressive malignancy that accounts for less than 1% of all sarcomas, characterized by a dismal 5 year survival of 20-30% at best. In striking contrast, atypical vascular lesion (AVL), which typically occurs secondary to radiation, follows for the most part, a benign course. However, debate rages over the true nature of AVL with reports describing both benign and malignant behavior. Further compounding the issue is the fact that overlapping histological features make the important differentiation between AVL and angiosarcoma difficult, especially on limited biopsy specimens. There have been a number of recent studies of c-MYC expression in vascular tumors in relation to this question, yielding varied results.

Objectives: This pilot study aimed to investigate c-MYC expression in atypical vascular lesions and angiosarcomas (primary and secondary) to evaluate the clinical utility of c-MYC testing as an adjunct to the histological diagnosis.

Methods: A retrospective search for biopsy, resection specimens and internal consult cases with diagnosis of angiosarcoma and/or atypical vascular lesion from January 2008- February 2014 was performed. A total of 32 cases (including controls) obtained after review were stained by dual colour c-MYC copy number probe set. The expression of c-MYC was read by two independent evaluators and final data was collated along with histology findings, follow-up and survival data.

Results: c-MYC amplification was found to be a major differentiating factor (p value: 0.00002, 68% sensitivity, 96% specificity) between AVL and angiosarcoma(median c-MYC expression 1.0 vs. 12.14, 95% confidence interval: 0.8-1.9 vs. 9.2-22.3 respectively). The amplification levels of primary (median c-MYC expression:10.9, 95% confidence interval: 3.8-16.6) and secondary angiosarcoma (median c-MYC expression:13.2, 95% confidence interval: 9.0-25.5) were statistically not found to be significantly different (p = 0.07). Although no correlation was found between level of c-MYC amplification and outcome, the study was underpowered to accurately evaluate this relation.

Conclusion: Amplification of c-MYC can be used as a reliable ancillary test to differentiate between diagnostically challenging cases of angiosarcoma and AVL.

Citation Format: Ipshita Kak, Bekim Sadikovic, Guillaume Pare, Tom Corbett, Snezana Popovic. c-MYC as a differentiating marker between angiosarcoma and atypical vascular lesion. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 521.
Abstract 5213: Remarkably stable sex-ratio in sporadic kidney cancer incidence
Authors: Scelo Ghislaine , Chanudet-van den Brink Estelle , Li Peng , Vinayanuwattikun Chanida , Muller David C.
Published: July 2016

Background: Patterns of sex-disparity in cancer incidence can provide clues on risk factors and susceptibility to the disease. While known kidney cancer genetic syndromes follow an autosomal dominant inheritance and equally affect males and females, kidney cancer occurs predominantly outside a syndromic context (97% of cases are sporadic) and more commonly in males than females.

Methods: We used cancer registry data from 10 registries around the world, from countries showing large variations in kidney cancer incidence in 2012 (from 5.2 to 16.7/100,000 person-years) and with at least 20 years of registration. Using age-standardized incidence rate (on the World population), we compared the male-to-female sex-ratio in incidence rates across registries and over time. We also evaluated whether the sex-ratio varied by categories of age at diagnosis. Finally, we compared the kidney cancer-specific mortality after diagnosis in males and females in 2,969 cases using Cox regression model.

Results and interpretation: From 1985 to 2005, the sex-ratio was on average 2.0 and showed little variation across countries: it was 1.7 in Iceland; 1.8 in Australia and Finland; 1.9 in the UK and Norway; 2.0 in Singapore, Estonia, the Czech Republic, and the USA; and 2.1 in Slovenia. The sex-ratios were also remarkably stable in all registries over time, arguing against the role of known risk factors such as tobacco smoking to which the proportion of exposed women has evolved drastically in the last 50 years. In line with the autosomal dominant inheritance, sex-ratio was on average 1.0 in younger ages and progressively increased to stabilize from around 40 years old on. In particular the ratio remained stable at older ages, which suggests that estrogen levels are unlikely to account for the lower risk experienced by women. In contrast to the observed difference in incidence, our survival analysis showed similar survival rates in both sexes after adjustment for age and stage at diagnosis.

Conclusion: Our results suggest that the difference in kidney cancer incidence rates between males and females are not due to varying prevalence of known risk factors or a protection by sex hormones. While the susceptibility to the disease varies, the tumor behavior seems similar in males and females as shown by similar survival rates.

Citation Format: Ghislaine Scelo, Estelle Chanudet-van den Brink, Peng Li, Chanida Vinayanuwattikun, David C. Muller. Remarkably stable sex-ratio in sporadic kidney cancer incidence. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5213.
Abstract 5214: Stage IV colorectal cancer sub-site and patterns of distant metastases
Authors: Robinson Jamaica R. , Newcomb Polly A. , Hardikar Sheetal , Cohen Stacey A. , Phipps Amanda I.
Published: July 2016

Approximately 20% of individuals diagnosed with colorectal cancer (CRC) in the United States are found to have distant metastases at the time of their diagnosis, indicating an extremely poor prognosis. Although it is well known that primary CRC typically metastasizes to the liver and/or lungs, little is known regarding which factors might explain the anatomic pattern of CRC metastatic spread. Using population-based registry data from the Surveillance, Epidemiology and End Results (SEER) cancer registry of the Seattle-Puget Sound region, we assessed the relationship between primary CRC sub-site and the presence of synchronous metastases in the liver, lungs, and both the liver and lungs. All individuals with stage IV CRC who were diagnosed between 2010-2014 in the 13-county catchment area and who also had complete data on site of metastasis at diagnosis were included in analyses (N = 1287). In total, 703 (55%) patients had distant metastases confined to the liver at the time of diagnosis, 78 (6%) had lung-only metastases, 190 (15%) had metastases in both the liver and lungs but not at other sites, and 316 (25%) exhibited different patterns of metastatic spread, including to the bone, brain, and other anatomic sites. Using multiple logistic regression models, we compared individuals with different patterns of metastatic spread at diagnosis with respect to primary CRC site and with separate models comparing cases with liver-only metastases to all other metastatic cases, comparing cases with lung-only metastases to all other metastatic cases, and comparing cases with metastases to both the liver and lungs to all other metastatic CRC cases. All models were adjusted for age at diagnosis and sex, as well as for depth of primary tumor growth within the colorectum (T-stage) and extent of cancer spread to lymph nodes (N-stage). The odds of having a primary CRC tumor in the rectum, versus proximal colon, were significantly lower among patients with liver-only synchronous metastases relative to those with other patterns of metastatic spread at diagnosis [odds ratio (OR): 0.62, 95% confidence interval (CI): 0.46 - 0.82]. Conversely, the odds of having a primary CRC located in the rectum were significantly higher among those with metastatic disease confined to the lungs (OR: 2.48, 95% CI: 1.38 - 4.47) and those with metastases to the liver and lungs (OR: 1.97, 95% CI: 1.29 - 3.01). Our findings suggest that a patient's site of primary CRC may be informative with respect to possible pattern of metastatic spread.

Citation Format: Jamaica R. Robinson, Polly A. Newcomb, Sheetal Hardikar, Stacey A. Cohen, Amanda I. Phipps. Stage IV colorectal cancer sub-site and patterns of distant metastases. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5214.
Abstract 5228: Estrogen receptor expression is associated with DNA repair capacity in breast cancer
Authors: Matta Jaime L. , Morales Luisa , Ortiz Carmen , Adams Damian , Vargas Wanda , Casbas Patricia , Dutil Julie , Echenique Miguel , Suarez Erick
Published: July 2016

Estrogen receptor (ER) status is an established therapeutic and prognostic biomarker for breast cancer (BC). ER signaling has a propensity to increase proliferation, which can lead to mutations when DNA repair is dysregulated. Deficiencies in DNA repair capacity (DRC) is a hallmark of BC. Recent studies have documented interactions between ER and DNA damage response/repair. Moreover, our previous work showed that DRC in BC patients is approximately 50% less than in women without the disease (p<0.001), and a deficiency in the Nucleotide excision repair (NER) pathway figures prominently in the pathobiology of sporadic BC. Estrogen-receptor-positive (ER+) tumors employ complex signaling that engages in crosstalk with multiple pathways through genomic and non-genomic regulation. A greater understanding of these pathways is important for developing improved biomarkers that can better determine treatment choices, risk of recurrence, and cancer progression. In this study, we aimed to determine whether ER signaling influences DRC. DRC, in terms of the NER pathway, was measured in lymphocytes by means of a host cell reactivation assay with a luciferase reporter gene. A multivariate linear regression model (MLRM) was used to estimate the mean of the DRC and analyze the association between ER positivity (% receptor activation) obtained from pathological reports and DRC in 270 BC patients. These were further stratified by HER2 receptor status. An ordinal logistic regression model (OLRM) was used to confirm the relationship between DRC and ER status using the maximum likelihood method for parameters estimation. Our results show an association between ER status and mean DRC values in BC patients who have HER2-negative (HER-) tumors: that is, the mean DRC value in ER-/HER2- tumors was significantly lower as compared with ER-/HER2+ tumors (p<0.05). In contrast, the mean DRC among patients with ER+/HER2+ tumors did not significantly differ from ER-/HER2+ tumors (p>0.05). The data followed similar patterns when DRC was categorized in tertiles. In conclusion, there is an association between DRC levels and ER status, and this association is modified by HER2 receptor status. Supported by grants from the NCI Center to Reduce Health Disparities and NIH-NIGMS MBRS SCORE and RISE Programs grants # S06 GM008239-20, 9SC1CA182846-04 GM082406 and PSM-MCC Partnership grant # 5U54CA163071-04.

Citation Format: Jaime L. Matta, Luisa Morales, Carmen Ortiz, Damian Adams, Wanda Vargas, Patricia Casbas, Julie Dutil, Miguel Echenique, Erick Suarez. Estrogen receptor expression is associated with DNA repair capacity in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5228.
Abstract 5238: The chemopreventive potential of silver nanoparticles against UVB-induced skin carcinogenesis in mouse model
Authors: Tyagi Nikhil , Arora Sumit , Srivastava Sanjeev K. , Carter James E. , Singh Ajay P. , Singh Seema
Published: July 2016

Solar ultraviolet (UV) radiation, particularly its UVB component, is an established cause of human skin carcinogenesis due to its ability to cause DNA damage in skin cells. Although several sunscreen formulations have been developed and commercialized to limit or minimize UVB exposure to skin cells, incidence of skin cancer has continued to increase suggesting their limited or no efficacy in preventing UV-induced skin cancer occurrence. Recently, we revealed the potential of silver nanoparticles (AgNPs; ≤ 50 nm) against UVB radiation-induced DNA damage in human keratinocytes (HaCaT). Here we performed preclinical evaluation of chemopreventive efficacy of AgNPs against UVB-induced skin tumorigenesis in SKH-1 hairless mouse model. The different concentrations (20 and 40 mg/kg) of AgNPs mixed with hydrophilic cream base were uniformly applied topically onto the dorsal area of mouse skin prior to UVB-irradiation to assess chemopreventive efficacy for several weeks. The UVB treatment group showed tumor formation within 13 weeks, and had high incidence (93.3%) rate by the end of the study (29 weeks). Interestingly, the pretreatment of mice with AgNPs significantly increased the latency period (6-9 weeks) of UVB-induced tumor formation. Moreover, overall tumor incidence was found to be significantly decreased (50 and 78%; in 20 and 40 mg/kg respectively) as compared to AgNPs-untreated mice. Tumor multiplicity and average tumor volume/tumor-bearing mouse were also observed to be significantly reduced in AgNPs-treated mice. Additionally, AgNPs treatment alone for 29 weeks did not induce any apparent signs of toxicity and changes in the body weight suggesting the safety of AgNPs. Altogether, these findings suggest that AgNPs are potential chemopreventive agents against UVB radiation-induced skin carcinogenesis and thus opening the ways for human applications.

Citation Format: Nikhil Tyagi, Sumit Arora, Sanjeev K. Srivastava, James E. Carter, Ajay P. Singh, Seema Singh. The chemopreventive potential of silver nanoparticles against UVB-induced skin carcinogenesis in mouse model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5238.
Abstract 525: Higher mutation rate is associated with more frequent expression of cancer/testis antigens in human tumors
Authors: Jing Junping , Mayes Patrick , Degenhardt Yan , Brown James R. , Sanseau Philippe
Published: July 2016

Tumors with high mutation rate such as those of melanoma and non-small cell lung cancers (NSCLC) have shown greatest response to the emerging immune therapies. These tumors harbor a large number of somatic mutations, some of which could be translated into neoantigens, potentially evoking host immune response. To what degree self antigens, many of which are cancer testis (CT) antigens, contribute to enhanced immune response in these tumors has never been systematically studied. Here we show that cancers with higher mutation rate frequently express a larger number of CT antigens than cancers with fewer mutations. In NSCLC, tumors with more than 300 non-synonymous mutations (75th percentile, n = 158) express more than 3 times as many CT antigens as those tumors with fewer than 100 mutations (25th percentile, n = 162), with a P-value of 1.6e-13. In head and neck cancers, tumors with more than 140 non-synonymous mutations (75th percentile, n = 79) express nearly twice as many CT antigens as those tumors with fewer than 60 mutations (25th percentile, n = 80), with a P-value of 0.004. Additionally, in NSCLC, tumors with high mutation rate are associated with higher expression of CD8B and granzyme B, markers representing cytotoxic lymphocytes. Tumors with more expressed CT antigens are also associated with higher expression of these markers. These data suggest that CT antigens, along with neoantigens, may contribute to a stronger host immune response in these hypermutative tumors.

Citation Format: Junping Jing, Patrick Mayes, Yan Degenhardt, James R. Brown, Philippe Sanseau. Higher mutation rate is associated with more frequent expression of cancer/testis antigens in human tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 525.
Abstract 5251: Chemoprevention of cadmium induced prostate carcinogenesis
Authors: Suman Suman , Das Trinath P. , Alatassi Houda , Ankem Murali K. , Damodaran Chendil
Published: July 2016

Cadmium is known carcinogen that causes damages to multiple organs. Cadmium acts as an agonist and activates androgen receptor (AR) in prostate epithelial cells which in turn promotes the carcinogenesis of prostate. Studies have indicated that occupational exposure of cadmium is a risk factor for prostate cancer and hence there is an immediate need to prevent cadmium induced prostate cancer in occupational workers. Various reports have shown that inhibition of AR signaling by AR inhibitors suppressed cadmium induced prostate carcinogenesis. So, the present study focuses to identify dietary agent which can effectively prevent cadmium induced prostate cancer and to dissect the mechanism of action on malignant transformed cells. We have disclosed one such compound, 6-(3, 9-dihydroxy-2-prenylcoumestan (Psoralidin) (Pso) a non-toxic, orally bioavailable compound, which effectively targets only prostate cancer cells and innocuous to healthy cells. Our results have shown cadmium transformed prostate epithelial cells (CTPE) exhibits high proliferative and high colony forming ability in soft agar assays. However, treatment of CTPE cells with Pso resulted in growth inhibition, without causing toxicity to normal prostate epithelial cells (RWPE-1). Finally, in vivo experiments showed that oral administration of Pso (20 mg/kg/BW) effectively suppresses the growth in CTPE xenografts, at physiologically achievable doses without any toxicity. The pathological findings suggest that CTPE tumors exhibits epithelial and mesenchymal transition (EMT) phenotype and infiltrating margins into the surrounding muscle and adipose tissue. However, Psoralidin treated tumors showed a decrease in tumor size with a significant central necrosis (up to 60% of the tumor size). More specifically, margins of Psoralidin treated tumors are less infiltrative and becoming more well circumscribed. We have also noticed that the mesenchymal component is not present and the only viable tumor is the epithelial one after Pso treatment. Altogether, our results confirm that consumption of natural compounds such as Psoralidin may play an important role in the chemoprevention for cadmium induced prostate carcinogenesis.

Citation Format: Suman Suman, Trinath P. Das, Houda Alatassi, Murali K. Ankem, Chendil Damodaran. Chemoprevention of cadmium induced prostate carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5251.
Abstract 5254: Andrographolide prevents prostate cancer by targeting CXCR3/CXCR7 and regulators of cell cycle
Authors: Mir Hina , Kapur Neeraj , Singh Rajesh , Sonpavde Guru , Lillard James W. , Singh Shailesh
Published: July 2016

Despite state of the art cancer diagnostics and therapies offered in clinics, prostate cancer (PCa) remains the second leading cause of cancer-related deaths in men. Hence, more robust therapeutic/preventive regimes are required to combat this lethal disease. In the current study, we have tested the efficacy of andrographolide (AG), a bioactive diterpenoid isolated from Andrographis paniculata, against PCa. This natural agent selectively affects PCa cell viability in a dose and time-dependent manner, without affecting primary prostate epithelial cells. Furthermore, AG showed differential effect on phases of cell cycle in LNCaP, C4-2b and PC3 cell lines compared to retinoblastoma protein (RB-/-) lacking DU-145 cells. This agent blocked the G2/M transition in LNCaP, C4-2b and PC3 whereas DU-145 cells failed to transit G1/S phase. This difference was primarily due to switching of the activation states of cell cycle regulators in these cell lines. AG induced its effect mainly via cyclin A2 and B1 in LNCaP, C4-2b and PC3 cell lines; whereas, cyclin E related regulation was affected in DU-145 cells. Phosphorylation status of Wee1, a nuclear kinase belonging to the Ser/Thr family and CDC2 was also affected by AG. Intriguingly, AG affected cell viability and the ability of PCa cells to migrate via modulating CXCL11 and CXCR3 and CXCR7 expression. The significant impact of AG on cellular and molecular processes involved in PCa progression suggest this agent has potential to be used as a therapeutic and/or preventive modality.

Citation Format: Hina Mir, Neeraj Kapur, Rajesh Singh, Guru Sonpavde, James W. Lillard, Shailesh Singh. Andrographolide prevents prostate cancer by targeting CXCR3/CXCR7 and regulators of cell cycle. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5254.
Abstract 5261: Novel resveratrol analogue, HS-1793, inhibits hypoxia-induced HIF-1 and VEGF expressions and inhibits tumor growth of human breast cancer cells in a nude mouse xenograft model
Authors: Kim Dong Hwan , Kim Min Jeong , Sung Bokyung , Kang Yong Jung , Hwang Seong Yeon , Hwang Na Lam , Kim Nam Deuk
Published: July 2016

Taking phytochemicals provide various benefits for human health. Among them, resveratrol, from the blueberry, is well known for its beneficial effects for human. However, resveratrol has photosensitive and easily decomposition by digestive enzyme. Thus we synthesized several synthetic analogues of resveratrol with potent activity. One of them, 4-(6-hydroxy-2-naphtyl)-1, 3-benzenediol (HS-1793) treatment showed potent antitumor activity in various human cancer cells. In this study, we investigated the effects of a novel analogue of resveratrol, HS-1793 on the expressions of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in MCF-7 with MDA-MB-231 human breast cancer cells. We found that HS-1793 inhibited hypoxia (1.0% oxygen) induced HIF-1α protein level and its downstream target, vascular endothelial growth factor (VEGF) expression dose-dependently in both cell lines. Decreased HIF-1α by HS-1793 modulated through 26S proteasome pathway. We also found that HS-1793 suppressed tumor growth in tumor xenograft mice model. Treatment with 10 mg/kg of HS-1793 suppressed Ki-67 and CD31 expressions in tumor tissues. Above all, HS-1793 shows more powerful effects than resveratrol. Taken together, these results implied that HS-1793, a novel analogue of resveratrol might be a new potent chemopreventive agent and anticancer therapy in human breast cancer.

Citation Format: Dong Hwan Kim, Min Jeong Kim, Bokyung Sung, Yong Jung Kang, Seong Yeon Hwang, Na Lam Hwang, Nam Deuk Kim. Novel resveratrol analogue, HS-1793, inhibits hypoxia-induced HIF-1 and VEGF expressions and inhibits tumor growth of human breast cancer cells in a nude mouse xenograft model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5261.
Abstract 5266: Fast and accurate fusion transcript detection using the Trinity Cancer Transcriptome Analysis Toolkit
Authors: Haas Brian , Tickle Timothy , Pochet Nathalie , Sun Jing , Hsu Peggy , Stewart Chip , Ganote Carrie , Fulton Ben , Wu Catherine , Regev Aviv
Published: July 2016

Chromosomal rearrangements leading to fusion transcripts represent a class of oncogenic aberrations that are of high interest for understanding cancer biology, treating cancer patients, and as targets for the development of new therapies. Transcriptome sequencing via RNA-Seq coupled with downstream bioinformatics software applications offers an effective method for identifying candidate fusion transcripts, and is more targeted and cost-effective than whole genome sequencing. Although many such fusion detection software tools have recently been made available, they often differ greatly in prediction accuracy, execution times, computational requirements, installation complexity, and in not being readily accessible to non-bioinformatician cancer researchers.

Here we present the Trinity Cancer Transcriptome Analysis Toolkit (CTAT), a newly developed suite of RNA-Seq targeted fusion detection tools leveraging a combination of reference genome read-mapping and de novo transcriptome assembly, coupled to in silico fusion transcript validation, annotation, and visualization. We show that components of our Trinity CTAT fusion detection toolkit, including STAR-Fusion and FusionInspector, yield improved accuracy and run times as compared to alternative leading tools. As a demonstration of the utility of Trinity CTAT, we explore fusion transcript discovery in a large cohort of ∼300 chronic lymphocytic leukemia (CLL) patient samples. We identify several novel recurrent fusions that may represent drivers of CLL etiology and provide new avenues to therapies.

In addition to fusion transcript identification, Trinity CTAT aims to provide cancer researchers with easy access to methods for analyzing cancer RNA-Seq, including transcript reconstruction, identification of mutations, expression analysis, and tumor heterogeneity. Trinity CTAT is freely available open source software and readily accessible to all cancer researchers via our public Galaxy web portal: https://galaxy.ncgas-trinity.indiana.edu/.

Citation Format: Brian Haas, Timothy Tickle, Nathalie Pochet, Jing Sun, Peggy Hsu, Chip Stewart, Carrie Ganote, Ben Fulton, Catherine Wu, Aviv Regev. Fast and accurate fusion transcript detection using the Trinity Cancer Transcriptome Analysis Toolkit. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5266.
Abstract 5281: Fast and scalable software for comparative variant analysis and visualization of massive next-generation sequencing data
Authors: Katainen Riku , Mäkinen Veli , Aaltonen Lauri A. , Pitkänen Esa
Published: July 2016

Next-generation sequencing (NGS) techniques produce high quantities of DNA and RNA sequencing data, enabling variation analysis at a whole genome level. Due to the massive availability of NGS data, the processing and analysis now constitute a serious challenge for research in life sciences. This necessitates the development of novel, user-friendly and scalable software tools, which are able to jointly handle large NGS data sets in order to break the bottleneck that has already moved from data generation to data analysis in high-throughput biology.

Here we introduce a highly efficient NGS analysis and visualization software tool (Rikurator), which is designed for researchers who are struggling with NGS data analysis and may not have access to a dedicated bioinformatics team. Rikurator can be applied to a multitude of genomic analysis tasks, including discovery of pathogenic mutations in familial or sporadic sample sets, analysis of structural variants and somatic characterization of cancer genomes. To these ends the software implements interactive variant filtering and annotation methods based on sample comparison, control data (e.g. ExAC), amino acid changes and quality scores, which provide an intuitive view at the studied samples. Shared candidate genes in a set of dozens of individuals can be discovered in a matter of minutes with an ordinary laptop computer. Importantly, the software is able to analyze hundreds of whole-genome sequenced samples using only a modest amount of RAM. The tool also visualizes and integrates genes, variants (VCF file format), sequence reads (BAM) and user defined features (BED/GFF). In addition, Rikurator is not limited to human studies, supporting reference genomes and genome annotations in standard formats. The software supports targeted (e.g. exome), whole-genome, RNA, Oxford Nanopore and PacBio sequencing data.

Rikurator can be run on Windows, Linux and Mac, and it will be freely available after publication.

Citation Format: Riku Katainen, Veli Mäkinen, Lauri A. Aaltonen, Esa Pitkänen. Fast and scalable software for comparative variant analysis and visualization of massive next-generation sequencing data. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5281.
Abstract 5290: ChimericSeq: an easy-to-use program for discovery and analysis of integration events from NGS data
Authors: Jongeneel Patrick , Lin Selena , Steffen Jamin , Jain Surbhi , Su Ying-Hsiu , Song Wei
Published: July 2016

The purpose of this study was to develop a computational method of extracting viral integration events from NGS data in an intuitive way that could accommodate access from users of all disciplines. Viral integration into the host genome is a characteristic of many pathogenic viruses, including the hepatitis B virus (HBV) and human papillomavirus (HPV). Gradual insertion of viral components near proto-oncogenes of the host genome over time can induce uncontrolled cellular proliferation, eventually leading to carcinogenesis. While increased availability of high-throughput next generation sequencing (NGS) has provided tools for researchers to discover these underlying host changes due to viral integrations, there is an emerging need for analytical support of this data. Here we present ChimericSeq, a user-friendly program that can quickly identify viral integration events from NGS data. To fully evaluate this program, we compared the functionality of ChimericSeq to other current viral integration programs. A number of synthetic data sets of HBV sequence fragments integrated into 100bp fragments of random human genomic DNA were created to mimic the nature of chimeric reads of NGS data. ChimericSeq was able to correctly identify reads containing at least 25bp of viral sequence at 100% accuracy. This was a major improvement over the current programs, VirusClip and ViralFusionSeq, which could not detect reads with only 25bp of viral sequence, and even had difficulty correctly identifying viral integration sites containing additional viral sequence. Furthermore, ChimericSeq could detect viral events nearly 10X and 100X faster than these current programs, respectively. Upon testing of NGS data from actual HBV-positive human tissue, we found that ChimericSeq was not only much faster, but was also able to detect more unique viral integration events than current viral integration tools. In conclusion, ChimericSeq expands NGS analytical support to a broader spectrum of the scientific community, being the first program of its kind to offer support in an intuitive graphical user interface (GUI) for commonly used operating platforms, such as Windows and Mac.

Citation Format: Patrick Jongeneel, Selena Lin, Jamin Steffen, Surbhi Jain, Ying-Hsiu Su, Wei Song. ChimericSeq: an easy-to-use program for discovery and analysis of integration events from NGS data. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5290.
Abstract 535: Deregulated Myc is an immunosuppressive switch
Authors: Kortlever Roderik M. , Sodir Nicole M. , Wilson Catherine H. , Burkhart Deborah L. , Swigart Lamorna , Littlewood Trevor D. , Evan Gerard I.
Published: July 2016

Early tumor evolution through sustained oncogene activity selectively bypasses the engagement of cell-intrinsic tumor-suppressor signaling and cell-extrinsic microenvironmental restrictions. How the immune system may be involved is virtually unknown. We describe here the contributions of a conditional and reversible low-level expression of Myc in a mouse model of KrasG12D-driven non-small cell lung cancer. Deregulated Myc activity results in highly expansive tumors that appear embedded in inflamed regions and leads to a rapid reduction of mouse survival. Myc activation imposes an immediate switch to an immunosuppressive and pro-angiogenic microenvironment, facilitated through IL23- and CCL9-associated recruitment of PD-L1 loaded macrophages and local exclusion of T-lymphocytes. Reversibly, blocking the activity of Myc-driven IL23 and CCL9 expression or withdrawal of deregulated Myc activity in tumors established by oncogene cooperation results in tumor cell death and regression, associated with a collapse of the established microenvironmental changes and re-engagement of cytotoxic T-cells. During oncogene cooperation with Ras, deregulated Myc directs a sufficient and necessary switch to a microenvironment that shields tumor growth and expansion from immune suppression.

Citation Format: Roderik M. Kortlever, Nicole M. Sodir, Catherine H. Wilson, Deborah L. Burkhart, Lamorna Swigart, Trevor D. Littlewood, Gerard I. Evan. Deregulated Myc is an immunosuppressive switch. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 535.
Abstract 546: Impact of therapeutic EGFR inhibition on immune checkpoint blockade in head and neck squamous cell carcinoma
Authors: Rogers Laura M. , Espinosa-Cotton Madelyn M. , Simons Andrean L. , Weiner George J.
Published: July 2016

Patients with advanced recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) have few effective treatment options and a poor median survival of 6-8 months. Limited improvement in overall survival has been observed in HNSCC patients treated with EGFR inhibitors despite high expression of epidermal growth factor receptor (EGFR) in these tumors. Remarkable clinical results are emerging from immunotherapy targeting programmed death-1 (PD1) and its ligand programmed death ligand-1 (PDL1). Blockade of the PD1/PDL1 interaction is believed to enhance endogenous anti-tumor immunity by restoring T cell cytotoxic action. PDL1 is highly expressed in primary, recurrent, and metastatic HNSCC and phase 1 clinical trials are ongoing for monoclonal antibodies targeting the PD1/PDL1 axis in HNSCC.

We found that activation of EGFR in HNSCC cells by epidermal growth factor (EGF) significantly increases PDL1 expression in a dose dependent manner. EGFR inhibition using tyrosine kinase inhibitors (TKI) or cetuximab suppresses this EGF-induced PDL1 expression in cells with both wild type and constitutively active EGFR. This is consistent with published data that constitutively active EGFR in lung cancer cells correlates with higher PDL1 expression, and this can be reversed by EGFR inhibition. These results suggest there may be interactions between EGFR-targeted therapy and immunotherapy involving the PD1/PDL1 axis.

To evaluate potential therapeutic interactions, we used an immunocompetent, syngeneic mouse model of human EGFR-expressing TUBO cancer cells on a BALB/c background. The murine TUBO-EGFR cells are sensitive to human EGFR inhibitors both in vitro and in vivo. Initial studies show that treatment of tumors with EGFR inhibitor (erlotinib) results in increased intratumoral CD8+ T cell infiltration and tumor regression, suggesting that EGFR inhibition can impact the anti-tumor T cell response. We are currently evaluating the effects of EGFR inhibition on PDL1 expression and tumor response to PD1/PDL1 blockade using this model. Further, a clinical trial investigating the impact of cetuximab treatment on intratumoral expression of PDL1 in HNSCC patients is planned to open shortly. We conclude that signaling mediated by EGFR can impact expression of PDL1 by HNSCC. Understanding the interactions between EGFR inhibitors and immune checkpoint blockade could lead to new approaches to combining TKI and cancer immunotherapy.

Citation Format: Laura M. Rogers, Madelyn M. Espinosa-Cotton, Andrean L. Simons, George J. Weiner. Impact of therapeutic EGFR inhibition on immune checkpoint blockade in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 546.