tbuckley/cabot-search huggingface dataset:
Abstract LB-274: Microenvironment mediates the efficacy of Cabozantinib in prostate cancer
Authors: Manisha Tripathi, Srinivas Nandana, Sandrine Billet, Edwin M. Posadas, Leland W.K. Chung, Neil A. Bhowmick
Journal: Cancer Research (2016)

Abstract Therapeutic targeting of the epithelial compartment alone in prostate cancer has resulted in unfavorable outcomes, including the development of resistance. Cabozantinib (XL184), a small molecule inhibitor of tyrosine kinases including c-MET and VEGFR2 has been shown to decrease tumor growth and metastasis. Our working rationale is that therapeutic strategies that target the prostate tumor microenvironment would have improved outcomes compared with those that solely target the cancer epithelia. Cabozantinib is demonstrated to have a role in inhibiting osteoclast and osteoblast differentiation and thereby limit prostate cancer (PCa) bone lesions, as determined by technetium-99 bone scan. However, the ultimate survival benefit of castrate resistant prostate cancer patients treated with cabozantinib has not born out in recent clinical trials for PCa patients with bone metastasis. In this study, utilizing various pre-clinical xenograft mouse models, prostate epithelial cell lines and human and mouse prostate fibroblasts, we investigated the effect of cabozantinib on prostate tumor microenvironment and delineated the cellular targets of cabozantnib. We found that cabozantinib affects prostate stromal cells at a significantly lower concentration compared with epithelial cells in vitro. We found that human cancer associated fibroblasts pre-treated with cabozantinib induced a significantly increased tumor growth in the intra-tibial mouse model of growth in the bone microenvironment. Further, in a novel and surprising discovery, we found that cabozantinib alters the immune microenvironment by reducing the M1 macrophages. However, cabozantinib depleted both basal and luminal epithelial progenitor cells in vivo. Taken together, we found that cabozantnib can have a tumor potentiating role by limiting M1 macrophages, yet the down regulation of carcinoma associated fibroblasts and associated epithelial progenitors could suggest interesting combination therapies. A lower dose of cabozantnib with traditional anti-proliferative therapies, like taxanes or radiation is supported by the pre-clinical experiments. Citation Format: Manisha Tripathi, Srinivas Nandana, Sandrine Billet, Edwin M. Posadas, Leland W.K. Chung, Neil A. Bhowmick. Microenvironment mediates the efficacy of Cabozantinib in prostate 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 LB-274.
Abstract 4753: Ovarian cancer stem cell marker ALDH1A2 is a candidate biomarker for patient selection for intraperitoneal chemotherapy
Authors: Brandon-Luke L. Seagle, Monica Dandapani, Chen Hui Luo, Claire Hoppenot, Robert Samuelson, Kevin H. Eng, Kunle Odunsi, Shohreh Shahabi
Journal: Cancer Research (2016)

Abstract Objective. To evaluate ovarian cancer stem cells as predictors of survival we analyzed associations of cancer stem cell markers ALDH1, CD117 and CD133 with survival outcomes among patients with high grade serous ovarian cancer (HGS OvCa). Methods. Data from HGS OvCa patients who were surgically staged prior to treatment with IP (n = 90) or IV-only (n = 398) chemotherapy was obtained from The Cancer Genome Atlas. Multivariate Cox proportional-hazards regression tested associations of tumor mRNA expression of 5 cancer stem cell markers with progression free survival (PFS) and overall survival (OS). Expression was analyzed as a continuous variable by restricted mean survival (RMS) analysis. Mean PFS or OS were compared between IP and IV groups by permutation testing stratified by expression. P-values were two-tailed. Results. Increased tumor ALDH1A2 expression was associated with decreased OS among patients treated with IP chemotherapy, HR 2.36 (1.16-4.80), p = 0.017. IP treated patients with upper 20th percentile ALDH1A2 expression had decreased OS compared to bottom 20th percentile expression (30.4 versus 51.1 months, -20.7 months difference, p = 0.017). RMS curves for PFS and OS of IP versus IV treated patients crossed at high ALDH1A2 expression, indicating that IP treated patients had decreased survival compared to IV-only treated patients. Patients with upper 20th percentile ALDH1A2 expression treated with IP versus IV-only chemotherapy had no difference in mean PFS (21.3 versus 21.6 months, -0.3 months difference, p = 0.67) and decreased OS (30.4 versus 35.3 months, -4.9 months difference, p &amp;lt; 0.0001). Upper 10th percentile ALDH1A2 expression was associated with decreased PFS (19.5 versus 22.0 months, -2.5 months, p = 0.005) and OS (27.1 versus 35.2 months, -8.1 months, p &amp;lt; 0.0001) comparing IP versus IV groups. Increased CD133 expression was associated with increased PFS among IV-only patients, HR 0.85 (0.74-0.97), p = 0.016. CD117 and the ALDH1 genes ALDH1A1/3 were not associated with survival. Conclusions. High primary tumor ALDH1A2 expression was independently associated with significantly decreased OS among patients treated with IP chemotherapy. High ALDH1A2 was associated with lack of benefit or decreased survival among patients treated with IP compared to IV-only adjuvant chemotherapy. Citation Format: Brandon-Luke L. Seagle, Monica Dandapani, Chen Hui Luo, Claire Hoppenot, Robert Samuelson, Kevin H. Eng, Kunle Odunsi, Shohreh Shahabi. Ovarian cancer stem cell marker ALDH1A2 is a candidate biomarker for patient selection for intraperitoneal chemotherapy. [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 4753.
The Retinoid Agonist Tazarotene Promotes Angiogenesis and Wound Healing
Authors: Ayman Al Haj Zen, Dorota A Nawrot, Alison Howarth, Andrea Caporali, Daniel Ebner, Aude Vernet, Jurgen E Schneider, Shoumo Bhattacharya
Journal: Molecular Therapy (2016)

Therapeutic angiogenesis is a major goal of regenerative medicine, but no clinically approved small molecule exists that enhances new blood vessel formation. Here we show, using a phenotype-driven high-content imaging screen of an annotated chemical library of 1,280 bioactive small molecules, that the retinoid agonist Tazarotene, enhances in vitro angiogenesis, promoting branching morphogenesis, and tubule remodeling. The proangiogenic phenotype is mediated by retinoic acid receptor but not retinoic X receptor activation, and is characterized by secretion of the proangiogenic factors hepatocyte growth factor, vascular endothelial growth factor, plasminogen activator, urokinase and placental growth factor, and reduced secretion of the antiangiogenic factor pentraxin-3 from adjacent fibroblasts. In vivo, Tazarotene enhanced the growth of mature and functional microvessels in Matrigel implants and wound healing models, and increased blood flow. Notably, in ear punch wound healing model, Tazarotene promoted tissue repair characterized by rapid ear punch closure with normal-appearing skin containing new hair follicles, and maturing collagen fibers. Our study suggests that Tazarotene, an FDA-approved small molecule, could be potentially exploited for therapeutic applications in neovascularization and wound healing.
Abstract 477: Correlation of PD-L1 expression and HPV status among primary and metastasized HNSCC tumors
Authors: Chenglu C. Quon, Xiaoling Xia, Lupe Manriquez, Crystal Schemp, Dawn Sloane, Shahad Alabagi, Mohammed G. Abdelwahab, Pengfei Gu, Lizhen Pang, Khalid Hanif, Nicole Schechter
Journal: Cancer Research (2016)

Abstract Dysregulation of the immune checkpoints has been identified as one of the mechanisms tumor cells employ for immune escape. Human papillomavirus (HPV) plays an important role in the etiology of one subset of Head and Neck Squamous Cell Carcinomas (HNSCC). Recent studies reported that PD-1/PD-L1 pathway may be correlated with HPV-associated HNSCC. The degree of PD-L1 expression has been reported to be increased in those patients with HPV-positive disease. Also, PD-L1 expression in HNSCC was observed in the primary, recurrent, and metastatic disease setting. However, the clinicopathological implications associated with PD-L1 in HNSCC, as well as in disease metastasis, remain largely unclear. Using immunohistochemistry (IHC) and In situ hybridization (ISH) on VENTANA BenchMark ULTRA automated stainers, 40 cases of HNSCC, with matching primary and metastatic cancer stages, were evaluated for expression of PD-L1, p16, a surrogate marker of transforming HPV infections, and presence of HPV. Formalin-fixed paraffin-embedded tumor samples were subjected to PD-L1- and p16-IHC as well as HPV-ISH. A potential association between PD-L1 expression and HPV status among primary tumors and matched metastases was analyzed. Our data show that expression of PD-L1 or p16 is concordant in the majority of HNSCC primary vs metastatic tumor cases tested. Agreement rate of p16 expression among 40 case pairs of primary vs metastatic tumor was 88.2% with a 95% Confidence Interval (CI) of (73.4-95.3). PD-L1 expression was 76.9% (61.7-87.4) concordant among the 40 case pairs. Agreement rate between PD-L1 and p16 was 77.1% (61.0-87.9) in primary cases and 51.3% (35.9-66.6) in metastatic cases. No obvious association between PD-L1 and p16 expression was observed. Citation Format: Chenglu C. Quon, Xiaoling Xia, Lupe Manriquez, Crystal Schemp, Dawn Sloane, Shahad Alabagi, Mohammed G. Abdelwahab, Pengfei Gu, Lizhen Pang, Khalid Hanif, Nicole Schechter. Correlation of PD-L1 expression and HPV status among primary and metastasized HNSCC 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 477.
Preclinical Development Of a Nanomedicne Approach For Multiple Myeloma Targeting The Myc Oncoprotein
Authors: Deepti Soodgupta, Dipanjan Pan, Grace Hu, Angana Senpan, Xiaoxia Yang, Katherine N Weilbaecher, Edward V. Prochownik, Gregory M Lanza, Michael H Tomasson
Journal: Blood (2013)
Demonstration of Response to Androgen Deprivation Therapy by 68Ga-PSMA PET/CT
Authors: Cigdem Soydal, Elgin Ozkan, Bektas Kaya, Ozlem Nuriye Kucuk
Journal: Clinical Nuclear Medicine (2016)

We present pretreatment and posttreatment 68Ga-PSMA PET/CT images of a 68-year-old man with metastatic prostate cancer who is a responder to androgen deprivation therapy.
Abstract 1614: Identification of FBXL4 as a bone metastasis-associated gene in prostate cancer
Authors: Elzbieta Stankiewicz, Xueying Mao, D Chas Mangham, Lei Xu, Gabrielle Fisher, Bernard North, Henrik Moller, Peter Scardino, Jack Cuzick, Dan Berney, Yong-Jie Lu
Journal: Cancer Research (2016)

Abstract Prostate cancer (PCa) is the most common cancer among men in Western developed countries. While the majority of PCa diagnosed by PSA screening are indolent, advanced and metastatic disease has a significant mortality and morbidity. Bone metastases are extremely common in PCa and identification of bone metastasis associated genes may provide insights into PCa progression and assist in finding new drug targets. However, the genetic study of bone metastases is very limited due to the difficulty of sampling. By analyzing PCa bone metastases using high density microarrays, we found a common genomic copy number loss at 6q16.1-16.2, containing the FBXL4 gene, which was confirmed in a separate and larger series of bone metastatic samples by fluorescence in situ hybridization (FISH). Loss of FBXL4 was also detected in primary PCa, although at a significantly lower frequency than in bone metastases, and it was highly associated with prognostic factors including high Gleason score, clinical stage, PSA and extent of disease, as well as poor patient survival in conservatively-managed localized PCa, suggesting that loss of FBXL4 contributes to PCa progression. We also demonstrated that FBXL4 deletion is detectable in circulating tumor cells, making it a potential disease prognostic or progression monitoring biomarker by ‘liquid biopsy’. Consistent with loss of FBXL4 being associated with aggressive tumors, we demonstrated in vitro that FBXL4 plays a role in regulating the migration and invasion of PCa cells. Therefore, FBXL4 is a potential novel PCa suppressor gene, which may prevent cancer progression and bone metastasis through controlling cell invasion. Citation Format: Elzbieta Stankiewicz, Xueying Mao, D Chas Mangham, Lei Xu, Gabrielle Fisher, Bernard North, Henrik Moller, Peter Scardino, Jack Cuzick, Dan Berney, Yong-Jie Lu. Identification of FBXL4 as a bone metastasis-associated gene in prostate 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 1614.
68Ga DOTATATE PET/CT of Non–FDG-Avid Pulmonary Metastatic Hemangiopericytoma
Authors: Te-Jui Hung, William Macdonald, Tracey Muir, Liesl Celliers, Zeyad Al-Ogaili
Journal: Clinical Nuclear Medicine (2016)

We present the FDG and Ga DOTATATE PET/CT findings of a 68-year-old woman with pulmonary metastases 28 years after her initial diagnosis of central nervous system hemangiopericytoma. The largest of the pulmonary lesions showed prominent Ga DOTATATE uptake with comparatively minimal FDG avidity. Hemangiopericytoma is a rare mesenchymal tumor that arises from malignant pericytes, cells that form the walls of capillaries and postcapillary venules. This case demonstrates the potential of radiolabeled somatostatin analogs as a therapeutic option in the setting of widespread metastatic disease.
Outcomes in neuroendocrine bladder cancer treated with radical cystectomy.
Authors: Brian Robin Hu, Vivian Pham, Hooman Djaladat, Anne K. Schuckman, Gus Miranda, Jie Cai, Tanya B. Dorff, David I. Quinn, Siamak Daneshmand
Journal: Journal of Clinical Oncology (2016)

e16004 Background: Management of localized or locally-advanced neuroendocrine (NE) bladder cancer is difficult as outcomes tend to be poor regardless of treatment. We sought to characterize our institutional experience to determine factors associated with survival. Methods: We utilized our bladder cancer database to identify patients with any NE component to their cancer who underwent radical cystectomy (RC) (1977-2012). Clinical and pathologic data were obtained. Kaplan-Meier curves estimated recurrence-free survival (RFS) and overall survival (OS) and were compared with the log rank test. Multivariable Cox proportional hazards determined factors associated with RFS and OS. Results: A total of 86 patients met the inclusion criteria with a median age of 68 years (range 37-89). The highest clinical stage prior to RC was ≤ T2 in 71 patients, > T2 in 8 patients, and lymph node positive in 7 patients. There were 35 (41%) patients with predominant NE histology (small cell n = 30, large cell n = 5) and the remaining 51 (59%) patients had < 50% NE components on histology. Twenty-two patients (26%) underwent neoadjuvant chemotherapy (NAChT) with cisplatin/etoposide representing the most common regimen. Lymph node upstaging was significantly higher in patients who did not receive NAChT when compared with patients who receive NAChT (51% vs. 19%, p < 0.02). The median OS and RFS for the entire cohort were 2.0 and 1.4 years, respectively. Patients with predominant NE histology had worse OS when compared with patients with < 50% NE histology (p = 0.002). A response to NAChT on imaging was associated with improved OS when compared with patients who had no response to NAChT (median 31 months vs. 10 months, p = 0.13). On multivariable analysis, a predominant NE histology, presence of pathologic upstaging, and not receiving adjuvant chemotherapy were independently associated with worse OS. Conclusions: Survival in patients with bladder cancer with NE histology is poor and occult LN positive disease is identified in almost half of patients at the time of RC. A predominant NE histology is independently associated with worse survival. Further investigation into the optimal timing of multimodal therapies is required to improve outcomes in this population.
Abstract 4012: Improving radiotherapy abscopal effects with anti-PD1 and anti-CD137-based immunotherapy
Authors: MariaE. Rodríguez-Ruiz, Inmaculada Rodriguez, Saray Garasa, Benigno Barbes, Jose Luis Solorzano, Jose Luis Perez Gracia, Sara Labiano, Arantza Azpilikueta, Elixabet Bolanos, Alfonso R. Sanchez-Paulete, M. Angela Aznar, Ana Rouzaut, Maria Jure-Kunkel, Iñaki Etxeberria, Carlos Alfaro, Carmen Oñate, Mariano Ponz, Ignacio Melero
Journal: Cancer Research (2016)

Abstract Radiotherapy is considered an efficacious local tool to erradicate or at least control cancer progression. However, recent lines of preclinical and clinical evidence indicate that proimmune effects of radiotherapy can be synergistically augmented with immunostimulatory monoclonal antibodies (mAb) to act both on irradiated tumor lessions and on distant, non-irradiated tumor sites. The combination of radiotherapy with immunostimulatory anti-PD1 and anti-CD137 mAbs was conducive to favourable effects on distant non-irradiated tumor lesions as observed on transplanted MC38 (colorectal cancer), B16OVA (melanoma) and 4T1 (breast cancer) models. Immunotherapy and radiotherapy synergized both when irradiation was given using external beams or provided with brachytherapy. The therapeutic activity was crucially performed by CD8 T cells, as found in selective depletion experiments. The irradiation regimen induced immune infiltrate changes in the irradiated and non-irradiated lesions featured by reductions in the content of effector T cells, Tregs, and myeloid-derived supresor cells (MDSC), while effector T cells were expressing more intracellular IFN gamma in both the irradiated and contralateral tumors. Importantly, 48h following irradiation CD8+ TILs showed brighter expression of CD137 and PD-1 thereby displaying more target molecules for the activity of the corresponding monoclonal antibodies. Likewise, PD-1 and CD137 were induced on tumor infiltrating lymphocytes from surgically excised of human carcinoma lessions that were irradiated ex-vivo. These findings advocate for clinical development of immunotherapy combinations with anti-PD1 plus anti-CD137 mAbs that can be synergistically accompained by radiotherapy strategies on treatable lesions, even if leaving disease outside the irradiation field. Citation Format: MariaE. Rodríguez-Ruiz, Inmaculada Rodriguez, Saray Garasa, Benigno Barbes, Jose Luis Solorzano, Jose Luis Perez Gracia, Sara Labiano, Arantza Azpilikueta, Elixabet Bolanos, Alfonso R. Sanchez-Paulete, M. Angela Aznar, Ana Rouzaut, Maria Jure-Kunkel, Iñaki Etxeberria, Carlos Alfaro, Carmen Oñate, Mariano Ponz, Ignacio Melero. Improving radiotherapy abscopal effects with anti-PD1 and anti-CD137-based immunotherapy. [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 4012.
Abstract 800: <i>ALDH2</i> rs671 polymorphism and alcohol consumption in the risk of gastric cancer: A Mendelian randomization study
Authors: Jeongseon Kim, Sarah Yang, Jeonghee Lee, Il Ju Choi, Young Woo Kim, Keun Won Ryu, Joohon Sung
Journal: Cancer Research (2016)

Abstract Background: The effect of increased alcohol consumption on the risk for gastric cancer (GC) has not been fully elucidated, due to the presence of confounders and gender differences. In this study, aldehyde dehydrogenase 2 (ALDH2) rs671, the genetic polymorphism related to the elimination of acetaldehyde, was used as an instrumental variable (IV) for Mendelian randomization analysis to dissect the role of alcohol in GC risk. Methods: The study included Korean 450 GC cases and 1,050 controls recruited at the National Cancer Center. Data of 795 GC patients and 4,893 controls from the Korean Centers for Disease Control were used for further validation. The odds ratios (OR) for the ALDH2 genotype and its interaction with alcohol consumption were estimated using multivariate logistic regression. The two-stage control function method was performed using rs671 as the IV for alcohol consumption. Results: All AG carriers had an OR of 1.26 (95% confidence interval, 1.11-1.42) compared with GG carriers. In a quantitative analysis of alcohol intake, the conventional OR was 1.21(1.09-1.36) and the IV-OR was 0.90(0.63-1.28). Females had low alcohol consumption and did not show a significant risk for GC while males had a high risk for GC. Conclusions: Alcohol consumption is not associated with a risk for GC by itself, and ALDH2 polymorphism should be considered simultaneously when assessing the risk. Females did not display an evident risk for GC regarding alcohol, partly due to their lower level of alcohol consumption. However, further dissection of gender difference is necessary. Citation Format: Jeongseon Kim, Sarah Yang, Jeonghee Lee, Il Ju Choi, Young Woo Kim, Keun Won Ryu, Joohon Sung. ALDH2 rs671 polymorphism and alcohol consumption in the risk of gastric cancer: A Mendelian randomization study. [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 800.
Abstract 4265: Automation-enabled 3D tumor chemosensitivity screening by imaging and flow cytometry analysis
Authors: Michael Kowalski, Vipat Raksakulthai, Kristin Prasauckas, Tara Jones-Roe
Journal: Cancer Research (2016)

Abstract Three-dimensional (3D) cancer cell cultures are being utilized for drug screening with increasing frequency since they provide a more physiologically relevant solid tumor model than two-dimensional cell cultures. Spheroids are a well characterized, in vitro tumor model system that has been utilized with multiple cancer cell lines. Growth and manipulation of these cultures in hanging drop plates (HDPs) can be challenging to manipulate and these challenges are amplified as sample throughput increases. We automated the culture and compound treatment of cancer spheroids in HDPs, as well as the preparation of these spheroids for analysis by high content imaging and flow cytometry. Automated cancer spheroid cultures showed excellent consistency in size and shape, providing higher confidence in the screening results. Creating single cell suspensions from the cancer spheroids for flow cytometry analysis was another significant challenge overcome through automation. Imaging provided information such as the location of drug-responding cells within the cancer spheroid while flow cytometry removed the potential for spheroid exclusion of staining reagents leading to false negatives. Automation enabled the use of these complementary analyses, thereby achieving a more complete understanding of compound sensitivity in solid tumors and illustrating how spheroids can be utilized to screen for novel cancer therapeutics. Citation Format: Michael Kowalski, Vipat Raksakulthai, Kristin Prasauckas, Tara Jones-Roe. Automation-enabled 3D tumor chemosensitivity screening by imaging and flow cytometry analysis. [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 4265.