tbuckley/cabot-search huggingface dataset:
Abstract 23: Caloric restriction slows tumor growth and metastases in both hormone-sensitive and hormone-resistant prostate cancers
Authors: Robert S. Gitman, Meredith LaRose, Edouard J. Trabulsi, Ajay Palagani, Tiziana DeAngelis, William K. Kelly, Leonard G. Gomella, Nicole L. Simone
Journal: Cancer Research (2016)

Abstract Introduction: The purpose of this study is to assess the effect of caloric restriction (CR) on prostate cancer (PCa) tumor burden, proliferation, and overall survival with and without radiation treatment (RT). Additionally, we determined if the beneficial effect of CR noted are due to a reduction in pro-inflammatory markers hypothesized to enhance PCa tumorgenesis. Methods: To assess the effect of CR in vivo, 40 male 12 week-old NCRNu-M mice were injected with LNCaP or PC3 tumor cells. Once tumors were palpable, mice were randomly assigned to one of four treatment groups in cohorts of 10: ad libitum (AL) diet, 6.5Gy of radiation (RT), 30% reduction in caloric intake (CR), or CR+RT. Tumor growth and proliferation rate were measured 3 times per week via calipers and live bioluminescent imaging. Additionally, PCa tumor tissue were analyzed to determine if CR can exert its effect on tumor growth and metastases via IGF-1R signaling pathway. Results: Adding CR to RT decreased tumor progression. In the PC3 murine model, when compared to AL, RT reduced tumor size by 22%, 77% with CR, and 80% with CR+RT. In the LNCaP murine model, compared with AL, CR reduced tumor size by 49% and a 55% reduction with CR+RT. Primary tumor formation began 9 weeks post tumor injection in the radiated cohort and was delayed to 15 weeks post tumor injection in the CR and CT+ RT cohorts. Additionally, time to metastasis was delayed with CR (86 days to metastasis in AL, 93 with RT, and 108 when combining CR+RT). Molecularly, CR decreased multiple members of the IGF-1R signaling pathway. The total IGF-1 and IGF-1R levels exhibited 50% reduction with CR and CR+RT but total INSR levels. CR also induced a significant decrease of pGSK3β and pAKT levels. Conclusions: For the first time, we have shown that decreasing calories by 30% in both hormone-sensitive and hormone-refractory prostate cancer models, enhance the efficacy of radiation. Our experiments show that even CR alone and in combination with RT can improve PCa tumor proliferation rate, tumor burden, time to metastasis, and overall survival. We hypothesize that these changes are in part, due to the decrease of the IGF-1R signaling pathway. We propose that CR may be used as a novel therapeutic intervention to enhance outcomes of radiation treatment by altering the molecular profile of prostate tumors. Citation Format: Robert S. Gitman, Meredith LaRose, Edouard J. Trabulsi, Ajay Palagani, Tiziana DeAngelis, William K. Kelly, Leonard G. Gomella, Nicole L. Simone. Caloric restriction slows tumor growth and metastases in both hormone-sensitive and hormone-resistant prostate cancers. [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 23.
Abstract LB-278: Cancer stem cells as the novel origin of cancer-associated fibroblast-like cells
Authors: Neha Nair, Arun Vaidyanath, Kenta Hoshikawa, Anna Sanchez Calle, Tomonari Kasai, Masaharu Seno
Journal: Cancer Research (2016)

Abstract Cancer associated fibroblast (CAF) is an indispensible component of stromal microenvironment mediating cancer progression notably in breast, prostate and pancreatic carcinoma. CAF heterogeneity is attributed to its possible multiple origin majorly from tumor resident fibroblast, mesenchymal stem cells, epithelial cells. The present work analyses the possibility of cancer stem cells (CSC) as the source of CAF like cells. For this, we have used the model of CSC established in our laboratory derived from mouse induced pluripotent cells (miPSCs) by culturing with conditioned medium from cancer cell lines mimicking tumor microenvironment. In the present study, human breast cancer derived T47D and BT549 cells have been cultured to collect the conditioned medium. Since the green fluorescent protein (GFP) gene was integrated under the control of Nanog promoter in the miPSCs used in this study, the resulting CSCs was assessed by the expression of GFP for the undifferentiated state. The differentiation of CSCs was tracked by the attenuation of GFP. The CSC population was multiplied by serial subcutaneous and orthotropic transplantation in nude mice. This population was further enriched by sphere formation. Then these spheres were allowed to differentiate into adhesive cells. The CAF-like cells were separated from the differentiated population. The expression of prominent CAF markers fibroblast specific protein (FSP), fibroblast activation protein (FAP), vimentin, collagen type1 α1, and smooth muscle actin (SMA) were assessed by real time PCR. Immuno-cytochemistry of the cells for the expression of FSP, FAP and SMA was further confirmed for the evidence that cancer stem cells should be a possible source of CAF. This model should elaborate the functional heterogeneity amongst CAFs and help design therapeutic interventions to inhibit such conversions. Citation Format: Neha Nair, Arun Vaidyanath, Kenta Hoshikawa, Anna Sanchez Calle, Tomonari Kasai, Masaharu Seno. Cancer stem cells as the novel origin of cancer-associated fibroblast-like cells. [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-278.
MRI apparent diffusion coefficient in a murine orthotopic glioblastoma model as a clinically translatable early readout of efficacy for AMG 595, an antibody drug conjugate targeting EGFRvIII.
Authors: Brittany Yerby, Juan Estrada, Matthew D. Silva, Kevin J. Hamblett, Suzanne K. Coberly, John S. Hill, Sharon E. Ungersma, Pedro J. Beltran
Journal: Journal of Clinical Oncology (2013)

11095 Background: Epidermal growth factor receptor variant III (EGFRvIII) is a constitutively active mutant of EGFR present in thirty to fifty percent of glioblastoma (GBM) patients. AMG 595, currently in Phase I trials, is composed of a fully human anti-EGFRvIII-specific antibody conjugated to the maytansinoid DM1 via a non-cleavable linker. The MRI apparent diffusion coefficient (MRI ADC) has been shown to correlate with tissue cellularity, and changes in MRI ADC can be an early indicator of therapeutic efficacy. The aim of this work is to evaluate MRI ADC as a clinically translatable early readout of tissue changes due to AMG 595 treatment in a murine orthotopic GBM model. Methods: D317 human GBM cells were intracranially injected into in female CB17 SCID mice at Day 0. Mice were randomized at Day 7, using tumor volumes calculated by MRI, and were treated with vehicle, 6.5, 11, or 22 mg/kg AMG 595 i.v. twice per week, or temozolomide 10 mg/kg p.o. daily five days per week (N=8/group). MRI was repeated at days 14 and 21. Tumor volumes were manually traced on multi-slice T 2 -weighted RARE images covering the entire tumor volume. The mean MRI apparent diffusion coefficients for each tumor in the vehicle and 22 mg/kg AMG 595-treated groups were calculated from diffusion-weighted spin echo images (b = 100-1200 s/mm 2 ). Results: A dose-dependent effect of AMG 595 on tumor volume was observed at Day 21; growth was inhibited in both the temozolomide and AMG 595-treated groups (22 and 11 mg/kg) relative to vehicle (p&lt;0.0001). At Day 14, this significant treatment effect on tumor volume was not yet detectable. However, mean MRI ADC values were already significantly higher in the AMG 595 (22 mg/kg) treated group than in the vehicle group (23% higher at Day 14, p&lt;0.01 vs vehicle; 32% higher at Day 21, p&lt;0.0001 vs vehicle). The increase in MRI ADC in the AMG 595-treated group preceded observable tumor growth inhibition in the AMG 595-treated animals. Conclusions: Increases in tumor MRI ADC in response to AMG 595 treatment precede measurable inhibition of tumor growth, supporting the use of MRI ADC as a clinically relevant early biomarker for therapeutic efficacy.
AR-V7 and CTC heterogeneity biomarkers additively to predict patient (pt) outcomes with taxanes relative to approved AR targeted therapy.
Authors: Howard I. Scher, Ryon Graf, Nicole A. Schreiber, Brigit McLaughlin, David Lu, Jessica Louw, Adam Jendrisak, Stephanie Greene, Angel Rodriguez, Lyndsey Dugan, Martin Fleisher, Jerry Lee, Yipeng Wang, Mark Andrew Landers, Ryan Vance Dittamore
Journal: Journal of Clinical Oncology (2016)

5013 Background: An unmet need in the management of mCRPC is how to use approved AR signaling inhibitors (AR tx) and taxanes (T) to maximize survival for the individual patient. Pts with AR-V7+ CTCs (V7+) and, separately, high phenotypic CTC heterogeneity, demonstrate improved OS with T over AR Tx relative to pts with no V7+ CTCs and low CTC heterogeneity. We studied both markers in concert in relation to clinical outcomes. Methods: 191 blood samples from 161 unique pts were collected prior to initiation of AR Tx (n=128) or T (n=63). CTCs were detected and analyzed on the Epic Sciences platform, identifying 20 discrete phenotypic digital pathology cell features inclusive of AR & CK protein expression to define 15 unique CTC phenotypes present at variable frequencies in the samples studied. Heterogeneity, the diversity in the number of types of cells present, was quantified with a Shannon Index. Using the Epic nuclear V7 immunofluorecent assay, heterogeneity scores and V7 status were associated with outcomes alone and in combination. Results: 63 (33%) pts were identified by either the V7 or High Heterogeneity (HH) biomarkers (20 V7+/HH+; 14 V7+/HH-; & 29 V7-/HH+). The addition of HH increased clinical sensitivity by 85% over V7 alone. V7+/HH+ pts had the worst outcomes with AR Tx and favored taxane tx (80% reduction of risk, p=0.011) after adjusting for line of tx and other pre-tx markers. Compared to biomarker(-), V7+/HH- and V7-/HH+ patient classes also had worse OS with AR Tx than with T. Conclusions: Characterization of AR-V7 status and CTC heterogeneity alone identifies pts with worse outcomes on AR Tx relative to T. Used together, the results may provide significant clinical utility to individual pts by informing the decision to select a tx from which he is most likely to benefit. Prospective validation of these biomarkers is ongoing. Comparison vs V7-/HH- Univariate OS HR of AR HR of T V7+/HH+ (n=20) HR: 22.7, p < 0.0001 (n=8) HR: 3.3, p = 0.0007 (n=12) V7+/HH- (n=14) HR: 12.7, p < 0.0001 (n= 8) HR: 4.0, p = 0.005 (n= 6) V7-/HH+ (n=29) HR: 4.7, p = 0.0156 (n=17) HR: 1.4, p = 0.54 (n=12) Either Biomarker+ (n=63) HR: 7.7, p < 0.0001 (n = 33) HR: 2.6, p = 0.0142 (n = 30)
Abstract 1684: Mesothelin regulates epithelial-to-mesenchymal transition and tumorigenicity of human lung cancer and mesothelioma cells
Authors: Xiaoqing He, Liying Wang, Emily Despeaux, Yon Rojanasakul
Journal: Cancer Research (2016)

Abstract Lung cancer and malignant mesothelioma are two of the most deadly forms of cancers. The prognosis of lung cancer and mesothelioma is poor due to limited treatment modalities and lack of understanding of the underlying disease mechanisms. Mesothelin (MLSN), a plasma membrane differentiation antigen, is expressed at a high level in several human cancers, including 70% of lung cancer and nearly all mesotheliomas. Recent studies have shown that plasma and/or pleural effusion MSLN may be used as a biomarker for certain cancers and malignant pleural mesothelioma. However, the role of MLSN in lung cancer and mesothelioma is relatively unknown. In this study, we found that MLSN plays an important role in controlling epithelial-to-mesenchymal transition (EMT) and stem properties of human lung epithelial and mesothelial cells, which control their tumorigenicity. Firstly, MLSN was found to be highly upregulated in human non-small cell lung cancer tissues and in lung cancer and mesothelioma cells, as compared to normal tissues and non-tumorigenic lung epithelial and mesothelial cells. Secondly, knockdown of MLSN by RNA interference significantly reduced anchorage-independent cell growth, tumor sphere formation, and cell migration and invasion in vitro, as well as tumor formation in vivo. Thirdly, knockdown of MLSN attenuated cancer stem cell marker (ALDH) activity and several EMT markers in lung cancer and mesothelioma cell lines. These findings indicate the essential role of MLSN in EMT and malignant properties of human lung cancer and mesothelioma cells. Since EMT is an important process in tumor progression and metastasis, our finding on the role of MLSN may provide new insights into the disease mechanisms and treatment strategies for aggressive lung cancer and mesothelioma. Citation Format: Xiaoqing He, Liying Wang, Emily Despeaux, Yon Rojanasakul. Mesothelin regulates epithelial-to-mesenchymal transition and tumorigenicity of human lung cancer and mesothelioma cells. [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 1684.
Abstract 1476: A therapeutic antibody that inhibits CD73 activity by dual mechanisms
Authors: Bryan C. Barnhart, Emanuela Sega, Aaron Yamniuk, Sandra Hatcher, Ming Lei, Haben Ghermazien, Anne Lewin, Xi-Tao Wang, Haichun Huang, Pingping Zhang, Alan Korman
Journal: Cancer Research (2016)

Abstract CD73 has a central role in dictating the adenosine concentration within the tumor as it is the final step in converting extracellular ATP to adenosine. Thus, substantial reduction of CD73 enzymatic activity has the potential to reduce immunosuppression of effector immune cells within the tumor. We present data describing an anti-human CD73 antibody that suppresses CD73 by two mechanisms: 1. direct inhibition of enzymatic activity upon binding to CD73 and 2. rapid, near-complete internalization of the enzyme. Durable reduction of cell-surface CD73 was observed in multiple tumor cell lines both in vitro and in vivo. The unique properties of this antibody are a result of the use of a human IgG2-IgG1 hybrid antibody with effector function eliminated by specific mutations of the Fc. The IgG2 sequence of this antibody drives superior internalization of CD73 and enhanced CD73 inhibition. Syngeneic tumor models demonstrate that CD73 contributes to resistance to anti-tumor therapy. Combination therapy with PD-1 blockade and a surrogate anti-mouse-CD73 antibody resulted in a better anti-tumor efficacy than either treatment alone. Finally, we demonstrate a novel technique for assessing CD73 enzymatic activity in situ that has potential for clinical application. These data support antibody-based anti-CD73 therapy in cancer and highlight a novel mechanism for inhibition of CD73 enzymatic activity. Citation Format: Bryan C. Barnhart, Emanuela Sega, Aaron Yamniuk, Sandra Hatcher, Ming Lei, Haben Ghermazien, Anne Lewin, Xi-Tao Wang, Haichun Huang, Pingping Zhang, Alan Korman. A therapeutic antibody that inhibits CD73 activity by dual mechanisms. [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 1476.
Recombinant fusion ESAT6-CFP10 immunogen as a skin test reagent for tuberculosis diagnosis: an open-label, randomized, two-centre phase 2a clinical trial
Authors: F. Li, M. Xu, C. Qin, L. Xia, Y. Xiong, X. Xi, X. Fan, J. Gu, J. Pu, Q. Wu, S. Lu, G. Wang
Journal: Clinical Microbiology and Infection (2016)
Phase II study of induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil for patients with node-positive esophageal cancer.
Authors: M. Watanabe, Y. Nagai, S. Iwagami, Y. Miyamoto, N. Hayashi, H. Baba
Journal: Journal of Clinical Oncology (2010)

e14535 Background: Despite an extended radical surgery, the prognosis of patients with esophageal cancer is still unsatisfactory, especially in cases with lymph node metastasis. Although the usefulness of neoadjuvant chemotherapy for node-positive esophageal cancer has been reported, an optimal regimen has not yet been established. This phase II study explores the efficacy and toxicity of docetaxel/cisplatin/5-FU (DCF) as induction chemotherapy for node-positive esophageal cancer. Methods: The modified DCF consisted of 60 mg/m2 of docetaxel on day1, given intravenously for 2 hours, 350 mg/m2 of 5-FU on day 1-5 as a 24-hour continuous intravenous infusion, and 6 mg/m2 of cisplatin on day 1-5, given intravenously for 1 hour. The regimen was given every 3 weeks and 2 scheduled courses has completed in all cases. Eligibility criteria were: i) a pathlogically defined esophageal cancer, ii) lymph node metastasis observed with PET/CT or US, iii) no previous treatment, iv) ECOG PS of 0 to 2, v) an age of 20 -80, and iv) adequate bone marrow, renal and hepatic function. Primary endpoint Treatment effect was evaluated according to RECIST v1.0. Changes in SUV with FDG-PET scan and tumor markers (SCC, CEA) were also used for the evaluation of efficacy, while adverse events were assessed according to CTCAE v3.0. Pathological response was evaluated in 26 resected cases. Results: CR and PR were observed in 5 (9.8%) and 25 (49.0%), respectively. SUV of the primary tumors reduced in 46 cases (90.2%) during the chemotherapy and the mean value was decreased from 14.1 to 7.0 (p < 0.0001). SCC was decreased in 25 out of 30 elevated cases (p = 0.029), while CEA reduced in 14 out of 16 elevated cases (p = 0.17). Down-staging was observed in 15 resected cases (57.7%), including 10 cases (38.7%) with pathlogical N0. Pathological complete response was observed in 3 cases. Grade 3 or 4 neutropenia was seen in 43 cases (84.3%), but neither treatment-related death nor delay in the treatment was observed. Conclusions: Induction chemotherapy with modified DCF is highly efficient with acceptable toxicity for patients with node-positive esophageal cancer. No significant financial relationships to disclose.
A phase I study of two different schedules of nab-paclitaxel (nab-P) with ascending doses of vandetanib (V) with expansion in patients (Pts) with pancreatic cancer (PC).
Authors: A. B. El-Khoueiry, S. Iqbal, H. Lenz, B. J. Gitlitz, D. Yang, S. Cole, V. Duddalwar, A. Garcia
Journal: Journal of Clinical Oncology (2011)

4124 Background: nab-P is an albumin bound paclitaxel. V is a potent inhibitor of VEGFR 2, RET and EGFR. Preclinical data reveal enhanced nab-P activity with concurrent VEGF inhibition. Primary objective was to determine the maximum tolerated dose (MTD). A secondary objective was to assess preliminary efficacy in pts with PC. Methods: Pts were randomized to one of 2 cohorts. Dose of nab-P was fixed (Cohort A: nab-p 100 mg/m2 IV weekly for 3 wks q 28 days; Cohort B: nab-P 260 mg/m2 IV q 3 wks) while 3 doses of V were evaluated (100 mg, 200 mg, 300 mg orally daily). A 3+3 design was used. Expansion at the MTD (15 pts) was planned in both cohorts. Cohort A expansion was restricted to PC pts who failed gemcitabine based therapy. Two single nucleotide polymorphisms (SNPs), SPARC rs1059829 and rs3210714, were evaluated by PCR-RFLP on genomic DNA extracted from peripheral whole blood in 25 pts. Results: Dose escalation results were presented at ASCO 2010 (J Clin Oncol 28:15s, 2010 suppl; abstr 3059).There was one DLT at each dose level in cohort A (grade 3 rash in 2 pts, grade 4 neutropenia in 1 pt). No DLTs observed in cohort B. MTD was nab-P 100 mg/m2 IV weekly for 3 /4 wks and V 300 mg daily in cohort A; nab-P 260 mg/m2 IV q 3 wks and V 300 mg daily in cohort B. 29 pts with PC were treated: 9 (cohort A dose escalation), 15 (cohort A dose expansion) and 5 (cohort B). Median age was 62; 16 males, 13 females. Median number of prior treatments 2 (range 1-4). 22 pts with PC were evaluable for response: 6 (27.5%) PR, 10 (45%) SD and 6 (27.5%) PD. Median PFS was 5.3 mo (95% CI: 3.7-7.3) and median OS 8.2 mo (95% CI: 6.2 -11.5). No statistically significant association was found between SNPs in SPARC and clinical outcome. Conclusions: Both schedules of nab-P with V are well tolerated. The MTD for both cohorts is the maximum planned dose. The preliminary efficacy in a cohort of pts with refractory PC is promising and warrants further evaluation. Grade 3 or 4 toxicities for all pts in all cycles Cohort A% Cohort B% Neutropenia 31 48 Diarrhea 13 12 Leukopenia 10 16 Acneiform rash 15 8 Fatigue 10 4 Hypertension 5 12 Prolonged QTC 5 8 Thombosis 8 4 Joint pain 5 4 Muscle pain 5 4 Anorexia 5 0 Dyspnea 5 0 Nausea 5 0 Pruritus 5 0
Abstract 3343: Targeting the Lin28A/B axis reverts stem cell-like phenotype and tumor-initiating properties in prostate cancer
Authors: Domenico Albino, Gianluca Civenni, Cecilia Dallavalle, Martina Roos, Hartmut Jahns, Jonathan Hall, Giuseppina M. Carbone, Carlo V. Catapano
Journal: Cancer Research (2016)

Abstract Cancer stem cells (CSCs) represent the most tumorigenic, metastatic and therapy resistant cell subpopulation within human tumors. Current therapies target bulk tumor cells while spare the most aggressive CSC subpopulation. Understanding the mechanisms responsible for the acquisition and maintenance of the CSC phenotype will help to identify new strategies to target CSCs. In this study, we describe a link between deregulated expression of the ETS transcription factor ESE3/EHF and upregulation of Lin28A and Lin28B in prostate CSC-enriched subpopulations. Furthermore, using various cell line models and in vitro/in vivo experimental systems we demonstrate the efficacy of targeting the Lin28A/B axis for selective elimination of cancer cells with tumor-initiating and stem-like properties. Mechanistically, we found that ESE3/EHF represses transcription of Lin28A and Lin28B in normal prostate epithelial cells. Downregulation of ESE3/EHF in prostate tumors led to upregulation of Lin28A and Lin28B and consequent reduction of microRNAs (miRNAs) of the let-7 family, which exert tumor suppressor functions. These events promoted cell transformation and expansion of the prostate CSC subpopulation. Conversely, targeting Lin28A/Lin28B with small interfering RNAs (siRNAs) in transformed prostate epithelial cells and prostate cancer cell lines restored the levels of let-7 miRNAs, decreased expression of several CSC marker genes, and restrained tumor-sphere formation and self-renewal properties in vitro and tumor-initiating capability in vivo. Notably, systemic treatment with a siRNA targeting Lin28B reduced growth of prostate tumor xenografts in mice. This was associated with a significant contraction of the CSC subpopulation in tumor xenografts, as demonstrated by the reduced content of ex vivo tumor-sphere forming cells, reduced expression of CSC marker genes, and upregulation of let-7 miRNAs. Furthermore, tumor cells derived from siLin28B-treated xenografts exhibited reduced in vivo tumor-initiating and self-renewal capability, in line with a persistent loss of CSC properties. Collectively, these data establish the Lin28/let-7 axis as a critical element in malignant transformation and acquisition of tumor-initiating and stem-like properties and identify a valid therapeutic strategy to antagonize CSCs in human prostate cancer. Citation Format: Domenico Albino, Gianluca Civenni, Cecilia Dallavalle, Martina Roos, Hartmut Jahns, Jonathan Hall, Giuseppina M. Carbone, Carlo V. Catapano. Targeting the Lin28A/B axis reverts stem cell-like phenotype and tumor-initiating properties 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 3343.
Identification and Validation of IMiD-14 Model Predictive of IMiD Resistance in Multiple Myeloma
Authors: Manisha Bhutani, Qing Zhang, Sarah A Baxter, Lawrence J Druhan, Bart Barlogie, Pieter Sonneveld, Belinda R Avalos, Edward A. Copelan, Saad Z Usmani
Journal: Blood (2015)