bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 395: Patient stratification and drug combination strategy based on drug response and genomic information from PDX clinical trials (PCTs)
Authors: Jiang Jingjing , Yu Tengfei , Yan Ying , Du Wei , Tan Tingting , Yang Xuqin , Gu Jiali , Ye Xin K. , Gu Zhenyu 
Published: July 2016

Abstract
Cancer is a heterogeneous disease with various molecular lesions and drug response profiles within the same tumor type. Patient stratification in clinical trials based on molecular features has contributed to recent success of several targeted cancer drugs on molecular aberrations such as BCR-ABL translocation in CML, Her2 amplification in breast and gastric cancers, EGFR mutations and ALK fusions in lung cancer and BRAF mutation in melanoma. However, in most cancers, the molecular features which can be used for patient stratification are not as simple as a single genetic aberration. Multiple drug resistance mechanisms caused by various mutations in cancer signaling pathways can also increase the uncertainty of clinical outcomes.
To increase the chance of success in human clinical studies, patient-derived xenograft (PDX) clinical trials (PCTs) have increasingly been used for predictive biomarker validation, resistance mechanism investigation and combination therapy selection. PDX tumor models have been demonstrated to have high correlations with human patients in tumor pathology, molecular characteristics and drug responses. Large scale PCTs have also shown consistency in results when compared to related human clinical trials.
At GenenDesign, we have established over 1000 PDX tumor models and more than 100 resistance models against various cancer drugs. Many of these PDX models have been characterized at RNA/Exome sequence, gene expression, gene copy number and hot-spot mutation levels. We carried out our PDX clinical trials by testing multiple approved drugs and clinical drug candidates such as targeted inhibitors against FGFRs, c-Met/ALK, HER2, EGFR, cell cycle regulators, Ras/Raf pathway, PI3K/Akt pathway, as well as chemotherapy drugs in biomarker-driven multi-drug multi-arm expanded PDX clinical trials. So far, we have accumulated more than 3000 efficacy data sets and associated PD samples.
Analysis of drug response and associated genomic information from PDX clinical trials yielded rich information for predictive biomarker identification and validation. At the same time, many potential resistance mechanisms were also revealed. These information can make human clinical trial better prepared, more efficient and focused. More importantly, testing of a targeted drug with multiple chemotherapies in the same models can also provide guidance on future combination selection strategy.
Citation Format: Jingjing Jiang, Tengfei Yu, Ying Yan, Wei Du, Tingting Tan, Xuqin Yang, Jiali Gu, Xin K. Ye, Zhenyu Gu. Patient stratification and drug combination strategy based on drug response and genomic information from PDX clinical trials (PCTs). [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 395.
Abstract 3950: Optimization of a method for FACS analysis of checkpoint receptor expression on tumor infiltrating lymphocytes in clinical tumor samples
Authors: Zhang Norman , Zhang Qiyao , Liu Yan , Yu Juntao , Wang Jingjing , Xu Jie , Ji Qunsheng , Wilcoxen Keith , Graves Jonathan 
Published: July 2016

Abstract
While immune checkpoint therapies against CTLA-4, PD-1 and PD-L1 have achieved promising clinical outcome recently, the dynamic therapeutic responses spanning individual patients and different cancer types warrant exploration and validation of additional therapeutic strategies. Since the expression of immune checkpoints in tumor infiltrating lymphocytes (TIL) has been of interest to the field, we attempted to analyze the expression of several checkpoint receptors on TILs in clinical tumor samples. Unexpectedly, a number of markers were subject to time-dependent degradation during the tissue disaggregation process. This degradation could be due to the proteolytic activity of a proteinase, which has been used commonly in various tissue disaggregation protocols. Analysis of the protein sequences verified the presence of the proteinase recognition sequences in the affected receptors. Using PHA-stimulated hPBMCs, we found and demonstrated that a specific protease was responsible for either partial or total degradation of these markers. To overcome this issue, we developed a protease-free tissue disaggregation method, which showed no adverse effect on protease affected cell membrane receptors, thus allowing for more reliable flow cytometric analysis of various TIL subpopulations. With this method, we analyzed these checkpoint receptors positivity of both CD4+ and CD8+ TILs and revealed a high degree of heterogeneity of these immune checkpoints in a number of tumor types, including lung, breast and gastric cancers. Analysis of the magnitude of lymphocyte infiltration to the tumor and expression of prominent immune checkpoints on CD4+ or CD8+ TILs will help understand the subtle interaction between tumor and the immune system in the tumor microenvironment and may provide guidance for clinical trials of novel combinatorial immuno-therapeutic strategies.
Citation Format: Norman Zhang, Qiyao Zhang, Yan Liu, Juntao Yu, Jingjing Wang, Jie Xu, Qunsheng Ji, Keith Wilcoxen, Jonathan Graves. Optimization of a method for FACS analysis of checkpoint receptor expression on tumor infiltrating lymphocytes in clinical tumor samples. [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 3950.
Abstract 3954: Prospective evaluation of circulating tumor cells (CTCs) in head and neck cancer patients receiving definitive radiotherapy with a nanotechnology based system
Authors: Caster Joseph M. , Eblan Michael J. , Wang Kyle , Myung Ja Hye , Chera Bhishamjit , Hong Seungpyo , Wang Andrew Z. 
Published: July 2016

Abstract
Background: Circulating tumor cells (CTCs) are an important biomarker in cancer. There has been substantial interest in utilizing CTCs to enable personalized treatment. However, there is limited data on CTCs in patients with head and neck cancers (HNC) where there is growing data that curative treatment needs to be risk-based. The purpose of this prospective, correlative study is to investigate the clinical significance of CTCs, as measured by a highly sensitive CTC capture technology UiChip, in HNC patients undergoing definitive treatment.
Methods: HNC patients (M0) undergoing definitive treatment (radiation+/- chemotherapy) were enrolled. Peripheral blood was collected prior to starting RT, at the first week, mid-point, final week of treatment, and every 4 to 12 weeks after completion. Quantification of CTCs was conducted using UiChip. The primary endpoint was change in CTCs pre- and post- RT.
Results: 35 patients are included in this analysis (median age 58, 34% non-smokers, 69% HPV/p16 positive, and 17% node (-)) and 90% received chemotherapy. CTCs were detected in all patients pre-RT (100%). There was no association between pre-RT CTC level and tumor or nodal stage. Median CTCs significantly decreased from 71 CTCs/mL (range, 7-849) before RT to 32 (2-209) at completion of RT and 27 (2-78) at 4 to 12 weeks post-treatment. Ten patients had persistent disease and/or distant metastasis at a median follow-up of 10.6 months (range, 3.7-17). CTCs declined throughout treatment in patients with complete clinical and/or radiographic responses, in contrast to an elevation in CTCs at mid or post-RT in the 7 patients with pathologic residual disease/distant failures.
Conclusions: We demonstrated that the novel UiChip can capture CTCs in a diverse population of head and neck cancer patients. Our pilot data suggest that individual patient CTC changes during and after treatment may be a predictive biomarker for radiotherapy response and clinical outcomes. Table: Median CTCs/mL Peripheral Blood (Median% of Pre-Treatment Baseline Count)Pre-RTMid-RTPost-RTNumber (%) of CTCs in Complete Responders to RT (N = 18)67 IQR: 39-11737 (38%) IQR: 22-79 (18-94%)21 (18%) IQR: 7-40 (13-42%)Number (%) of CTCs in Partial Responders to RT (N = 7)120 IQR: 36-30366 (123%) IQR: 20-134 (30-172%)51 (45%) IQR: 23-54 (17-63%)
Citation Format: Joseph M. Caster, Michael J. Eblan, Kyle Wang, Ja Hye Myung, Bhishamjit Chera, Seungpyo Hong, Andrew Z. Wang. Prospective evaluation of circulating tumor cells (CTCs) in head and neck cancer patients receiving definitive radiotherapy with a nanotechnology based system. [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 3954.
Abstract 3978: Lipid tethering to enable real-time imaging of breast tumor cell cytoskeletal dynamics and rapid drug testing in free-floating metastatic microenvironments
Authors: Chakrabarti Kristi Riti , Andorko James , Whipple Rebecca , Zhang Peipei , Sooklal Elisabeth , Jewell Christopher , Martin Stuart 
Published: July 2016

Abstract
Free-floating tumor cells located in the peripheral circulation of cancer patients, known as circulating tumor cells (CTCs), play an important role in cancer and have become key targets for studying metastasis. The presence of CTCs in the bloodstream or lymphatics correlates with decreased cancer patient survival and provides a minimally invasive method to study disease progression and treatment response. Understanding the molecular characteristics and functional properties of CTCs have been impeded by the challenges of imaging CTCs under conditions that model the free-floating microenvironments of the circulation. Upon extracellular-matrix (ECM) detachment, breast tumor cells form tubulin-based protrusions known as microtentacles (McTNs) that play a role in the aggregation and re-attachment of tumor cells to increase their metastatic efficiency. In this study, we have designed a strategy to spatially immobilize ECM-detached tumor cells within a microfluidic device while maintaining their free-floating character. We use cytophobic polyelectrolyte multilayers deposited on microfluidic substrates to prevent tumor cell adhesion and the addition of lipid moieties to tether tumor cells to these surfaces through interactions with the cell membrane. This approach enables high-resolution time-lapse microscopy of McTNs on viable free-floating tumor cells and real-time analysis of dynamic cellular features. In addition, tethering makes it now possible to rapidly measure drug responses of tumor cells in free-floating microenvironments to select effective therapies and avoid drugs that could inadvertently increase metastasis. The ability to image tumor cells in the absence of ECM attachment can immensely enhance our understanding of CTCs under conditions that better recapitulate the free-floating microenvironments that tumor cells encounter during metastasis.
Citation Format: Kristi Riti Chakrabarti, James Andorko, Rebecca Whipple, Peipei Zhang, Elisabeth Sooklal, Christopher Jewell, Stuart Martin. Lipid tethering to enable real-time imaging of breast tumor cell cytoskeletal dynamics and rapid drug testing in free-floating metastatic microenvironments. [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 3978.
Abstract 3982: Prediction and selection of cancer drug treatments using personalized tumor models or models with matching genomic profiles
Authors: Jiang Jingjing , Yan Ying , Luo Zhongguang , He Jia , Yu Tengfei , Du Wei , Yang Xuqin , Gu Jiali , Ye Xin K. , Zhuang Guanglei , Liu Jie , Gu Zhenyu 
Published: July 2016

Abstract
The main purpose of precision medicine is to find the right drug for the right patient at the right time. Current progress in cancer drug target identification and development of new targeted drugs has presented many successful examples. However, for majority of patients, finding treatments based on the unique mutations in their own tumor cells are still hard. New approaches for precision medicine are in great needs and thus being investigated.
A mouse “avatar”, also known as Patient-Derived Xenograft (PDX) model, is a personalized cancer model derived from a patient tumor sample and used to test different drugs for the patient. “GIFTS” (or Genomic Information Fitting based Therapeutics Selection) is a method with which a patient's cancer genomic information is compared to PDX model genomic profiles to find the best genomic fit and related therapeutic options in GenenDesign Drug Response Database and Genomic Information database.
So far we have successfully derived more than 1000 PDX models from patient tumor tissues of various cancer types including lung, gastric, liver, esophageal, colorectal, pancreatic and many other cancers. In some cases, both patients and their avatars were tested with same cancer drugs including targeted drugs and chemotherapies. By comparing drug responses in mouse avatars with patient clinical results, we found high correlations between them in both sensitivity and unresponsiveness.
We have also developed a bioinformatics algorithm to analyze PDX model genomic and drug response information. Both drug sensitivity and resistance biomarkers have been used in matching cancer patient genomic profiles to those of PDX models in GenenDesign database as a part of our GIFTS method. Our preliminary results show that there are high degree of similarities in drug response profiles between patients and their matched PDX models.
Avatar and GIFTS methods can provide predictions of therapeutic effectiveness on both targeted drugs and chemotherapies. Avatar is a drug screening based method, while GIFTS is a genomic profile matching based method. Both methods are especially useful for patients, whose tumors could not be treated with known targeted drugs.
Citation Format: Jingjing Jiang, Ying Yan, Zhongguang Luo, Jia He, Tengfei Yu, Wei Du, Xuqin Yang, Jiali Gu, Xin K. Ye, Guanglei Zhuang, Jie Liu, Zhenyu Gu. Prediction and selection of cancer drug treatments using personalized tumor models or models with matching genomic profiles. [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 3982.
Abstract 3986: Diagnostic significance of cathepsin L and cathepsin B expression in human gallbladder cancer - A pilot study
Authors: MEHRA SIDDHARTH , KUMAR MANISH , PANWAR RAJESH , DASH NIHAR RANJAN , SINGH RATNAKAR , YADAV RAJNI , GUPTA SIDDHARTHA DATTA , SAHNI PEUSH , CHAUHAN SHYAM S. 
Published: July 2016

Abstract
Background: Gallbladder cancer (GBC) is the most common biliary tract malignancy worldwide. Cancer of gallbladder usually refers to as an Indian disease as it is more common in Indian subcontinent especially in north and central India. Incidence rate of GBC in women in Delhi is as high as 21.5 per 100,000 population. It is an aggressive malignancy, which spreads locally to liver, adjacent organs and lymph nodes as well as to distant organs. Cathepsin L (CTSL) and B (CTSB) are lysosomal cysteine proteases implicated in protein turnover and tissue remodeling. Deregulated expression of these proteases has been associated with invasion and metastasis in several solid tumors.
Objective: To assess the expression and clinical significance of CTSL and CTSB in human gallbladder cancer.
Methods: We assayed the activities of CTSL and CTSB via spectroflurometrically in whole tissue lysates of gallbladder cancer patients (N = 23) and normal gall bladder tissue samples with gallstones (N = 31) / without gallstones (N = 34), which served as controls. Activities of these proteases were correlated with several clinic pathological parameters in GBC patients. CTSL and CTSB mRNA levels were determined in tissues samples by Real time PCR. Furthermore serum levels of these proteases were also assayed using sandwich based ELISA in GBC patients and controls.
Results: Significant increase in the enzymatic activities of CTSL+B, CTSL and CTSB was observed in gallbladder cancer tissue samples in comparison to normal gall bladder both with and without gallstones (p &lt; 0.001). ROC analysis confirmed the diagnostic relevance of CTSL and CTSB analysis with area under the curve 0.791 and 0.840 respectively for gallbladder cancer patients with respect to controls. Over expression of CTSB was also significantly associated with involvement of lymph node (p = 0.05) in gall bladder carcinoma. Secretory levels of CTSL and CTSB in serum were significantly elevated in GBC patients (p &lt;0.01). Increased expression of these cysteine proteases were also confirmed at the mRNA level by Real time PCR.
Conclusion: Our study for the first time demonstrated a significant increase in the levels of cathepsin L and B in GBC patients as compared to controls. Elevated levels of these proteases may serve as potential biomarkers for human gall bladder cancer.
Citation Format: SIDDHARTH MEHRA, MANISH KUMAR, RAJESH PANWAR, NIHAR RANJAN DASH, RATNAKAR SINGH, RAJNI YADAV, SIDDHARTHA DATTA GUPTA, PEUSH SAHNI, SHYAM S. CHAUHAN. Diagnostic significance of cathepsin L and cathepsin B expression in human gallbladder cancer - A pilot 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 3986.
Abstract 3993: Th1 cytokines regulate apoptotic cell death and HER family RTK expression in murine and human breast cancer lines
Authors: Namjoshi Prachi M. , Showalter Lori , Czerniecki Brian , Koski Gary K. 
Published: July 2016

Abstract
A recent neoadjuvant vaccine trial to treat early breast cancer demonstrated powerful induction of Th1 immunity against the HER-2, complete pathologic responses in over 18% of subjects, and for many subjects, evidence of down-regulated HER-2 expression on residual disease. To explain these observations, we investigated the action of archetypical Th1 cytokines (TNF-α + IFN-γ) on both murine and human breast cancer cell lines that varied in the surface expression of HER-family receptor tyrosine kinases. We found that most tumor cell lines were sensitive to dual Th1 cytokines as evidenced by lower metabolic activity (alamar blue assay), lower proliferation, and enhanced apoptosis (AnnexinV/PI staining and TUNEL assay) as well as a reversible inhibition of surface expression of HER proteins. Apoptotic cell death was accompanied by demonstrated increases in activated caspase-3. Furthermore, the pharmacologic caspase-3 activator, procaspase-activating compound (PAC-1), mimicked both the killing effects and HER-2 suppressive activities of Th1 cytokines, while the caspase 3/7 inhibitor ((5-[(S)-(+)-2-(Methoxymethyl)pyrrolidino]sulfonylisatin), prevented cytokine-induced HER-2 downregulation. These studies therefore demonstrated that many of the in vivo effects of vaccination (apparent tumor cell death and loss of HER-2 expression) could be replicated in vitro using only the principle Th1 cytokines. These findings are consistent with the notion that IFN-γ and TNF-α work in concert to mediate some of the biological effects of therapeutic Th1-polarizing vaccination through the induction of a caspase 3-dependent cellular death mechanism.
Citation Format: Prachi M. Namjoshi, Lori Showalter, Brian Czerniecki, Gary K. Koski. Th1 cytokines regulate apoptotic cell death and HER family RTK expression in murine and human breast cancer lines. [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 3993.
Abstract 4013: Transcriptionally mediated effects of radiation on the expression of immune susceptibility markers in murine and human melanoma
Authors: Werner Lauryn R. , Gressett Monica , Riegert Maureen , Huang Shyhmin , Kern Joseph G. , Erbe Amy , Harari Paul M. , Sondel Paul M. , Morris Zachary S. 
Published: July 2016

Abstract
Radiation therapy (RT) may enhance tumor susceptibility to immune response. We and others have observed a cooperative interaction between RT and various immunotherapies, which appears dependent on the relative sequencing of each therapy. We reported a synergistic interaction between RT and the antibody-dependent cell-mediated cytotoxicity (ADCC) response to tumor-specific monoclonal antibodies (mAb) in murine melanoma. We reported enhanced cooperative effect when immunotherapy is administered 6-10 days after RT compared to administration on days 1-5 or 11-15. We hypothesized that this might reflect a delayed, transcriptionally-mediated effect of RT on the expression of tumor markers of immune susceptibility. In this study, we investigated the effect of RT on a variety of immune susceptibility markers at both transcriptional and post-translational levels to explore mechanisms behind the observed RT-induced changes.
We used flow cytometry to examine the time course of phenotypic changes in immune susceptibility markers in B78 murine melanoma cells following in vitro RT. We observed a time- and RT dose-dependent increase in the expression of specific death receptors (Fas, DR5), as well as T cell co-stimulatory/co-repressor ligands (PD-L1, CD80). The timing of these changes correlated with tumor susceptibility to ADCC immune response in vivo. All protein expression changes observed by flow cytometry were found to occur over a similar time course by quantitative polymerase chain reaction (qPCR), suggesting that RT-induced protein expression changes were mediated by changes in transcriptional activity. Using high throughput qPCR, we observed a similar time course of transcriptional effects in additional markers of tumor cell immune susceptibility, including Fas, MHC I, CD40, and others. We compared the effect of RT on these markers in human and mouse melanoma cell lines and observed a comparable time course for transcript-level changes across species.
This study sheds light on the mechanistic basis of time sensitivity in the interaction of RT with ADCC in vivo and suggests opportunities to enhance anti-tumor immune response by combining RT and immunotherapeutic agents. Such findings bear relevance for research investigating the potential role for RT in driving and optimizing the response to various cancer immunotherapies.
Citation Format: Lauryn R. Werner, Monica Gressett, Maureen Riegert, Shyhmin Huang, Joseph G. Kern, Amy Erbe, Paul M. Harari, Paul M. Sondel, Zachary S. Morris. Transcriptionally mediated effects of radiation on the expression of immune susceptibility markers in murine and human 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 4013.