tbuckley/cabot-search huggingface dataset:
Abstract CT084: Long-term exposure (LTE) to Tislelizumab, an investigational anti-PD-1 antibody, in a first-in-human Phase I study
Authors: Jayesh Desai, Benjamin Markman, Michael Friedlander, Hui Gan, Lisa Horvath, Amanda Townsend, Michael Millward, Michael Jameson, Chia-Jui Yen, Ming-Mo Hou, Jeannie Hou, John Wu, Liang Liang, Sanjeev Deva
Journal: Cancer Research (2019)

Abstract Background Tislelizumab (BGB-A317), an investigational monoclonal antibody with high affinity and specificity for PD-1, was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. Previous reports from early phase studies suggest tislelizumab was generally well tolerated and had antitumor activity in patients (pts) with advanced solid tumors. Clinical effects of tislelizumab LTE (&amp;gt;12 mo) in pts enrolled in the first-in-human study (NCT02407990) are presented here. Methods Patients with advanced solid tumors received IV tislelizumab 0.5, 2, 5, or 10 mg/kg Q2W, 2 or 5 mg/kg administered Q2W or Q3W, or 200 mg IV Q3W. Antitumor activity was assessed by RECIST v1.1 criteria; PD-L1 expression was retrospectively assessed with the VENTANA PD-L1 (SP263) assay. Results As of 31 Aug 2018, 63 of the 451 pts received tislelizumab for &amp;gt;12 mo. In these 63 pts, median age was 64 yr and 70% had received ≥1 prior systemic therapy. Tislelizumab LTE was most common in NSCLC (n=9), HCC (n=7), and bladder and ovarian (n=5 each) cancers. Four of the 5 pts who achieved CR during this study had LTE to tislelizumab (Table); all 4 pts were PD-L1+ (≥1% expression on tumor cells). Across the LTE cohort, ORR was 66.7%; PR and SD were observed in both PD-L1+ and PD-L1- tumors. The median time to CR/PR (3.7 mo) and duration of CR/PR (21.1 mo) were longer in pts with LTE than pts who responded but did not remain on treatment for &amp;gt;12 mo (2.1 and 6.3 mo, respectively). Rash was the only treatment-related AE (TRAE) reported in ≥15% of pts. Most TRAEs were of mild or moderate severity; arthritis, diarrhea, fatigue, granuloma, hyperglycemia, and lichenoid keratosis (n=1 each) were the only grade ≥3 TRAEs reported with tislelizumab LTE. Conclusion Tislelizumab remained well tolerated for &amp;gt;12 mo and elicited durable responses in pts with a variety of tumor types regardless of PD-L1 status. PD-L1+ (n=35)PD-L1- (n=22)Missing (n=6)Total (N=63)CR4004 (6.3%)PR2113438 (60.3%)SD99220 (31.7%)PD1001 (1.6%)Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD stable disease. Citation Format: Jayesh Desai, Benjamin Markman, Michael Friedlander, Hui Gan, Lisa Horvath, Amanda Townsend, Michael Millward, Michael Jameson, Chia-Jui Yen, Ming-Mo Hou, Jeannie Hou, John Wu, Liang Liang, Sanjeev Deva. Long-term exposure (LTE) to Tislelizumab, an investigational anti-PD-1 antibody, in a first-in-human Phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT084.
Abstract 2654: Synergistic inhibition of cancer cell viability and suppression of HIF1α by CDK4 inhibitors and HSP90 inhibitors across cancer types
Authors: Shuai Zhao, Lanlan Zhou, David T. Dicker, Wafik S. El-Deiry
Journal: Cancer Research (2019)

Abstract Hypoxia is common and hypoxia-inducible factor 1α (HIF1) promotes various aspects of cancer, such as angiogenesis, or metastasis, and confers therapy resistance. Targeting HIF’s is a promising cancer treatment strategy. We previously showed that cyclin-dependent kinase 1 and 4 (CDK1, CDK4) stabilize HIF1α protein in cancer cells (Warfel et al., Cell Cycle, 2013). We also found that CDK activity facilitates HSP90 stabilization of HIF1α and that targeting CDK1 or CDK4/6 and HSP90 simultaneously reduces HIF1α levels and inhibits colorectal cancer (CRC) cell viability. The CDK4/6i palbociclib plus HSP90i ganetespib synergistically inhibit cell viability in HCT116 CRC cells under normoxia and hypoxia, show anti-tumor efficacy in vivo, and reduce both HIF1 and HIF2 levels. To investigate the translational potential of the combination strategy, we explored use of a HSP90i in clinical trials as no HSP90i has been FDA-approved for cancer treatment. Onalespib is a HSP90i undergoing phase I trials for solid tumors and lymphoma. and XL888 is being tested in GI cancer and melanoma. A third HSP90i, TAS116, is under investigation in solid tumors. We found that all these HSP90 inhibitors, in combination with palbociclib, reduce HIF1α levels in CRC cells. Cell viability was inhibited by the combination treatment in a synergistic manner. Similar effects were observed in pancreatic cancer, breast cancer and other tumor types upon treatment with TAS116 and palbociclib. As palbociclib is not the only FDA-approved CDK4/6 inhibitor, we examined the anti-tumor effects of HIF targeting effect using an alternative FDA-approved CDK4/6 inhibitor, abemaciclib. Abemaciclib, in combination with TAS116, decreased HIF1α levels and inhibited cancer cell viability. Our findings demonstrate a class effect towards HIF1α inhibition and cancer cell viability across multiple tumor types from the combination of a CDK4/6i and HSP90i. Ongoing experiments are examining the role of HIF in the sensitivity to the drug combination and the impact of the combined inhibitor therapy on cancer cell migration and invasion. Further clinical translation of this concept is warranted for cancer therapy. Citation Format: Shuai Zhao, Lanlan Zhou, David T. Dicker, Wafik S. El-Deiry. Synergistic inhibition of cancer cell viability and suppression of HIF1α by CDK4 inhibitors and HSP90 inhibitors across cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2654.
Abstract 4795: Oxidative stress by proguanil suppresses breast tumor growth
Authors: Nehal Gupta, Sanjay Srivastava
Journal: Cancer Research (2019)

Abstract Breast cancer is one of the most common malignancies and the second leading cause of cancer related mortality among women in U.S., thus developing new strategies to control breast cancer is an important mission. Repurposing of old drugs as new anti-cancer drugs is important as it can save time and cost of drug development. Proguanil is used in combination with atovaquone for the treatment of malaria. In this study, we determined the anticancer effects of proguanil in breast cancer cells. Proguanil significantly reduced the viability of MDA-MB-231, HCC1806 and MCF-7 breast cancer cells with IC50 of 42μM, 44μM and 40μM respectively after 72 h of treatment and induced apoptosis as exhibited by FITC/Annexin assay and cleavage of caspase 3 as well as PARP. Proguanil also reduced the survival of several patient-derived cells with IC50 in the range of 30-40μM. The anti-cancer effects of proguanil were associated with the generation of ROS and persistent disruption of mitochondrial membrane potential. ROS generation by proguanil was about 2-3 fold more as compared to control in MDA-MB-231 and HCC1806 cells. The generation of ROS was inhibited when the cells were pretreated with a general antioxidant N-acetyl cysteine (NAC). Moreover, exposure of MDA-MB-231 and HCC1806 cells to proguanil was also associated with increased expression of Bax, p-H2AX, c-caspase9 and down-regulation of bcl-2 and survivin. We further evaluated the oxygen consumption rate with proguanil treatment in breast cancer cells using flux analyzer. Our results showed significant decrease in the mitochondrial respiration rate and ATP production rate after proguanil treatment. Furthermore, 20mg/kg proguanil when given orally suppressed the growth of 4T1 breast tumors in female Balb/c mice by 55%. Tumors from proguanil treated mice demonstrated increased apoptosis, which was related to the increased expression of p-H2AX and Bax. Taken together, these results show that proguanil is an effective inhibitor of in vitro and in-vivo growth of breast cancer cells. These findings provide the rationale for further clinical investigation of proguanil against breast cancer. Citation Format: Nehal Gupta, Sanjay Srivastava. Oxidative stress by proguanil suppresses breast tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4795.
Hypofractionated adjuvant radiation therapy of soft tissue sarcoma in elderly patients.
Authors: Ofer Merimsky, Viacheslav Soyfer, Benjamin W. Corn, Solomon Dadia, Yehuda Kollender
Journal: Journal of Clinical Oncology (2013)

e21521 Background: Adjuvant radiation therapy is an essential part of combined limb sparing treatment of STS. The recommended dose of radiation lies in the range of 60 Gy in standard fractionation of 1.8-2 Gy. Elderly or medically unfit patients often have difficulty in completing 6-7w of daily treatment. A prolonged course of radiation may be interrupted by acute side effects, which sometimes demands further extension of the overall course or even discontinuation of treatment. We intended to evaluate the efficacy of a hypofractionated adjuvant approach with radiation therapy for STS in the elderly and debilitated patients. Methods: 21 elderly patients were treated with a short course of adjuvant RT (39 to 48 Gy, 3 Gy per fraction) for STS. The medical records of the patients were retrospectively reviewed for the local or distant recurrence and side effects of RT. Results: Overall, the hypofractionated irradiation regimen of 39-48 Gy in 13-16 fractions was well tolerated with only 3 patients developing Grade 2-3 acute toxicity (mainly dermatitis). Three patients suffered from delayed Grade 2-3 toxicity (chronic pain, skin atrophy, teleangiectasiae) scaled according to CTSC. The mean time from the surgery until the initiation of RT was 65 days (SD 21.6). Mean RT time was 18.4 (SD 3) days. No delay of treatment due to acute toxicity was registered. All patients except for one were able to receive RT in the ambulatory setting. With a mean follow-up of 532 days (SD: 325), three local recurrences (14%) were detected. Three of eight patients with distant metastases died of sarcoma (graph 1). One patient with metastatic disease in the lung received salvage stereo tactic radiation therapy and was still alive 6 month after completion of SBRT with no evidence of disease. At a mean 532 days of follow up three local recurrences (14%) were detected .Eight patients (38%) had lung metastases during the observed period. Three of them died from metastatic disease. The hypofractionated radiation was well tolerated with minimum long term side effects. Conclusions: Hypofractionated adjuvant radiation appears to be an effective treatment in terms of local control in elderly and debilitated patients.
Multicentric prospective study of validation of angiogenesis-related gene polymorphisms in hepatocellular carcinoma patients treated with sorafenib: results of INNOVATE study
Authors: A. Casadei Gardini, G. Marisi, V. Dadduzio, L. Ielasi, C. Vivaldi, M. Rizzato, L. Fornaro, S. Lonardi, L. Gramantieri, I. Pecora, F. Foschi, N. Silvestris, F. Fornari, G. Orsi, G. Rovesti, D. Santini, V. Zagonel, S. Cascinu, M. Scartozzi
Journal: Annals of Oncology (2019)
Abstract 1777: Correlation between different C-KIT exon mutation and clinical outcome to Imatinib Mesylate treatment in patients with gastro-intestinal stromal tumors (GIST)
Authors: Abeer A. Bahnnasy, Ola Khorshid, Mona S. Abdellateif, Ghada Y. Zakaria, Nasr M. Allahloubi, Auhood Nassar, Abdel-Rahman N. Zekri
Journal: Cancer Research (2019)

Abstract Aim: C-KIT exon mutations were assessed in patients with gastrointestinal stromal tumor (GIST) in relation to patients’ characteristics, response to treatment and survival rates. Methods: C-KIT mutations were assessed in the representative formalin fixed paraffinembedded tissues (FFPETs) of 89 patients with GIST compared to 35 normal control (NC) subjects using the Real Time PCR (Rt-PCR) and immunohistochemistry (IHC). Results: C-KIT mutations were detected in 61/89 (68.5%) patients, compared to none of the NC subjects (P=&amp;lt;0.001). Most mutations were detected in exon 11 (50.8%), followed by exon 9 (24.5%), exon 13 (19.6%), exon 7 (4.1%), and exon 12 (only 1%). C-KIT protein expression was detected in 69 (77.5%) patients compared to none of the NC subjects (p=&amp;lt;0.001). Significant measure of agreement was detected between C-KIT expression by IHC and and RT-PCR (K=0.774, p=0.0001). The presence of C-KIT mutations associated significantly with large tumor size (P=0.01), High mitotic rate, lymph nodes metastasis and high tumor risk (p=0.001, for all). Patients with exon 11 mutations 26/31 (83.9%) had a better response to treatment compared to those with exon nine 7 (46.7%) and exon 13 mutation 1/12 (8.3%; P=0.001). Exon 11 mutations associated significantly with better PFS and OS compared to those with exon 9 and 13 mutations (P= 0.001, P= 0.0001; respectively). On univariate analysis, Exon 13 mutations was the most significantly associated with reduced PFS (P=0.0001), whereas advanced disease stage, absence of adequate safety margins and the site of exon mutation associated significantly with reduced OS. (P=0.012, P=0.05 and P=0.005; respectively. Conclusion: GIST patients with C-KIT exon 11 mutations have a better response to imatinib treatment (predictive value), better OS and lower risk of disease progression than those with exon 9 and 13 mutations. Our specified mutations in exons 9&amp; 13 mutations could be used as an independent prognostic factor for GIST patients. Citation Format: Abeer A. Bahnnasy, Ola Khorshid, Mona S. Abdellateif, Ghada Y. Zakaria, Nasr M. Allahloubi, Auhood Nassar, Abdel-Rahman N. Zekri. Correlation between different C-KIT exon mutation and clinical outcome to Imatinib Mesylate treatment in patients with gastro-intestinal stromal tumors (GIST) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1777.
Comparative Effectiveness of High-Dose Bendamustine-EAM Versus BEAM in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma Undergoing Autologous Stem Cell Transplantation
Authors: Erica Tsang, Diego Villa, Federica Loscocco, Alina S Gerrie, Giuseppe Visani, Maryse Power, Barbara Guiducci, Cristina Clissa, Joseph M Connors, Kerry J Savage, Kevin W Song, Cindy Toze, Yasser Abou-Mourad, Heather Sutherland, David Sanford, Stephen H Nantel, Laurie H. Sehn, David W. Scott, Alessandro Isidori
Journal: Blood (2017)
Abstract 13733: Circulating Matrix Metalloproteinase Levels Correlate with Severity in Marfan Syndrome
Authors: Yaxin Lu, Richmond Jeremy, Murat Kekic, Jianlin Yin, Donna Lai, Brett D Hambly
Journal: Circulation (2012)

Tissue matrix metalloproteinases (MMPs) participate in extra-cellular matrix destruction in aneurysm disease, with MMP2, MMP3 and MMP9 being elevated in atherosclerotic thoracic aneurysm. MMP2 and ...
Abstract 1213: RNA-based screens in primary human immune cells
Authors: Bronwyn Joubert, Cristina Ghirelli, Isabelle Nett, John Prime, Glynn Martin, Jonathan Moore, Benedict Cross, Nicola J. McCarthy
Journal: Cancer Research (2019)

Abstract Genetic screens have long been used as an approach to identify and validate new targets for drug discovery. The vast majority of these have been carried out in cell lines: mostly cancer cell lines. However, with improvements in tissue culture techniques, the increasing interest in using the immune system to tackle disease and the discovery of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-Cas9 mediated genome editing, screening primary cells that have not been subverted by transformation into immortal lines, is both appealing and feasible. We have successfully carried out a CRISPR-Cas9 screen in primary T cells using a combined lentivirus and electroporation protocol. Freshly isolated primary T cells are stimulated with anti-CD3 and anti-CD28 antibodies and then transduced with a pooled sgRNA library. After antibiotic selection, T cells successfully transduced with sgRNAs are electroporated to introduce Cas9 mRNA. We chose to validate this approach by carrying out a screen similar to that published by Birsoy et al., 2015, in which they ran a CRISPR-Cas9 screen in Jurkat T cells in the presence and absence of the electron transport chain inhibitor phenformin. In our screen, we exposed the CRISPR-Cas9 edited pool of primary T cells to a dose of phenformin that resulted in growth inhibition to a similar degree to that used by Birsoy and colleagues. Our data are in agreement with the published screen, showing that loss of the cytosolic aspartate aminotransferase GOT1 sensitises primary T cells to phenformin. We took multiple time points in our primary T cell screen and used T cells isolated from three different donors, allowing for the analysis of guide drop-out kinetics and reproducibility between donors. We anticipate that these data will be useful in building more complex screens that assess T cell biology in the presence of additional cells, such as myeloid derived suppressor cells (MDSCs). With a view to this, we have also carried out an arrayed siRNA screen in MDSCs to look for genes that when knocked down reduce the capacity of MDSCs to inhibit T cell proliferation. The endpoint for this screen is based on co-culture of siRNA transfected MDSCs with proliferating primary T cells. Using this complex data set, we have identified several potential targets, which when validated could provide new therapeutic targets through which the immunosuppressive nature of MDSCs in the tumour microenvironment can be mitigated. Birsoy, K., et al. (2015) http://dx.doi.org/10.1016/j.cell.2015.07.016 Citation Format: Bronwyn Joubert, Cristina Ghirelli, Isabelle Nett, John Prime, Glynn Martin, Jonathan Moore, Benedict Cross, Nicola J. McCarthy. RNA-based screens in primary human immune cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1213.
Abstract 1466: Combination immunotherapy successfully control tumor growth in a transgenic mouse model
Authors: Kue Peng Lim, Syafinaz Zainal, Natasha Zulaziz, Chai Phei Gan, San Jiun Chai, Bryan Kit Weng Lye, Chuan Wang, Ruhcha V. Sutavani, Christian Ottensmeier, Emma King, Gareth Thomas, Natalia Savelyeva, Sok Ching Cheong
Journal: Cancer Research (2019)

Abstract The use of checkpoint inhibitor anti-PD1 has achieved significant clinical benefit, in recurrent and metastatic head and neck cancer patients, where the overall response rate is between 16-20%. The use of antigen-specific cancer vaccine to increase the level of cytotoxic T cells is believed to work synergistically with anti-PD1. In this study, we evaluated the efficacy of antigen-specific DNA vaccine when it’s used in combination with anti-PD1. The B6.Cg-Tg(HLA-A/H2-D)2Enge/J mice bearing established tumours overexpressing the tumour antigen were vaccinated either with anti-PD1, DNA vaccine or anti-PD1 in combination with DNA vaccine. Tumour volume was monitored and antigen-specific immune responses were evaluated at the endpoint. Our data demonstrated DNA vaccine induced antigen-specific immune responses and animals vaccinated with DNA vaccine harboured smaller tumour volume compared to controls. Significantly, animals that received DNA vaccine expressed consistently higher levels IFN-γ and resulted in the upregulation of PD1 compared to control animals. We then demonstrated mice vaccinated with both DNA vaccine and anti-PD1 had near to complete tumour control, indicating a synergistic effect of DNA vaccine with anti-PD1. Animals treated with DNA vaccine in combination with anti-PD1 also have better overall survival. Importantly, these animals showed increased antigen-specific responses by the ELISPOT assay. In summary, our data suggest antigen-specific DNA vaccine works synergistically with anti-PD1 and conferred an excellent tumour control; this opens up a new opportunity of combinatory immunotherapy that might benefit a wider population of patients in an antigen-specific manner. Citation Format: Kue Peng Lim, Syafinaz Zainal, Natasha Zulaziz, Chai Phei Gan, San Jiun Chai, Bryan Kit Weng Lye, Chuan Wang, Ruhcha V. Sutavani, Christian Ottensmeier, Emma King, Gareth Thomas, Natalia Savelyeva, Sok Ching Cheong. Combination immunotherapy successfully control tumor growth in a transgenic mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1466.
Изменения сосудов головного мозга у пациентов с неалкогольной жировой болезнью печени и нарушением углеводного обмена
Authors: Ye.S. Sirchak, V.I. Griga, N.Yu. Kurchak, A.Yu. Kutsenko
Journal: GASTROENTEROLOGY (2019)

Актуальность. Исследование сосудов головного мозга у пациентов с неалкогольной жировой болезнью печени (НАЖБП) может раскрыть новые аспекты раннего выявления нарушений церебральной гемодинамики, а также обнаружить группу больных высокого риска. Цель исследования: изучить особенности изменений в сосудах головного мозга у пациентов с НАЖБП в сочетании с инсулинорезистентностью (ИР) или сахарным диабетом (СД) 2 типа. Материалы и методы. Обследовано 74 пациента с НАЖБП (34 больных с неалкогольным жировым гепатозом (НАЖГ) и 40 больных с неалкогольным стеатогепатитом (НАСГ)). Группа сравнения включала 38 пациентов (16 больных с ИP и 22 пациента с СД 2 типа). Состояние кровотока в cосудах головного мозга изучали с помощью ультразвукового дуплексного сканирования экстракраниального отдела общей сонной артерии (ОСА), наружной сонной артерии (НСА), экстракраниального отдела внутренней сонной артерии, средней мозговой артерии, вертебральной артерии (ВА), глазной артерии. Определяли пиковую систолическую скорость (ПСС) и среднюю по времени максимальную скорость кровотока (ТАМХ) в исследуемых сосудах. Результаты. Обращает на себя внимание асимметричное поражение сосудов головного мозга с более выраженным дефицитом кровотока слева при НАЖБП, что более выражено у больных со стадией НАСГ, особенно в сочетании с ИP. Гемодинамически наиболее значимые изменения установлены в ОСА, а именно выявлено снижение ПСС до (38,1 ± 2,3) см/с справа и до (36,6 ± 3,4) см/с слева, снижение ТАМХ — до (20,4 ± 2,1) см/с справа и до (16,7 ± 1,8) см/с слева. Выводы. У пациентов с НАЖБП, ИP и СД 2 типа выявлено снижение скоростных показателей кровотока по экстракраниальным сосудам головного мозга, преимущественно по ОСА, НСА и ВА (сегмент 3). Наиболее выраженный дефицит кровотока установлен у больных НАСГ в сочетании с ИP, преимущественно слева, особенно по ОСА.