tbuckley/cabot-search huggingface dataset:
Abstract 2353: CDKI-15, a novel and highly selective CDK4/6 inhibitor: discovery, <i>in vitro</i> and <i>in vivo</i> anticancer efficacy
Authors: Solomon Tadesse, Laychiluh Bantie, Khamis Tomusange, Saiful Islam, Muhammed H. Rahaman, Benjamin Noll, Frankie Lam, Mingfeng Yu, Shudong Wang
Journal: Cancer Research (2017)

Abstract Cyclin D dependent kinases CDK4 &amp; CDK6 are crucial regulators of the G1 to S phase transition of the cell cycle. The facts that myriad cancer types show aberrance in INK4-CDK4/6-cyclin D-Rb-E2F pathway, &amp; the rapidly emerging positive clinical data of pharmacological inhibitors have validated CDK4/6 as anticancer drug targets. As the first commercialized CDK inhibitor, palbociclib in combination with letrozole or fulvestrant has received regulatory approval for the treatment of breast cancer. This represents an important scientific advance in the field. However, the limited structural diversity &amp; undesired side effects due to broader kinase interactions of existing inhibitors mean that the hunt for new &amp; highly selective CDK4/6 inhibitor drug candidates continues. Using our advanced medicinal chemistry, targeted biochemical &amp; cell-based assays, &amp; animal pharmacology, we synthesized &amp; evaluated a novel series of inhibitors. Many compounds were highly potent &amp; selective against CDK4/6, &amp; exhibited low nanomolar potency against a range of human cancer cell lines. Notably, inhibition of CDK4D1 by compound CDKI-15 (Ki = 4 nM) was over 3 orders of magnitude greater than CDK1B, CDK2A, CDK7H &amp; CDK9T1. Interrogation of a panel of 369 protein kinases revealed CDKI-15 to be highly selective for CDK4/6 with only 3 other kinases inhibited potently. CDKI-15 reduced the level of Rb phosphorylation &amp; induced G1 cell cycle arrest, confirming cellular inhibition of CDK4/6 in cancer cells. Moreover, CDKI-15 possesses superior pharmacokinetic profile with oral bioavailability of 100% in mice. Treatment of nude BALB/c mice bearing human MV4-11 acute myeloid leukemia cells with CDKI-15 at daily dose of 100 mg/kg by oral administration resulted in a robust inhibition of tumor growth compared to vehicle treated animals (T/C = 30%, p &amp;lt; 0.00001). Strikingly, CDKI-15 caused a complete &amp; sustained tumor regression in one-third of the animals. No detectable toxicity was observed in the animals during &amp; post treatment. Taken together, our data provide a rationale for CDKI-15 to be developed towards clinic for cancer therapy. Citation Format: Solomon Tadesse, Laychiluh Bantie, Khamis Tomusange, Saiful Islam, Muhammed H. Rahaman, Benjamin Noll, Frankie Lam, Mingfeng Yu, Shudong Wang. CDKI-15, a novel and highly selective CDK4/6 inhibitor: discovery, in vitro and in vivo anticancer efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2353. doi:10.1158/1538-7445.AM2017-2353
08.15 Stability of infliximab under different storage conditions used as a standard for in-house infliximab elisa
Authors: Manca Ogrič, Polona Žigon, Sonja Praprotnik, David Drobne, Borut Štabuc, Matija Tomšič, Snezna Sodin-Semrl, Saša Čučnik
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Infliximab (IFX) is a therapeutic chimeric monoclonal antibody targeting tumour necrosis factor-alpha (TNF-α) used for treating chronic inflammatory diseases, such as Crohn`s disease, ulcerative colitis, spondyloarthritis and rheumatoid arthritis. Assessing IFX serum levels is recommended to optimally evaluate patient's response to therapy using well-selected methodology. Our <i>in-house</i> IFX ELISA proved to be highly comparable to commercially available apDia (r=0.925, p&lt;0.001) and Promonitor kits (r=0.943, p&lt;0.001), with 100% agreement between <i>in-house</i> IFX ELISA and both kits. In the current study we aimed to examine the stability of the original IFX medication (Remicade) and its biosimilar (Remsima) under different storage conditions, for later use as standard in our <i>in-house</i> IFX ELISA. <h3>Materials and methods</h3> Lyophilized Remicade and Remsima were reconstituted to a final concentration of 12 µg/mL in: a) sterile water stored at 4°C, b) phosphate buffered saline with 1% bovine serum albumin (1% BSA/PBS) and c) 1% BSA/PBS with 25% glycerol, both stored at −20°C. <i>In-house</i> IFX ELISA, using the differently stored standards, was performed at days 0, 2, 7, 35, 93 and 180 after first reconstitution. Briefly, high binding microtiter plates were coated overnight at 4°C with TNF-α. After washing and blocking with 1% BSA/PBS, followed by an additional wash, samples and standards were applied and incubated for 2 hour at 37°C. The binding was detected with an alkaline phosphatase-conjugated anti-IgG antibody. <h3>Results</h3> Measured IFX concentrations in different time points were most consistent for Remsima stored in 1% BSA/PBS at −20°C (12.14±0.44 µg/mL, with coefficient of variation (CV) 3.7%) or 1% BSA/PBS with 25% glycerol (12.15±0.45 µg/mL, CV 3.7%). Under these conditions IFX concentrations determined at different time points, differed from actual 12 µg/mL concentration, on average for 0.15 µg/mL (range 11.52–12.79 µg/ml). Remicade stored either in water, 1% BSA/PBS or 1% BSA/PBS with 25% glycerol yielded less repeatable results with standard deviation 0.67–1.30 µg/mL and CV 6.3%–10.9%. <h3>Conclusions</h3> Remsima stored in either 1% BSA/PBS or 1% BSA/PBS with 25% glycerol at −20°C proved to be the most stable standard solution for use in our <i>in-house</i> IFX ELISA.
Assessment of Organ Dosimetry for Planning Repeat Treatments of High-Dose 131I-MIBG Therapy
Authors: Neeta Pandit-Taskar, Pat Zanzonico, Patrick Hilden, Irina Ostrovnaya, Jorge A Carrasquillo, Shakeel Modak
Journal: Clinical Nuclear Medicine (2017)

Purpose To evaluate detailed organ-based radiation-absorbed dose for planning double high-dose treatment with 131I-MIBG. Methods In a prospective study, 33 patients with high-risk refractory or recurrent neuroblastoma were treated with high-dose 131I-MIBG. Organ dosimetry was estimated from the first 131I-MIBG posttherapy imaging and from subsequent 123I-MIBG imaging prior to the planned second administration. Three serial whole-body scans were performed per patient 2 to 6 days after 131I-MIBG therapy (666 MBq/kg or 18 mCi/kg) and approximately 0.5, 24, and 48 hours after the diagnostic 123I-MIBG dose (370 MBq/kg or 10 mCi/1.73 m2). Organ radiation doses were calculated using OLINDA. 123I-MIBG scan dosimetry estimations were used to predict doses for the second 131I-MIBG therapy and compared with 131I-MIBG posttherapy estimates. Results Mean ± SD whole-body doses from 131I-MIBG and 123I-MIBG scans were 0.162 ± 112 and 0.141 ± 0.068 mGy/MBq, respectively. 123I-MIBG and 131I-MIBG organ doses were variable—generally higher for 123I-MIBG–projected doses than those projected using posttherapy 131I-MIBG scans. Mean ± SD doses to liver, heart wall, and lungs were 0.487 ± 0.28, 0.225 ± 0.20, and 0.40 ± 0.26, respectively, for 131I-MIBG and 0.885 ± 0.56, 0.618 ± 0.37, and 0.458 ± 0.56, respectively, for 123I-MIBG. Mean ratio of 123I-MIBG to 131I-MIBG estimated radiation dose was 1.81 ± 1.95 for the liver, 2.75 ± 1.84 for the heart, and 1.13 ± 0.93 for the lungs. No unexpected toxicities were noted based on 123I-MIBG–projected doses and cumulative dose limits of 30, 20, and 15 Gy to liver, kidneys, and lungs, respectively. Conclusions For repeat 131I-MIBG treatment planning, both 131I-MIBG and 123I-MIBG imaging yielded variable organ doses. However, 123I-MIBG–based dosimetry yielded a more conservative estimate of maximum allowable activity and would be suitable for planning and limiting organ toxicity with repeat high-dose therapies.
Abstract 3206: A potent and selective CSF-1R inhibitor, DCR-0064, inhibits colony stimulating factor 1 signaling <i>in vitro</i> and <i>in vivo</i>
Authors: Chu-Bin Liao, Shao-Zheng Peng, Chen-Hsuan Ho, Chao-Pin Lee, Jia-Ming Chang, Hung-Jyun Huang, Sian-Yi Ciou, Yu-Chih Pan, Yu-Kai Chen
Journal: Cancer Research (2017)

Abstract Tumor-associated macrophages (TAMs) are major components of leukocytic infiltrate of tumors. It has been reported that high TAMs density is associated with poor clinical prognosis. Within the tumor microenvironment, TAMs rely on signaling through CSF-1/CSF-1 Receptor kinase axis to promote tumor growth, angiogenesis, and metastasis. Therefore, decrease of TAMs density in tumors through inhibition of CSF-1R kinase is considered a potential target for drug development. In this study, we report that a novel small molecule DCR-0064 inhibits CSF-1R kinase with IC50 value below 10 nM and possesses specificity for CSF-1R over other tyrosine or serine/threonine kinases. DCR-0064 selectively inhibits CSF-1 induced growth of M-NFS-60 myeloid cells and effectively suppresses intracellular CSF-1R activation with IC50 value less than 100 nM. The potency and selectivity of DCR-0064 is superior to the current lead CSF-1R inhibitor, PLX3397, which is in phase III clinical development for treating tenosynovial giant cell tumor. The selectively growth inhibitory activity of DCR-0064 is consistent with inhibition of CSF-1R signaling. Oral administration of DCR-0064 reduces TAMs density in vivo in mice. DCR-0064 is being developed as a candidate for preclinical development. Citation Format: Chu-Bin Liao, Shao-Zheng Peng, Chen-Hsuan Ho, Chao-Pin Lee, Jia-Ming Chang, Hung-Jyun Huang, Sian-Yi Ciou, Yu-Chih Pan, Yu-Kai Chen. A potent and selective CSF-1R inhibitor, DCR-0064, inhibits colony stimulating factor 1 signaling in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3206. doi:10.1158/1538-7445.AM2017-3206
Abstract 4865: The functional and clinicopathological analysis of hypoxia inducible factor-1α (HIF1-α) in head and neck squamous cell carcinoma
Authors: Yuichi Ikari, Hiroyuki Ozawa, Yorihisa Imanishi, Toshiki Tomita, Mariko Sekimizu, Yoshihiro Watanabe, Fumihiro Ito, Shin Saito, Kaoru Ogawa
Journal: Cancer Research (2017)

Abstract Introduction: Tumor hypoxia is considered to be associated with progression in various cancers. Hypoxia inducible factor-1α (HIF-1α) is one of the molecules which play a key role in tumor hypoxia. High HIF-1α expression is reported to have an impact on poor prognosis and resistance to chemotherapy or radiotherapy in head and neck squamous cell carcinoma (HNSCC). However, the effect and mechanism of HIF-1α on tumor metastasis in HNSCC is still unclear. The aim of the present study was to investigate the molecular targets of HIF1-α relevant to metastasis, and to reveal the impact of HIF1-α on HNSCC metastasis by using clinicopathological assays. Methods: The cell proliferation rate with or without HIF-1 inhibitor (KC7F2) in HNSCC cell lines (FaDu, Detroit512) was evaluated by MTS assay. Gene expression levels related to epithelial-mesenchymal transition (EMT), cancer stem cell (CSC) and HIF-1α in each HNSCC cell lines were measured by quantitative real-time PCR. Immunohistochemical expressions of HIF-1α and clinicopathological factors were analyzed using surgical specimens from 33 patients with hypopharyngeal carcinoma who had undergone trans-oral tumor resection without previous chemotherapy nor radiotherapy. Results: HIF-1 inhibitor suppressed the cell growth of HNSCC cell lines in a dose dependent manner. HIF-1 inhibitor downregulated the expression of HIF-1α, twist, Oct3/4 and Nanog. In immunohistochemical study, the HIF-1α expression was higher in cancer cells than in normal cells of the adjacent normal mucosa. Univariate analysis revealed that high expression of HIF-1α was significantly correlated with T-classification (P=0.012), lymph node metastasis (P=0.002) and lymphatic invasion (P=0.03). Conclusion: These results suggest that HIF-1α plays a key role in tumor progression of HNSCC through EMT and CSC properties. From the present study, HIF-1α inhibition may have the possibility to suppress tumor metastasis, making HIF-1α an attractive target for the treatment of HNSCC. Citation Format: Yuichi Ikari, Hiroyuki Ozawa, Yorihisa Imanishi, Toshiki Tomita, Mariko Sekimizu, Yoshihiro Watanabe, Fumihiro Ito, Shin Saito, Kaoru Ogawa. The functional and clinicopathological analysis of hypoxia inducible factor-1α (HIF1-α) in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4865. doi:10.1158/1538-7445.AM2017-4865
Abstract 2915: The timing of mutational burst events impact the growth of tumors in the colon
Authors: Chelsie K. Sievers, Tien N. Vo, Perry J. Pickhardt, Bryan D. Pooler, Kristina A. Matkowskyj, Dawn M. Albrecht, Quincy Rosemarie, Michael A. Newton, Richard B. Halberg
Journal: Cancer Research (2017)

Abstract Basic and clinical scientists believe that benign polyps in the colon progress to cancers through the slow, stepwise accumulation of mutations. Interestingly, only a small percentage of all tumors progress, whereas a significant number remain static in size, regress, or resolve completely. The mechanisms underlying these differential fates are unknown, and mechanisms of tumor evolution during this premalignant phase are still under investigation and continued debate. We previously reported that sub-clonal diversity arises early in small human adenomas and contributes to the growth of tumors in the colon. An emerging hypothesis is that colorectal tumors form and progress via a process of punctuated equilibrium, where multiple copy number alterations and mutational events happen simultaneously in a burst-like fashion. In this study, we prospectively test this concept using a mouse model in which tumor induction is spatially and temporally controlled via a non-surgical delivery of adenovirus expressing CRE recombinase and a temporally controlled mutational burst via administration of the carcinogen Azoxymethane. Tumors are induced at a similar rate regardless the timing of the burst relative to tumor induction with a mean tumor incidence of 62% at three weeks post induction. However, tumor growth may be affected by the timing of the burst. Animals that had a mutational burst event prior to tumor induction or those that had a late mutational burst event had a lower average in vivo growth rate compared to controls and those with an early burst event, but the average in vivo tumor size was comparable across all groups. Taken together, these preliminary data provide evidence that the timing of a mutational burst event contributes to tumor growth. This prospective experiment is being extended through computer modeling and statistical inference to compare in silico mutational landscapes to a cohort of colon polyps removed from patients at normal screening. The findings will provide new insights into the earliest stages of tumorigenesis. Citation Format: Chelsie K. Sievers, Tien N. Vo, Perry J. Pickhardt, Bryan D. Pooler, Kristina A. Matkowskyj, Dawn M. Albrecht, Quincy Rosemarie, Michael A. Newton, Richard B. Halberg. The timing of mutational burst events impact the growth of tumors in the colon [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2915. doi:10.1158/1538-7445.AM2017-2915
Abstract 5273: Detection of sessile serrated adenomas/polyps in African Americans
Authors: Nazli Atefi, Sanmet Singh, Babak Shokrani, Edward Lee, Ali Afsari, Mehdi Nouraie, Adeyinka Laiyemo, Joseph Mathews, Carla Williams, Hassan Brim, Hassan Ashktorab
Journal: Cancer Research (2017)

Abstract Introduction: The majority of colorectal cancers (CRCs) develop through the adenoma-carcinoma sequence, while 15-20% develop via the serrated pathway. Sessile Serrated Adenoma/Polyps (SSA/P) are more difficult to detect during colonoscopy and generally require a shorter time follow-up than other lesions (3 vs. 5 years). These polyps lead to cancer faster than conventional adenomas. In order to better define patients at risk for these lesions, we performed a retrospective study to evaluate clinicopathological features of patients diagnosed with SSA/P. Methods: We reviewed pathology reports of patients at Howard University Hospital from 2010-2015. We identified 5,900 patients with colorectal lesions, of whom 312 (5.3%) were diagnosed with SSA/P. We analyzed the specific clinical, pathological and demographic features of patients with SSA/P lesions. Results: We identified 312 cases with SSA/P. The incidence of SSA/P over the 5 years period was 5.3%: 198/312 (63.4%) patients had 2 or more polyps, 54.5% of the SSA/P patients were females, 70.5% of patients were 50-64 years of age and 18% were older than 65. SSA/P lesions’ locations were as follows: rectal: 32.1%; rectosigmoid: 18.6%; sigmoid: 16.8%; Ascending Colon: 13.2 % and Descending Colon: 7.1%. Reasons for colonoscopy were as follows: Screening: 43.6 %; GI bleeding: 15.1%; Abdominal Pain: 13.1%and Change in Bowel Habits: 10.2%. Conclusion: Our results show that there is a slightly increased predominance of SSA/P occurrence in females. Most SSA/P occurred in patients 50 to 64 years old. This age range is younger in comparison to patients with conventional adenomas. SSA/Ps were predominantly distal (rectal, rectosigmoid, sigmoid) whereas previous literature reports a proximal location. Most patients in our study were diagnosed in screening colonoscopies; however, other patients presented with symptoms such as GI bleeding, abdominal pain, or change in bowel habits. Citation Format: Nazli Atefi, Sanmet Singh, Babak Shokrani, Edward Lee, Ali Afsari, Mehdi Nouraie, Adeyinka Laiyemo, Joseph Mathews, Carla Williams, Hassan Brim, Hassan Ashktorab. Detection of sessile serrated adenomas/polyps in African Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5273. doi:10.1158/1538-7445.AM2017-5273
Abstract 5672: Quantitative cell-based assays for characterization of antibodies targeting co-stimulatory immune checkpoint receptors
Authors: Julia K. Gilden, Jun Wang, Michael Beck, Jamison Grailer, Jim Hartnett, Frank Fan, Mei Cong, Zhe-jie Jey Cheng
Journal: Cancer Research (2017)

Abstract The human immune system is regulated by a broad network of co-inhibitory and co-stimulatory receptors that control the type, scale, and duration of immune responses. These receptors are now recognized as promising immunotherapy targets for the treatment of many cancers and autoimmune diseases. Immunotherapies that block co-inhibitory receptors such as PD-1 and CTLA-4 are showing unprecedented efficacy in the treatment of some tumors, and have generated interest in the characterization of additional immunotherapy targets that may broaden the number of patients who can be helped by these drugs. Immunotherapy research programs are now exploring a wide range of both co-inhibitory (e.g. LAG-3, TIGIT, Tim-3) and co-stimulatory (e.g. GITR, 4-1BB, OX40) receptors, individually and in combination. Quantitative and reproducible functional bioassays are essential tools in the development of biologics for cancer immunotherapy. Most existing assays rely on primary cells and suffer from lengthy protocols and high day-to-day and donor-to-donor variability. These approaches are cumbersome, error-prone, and do not produce data of the quality required for drug development in a quality control environment. To address this, we have developed a suite of cell line-based reporter bioassays for co-stimulatory immune checkpoint targets including GITR, 4-1BB, OX40, and CD40. In these assays, stable cell lines express luciferase reporters driven by response elements under the precise control of intracellular signals mediated by each co-stimulatory receptor. These bioassays reflect mechanisms of action for drug candidates designed for each co-stimulatory receptor and demonstrate high specificity, sensitivity and reproducibility. Reporter-based bioassays can serve as powerful tools in immunotherapy drug development for antibody screening, potency testing and stability studies. Citation Format: Julia K. Gilden, Jun Wang, Michael Beck, Jamison Grailer, Jim Hartnett, Frank Fan, Mei Cong, Zhe-jie Jey Cheng. Quantitative cell-based assays for characterization of antibodies targeting co-stimulatory immune checkpoint receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5672. doi:10.1158/1538-7445.AM2017-5672
Abstract 1418: G9a methyltransferase plays a role in ATM-dependent DNA damage response
Authors: Lizahira Rodriguez-Colon, Vasudeva Ginjala, Atul Kulkarni, Safia Ansari, Shridar Ganesan
Journal: Cancer Research (2017)

Abstract Induction of DNA damage leads to a choreographed set of local chromatin changes that ensures an efficient recruitment of DNA repair factors. One principal regulator of the DNA Damage Response (DDR) signaling pathway is ATM kinase, which phosphorylates key factors at early stages of the response. G9a protein methyltransferase has been identified as a novel substrate for ATM. We have found that G9a localizes to sites of DNA damage in an ATM-dependent fashion and that inhibition of its activity affects recruitment of multiple DNA repair factors. Moreover G9a catalytic inhibition using UNC0638 leads to hyperactivation of ATM induced by DNA breaks. This was associated with an increased ATM-dependent “spreading” of pH2AX and MDC1 signals seen at regions of localized DNA breaks induced by UV-laser scissors. These data suggest that G9a activity is required for regulating the extent of ATM activation as well as for efficient recruitment of downstream DNA repair factors. Biochemical data will be presented that explore potential mechanisms for these findings. Overall our data suggests that G9a plays a critical role in the regulation of ATM-dependent signaling during the DNA damage response, and raises the possibility of using G9a inhibitors to target cancers with certain DNA repair defects. Citation Format: Lizahira Rodriguez-Colon, Vasudeva Ginjala, Atul Kulkarni, Safia Ansari, Shridar Ganesan. G9a methyltransferase plays a role in ATM-dependent DNA damage response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1418. doi:10.1158/1538-7445.AM2017-1418