tbuckley/cabot-search huggingface dataset:
Abstract 2731: A novel PDE10/beta-catenin inhibitor, MCI-048, suppresses lung tumorigenesis to block metastasis
Authors: Bing Zhu, Veronica Ramirez-Alcantara, Antonio Ward, Kristy Berry, Adam B. Keeton, Michael R. Boyd, Yulia Maxuitenko, Xi Chen, Gary A. Piazza
Journal: Cancer Research (2019)

Abstract We previously reported that phosphodiesterase 10A (PDE10) is overexpressed during early stages of lung cancer and is essential for lung tumor cell growth. Here we characterize a novel PDE10 inhibitor, MCI-048, that was identified by screening a library of indene compounds. MCI-048 potently inhibited the growth and induced apoptosis of multiple human lung cancer cell lines expressing PDE10, while normal human airway epithelial cells lacking PDE10 expression were appreciably less sensitive. The mechanism of action of MCI-048 involves PDE10 inhibition, cGMP elevation, PKG activation, and phosphorylation of β-catenin at key residues that induce ubiquitination and proteosomal degradation of the oncogenic pool of β-catenin in cytoplasm to suppress the translocation of active β-catenin to the nucleus and Lef/Tcf-mediated transcription of genes encoding for proteins such as c-myc, cyclin D, and survivin, which are essential for tumor cell proliferation and survival. Pharmacokinetic and tissue distribution studies revealed a unique feature of MCI-048 to accumulate at high concentrations in lungs relative to plasma and other tissues. To assess the potential of MCI-048 for the treatment of lung cancer and blocking metastasis, we tested the drug in two mouse models of lung cancer involving either orthotopic implantation of KRAS mutant A549 lung tumor cells or the chemical carcinogen, urethane. Oral administration of MCI-048 significantly inhibited tumor growth and extended survival in the orthotopic model using two different protocols to either treat the primary tumor or metastasis. Similarly, MCI-048 significantly reduced tumor burden as measured by both surface counting and histopathological analysis in the urethane-induced model of lung tumorigenesis. Biochemical analysis showed that MCI-048 reduced levels of urethane-induced active Ras-GTP and PDE10 levels, as well as other oncogenic markers, including pEGFR and c-Myc. Both mouse models revealed that MCI-048 was well tolerated with no discernable toxicity, thus supporting preclinical development for the treatment of lung cancer. Funding provided by NCI grants R21CA182941, R01CA131378, R01CA148817, R01CA197147, and R01CA155638. Citation Format: Bing Zhu, Veronica Ramirez-Alcantara, Antonio Ward, Kristy Berry, Adam B. Keeton, Michael R. Boyd, Yulia Maxuitenko, Xi Chen, Gary A. Piazza. A novel PDE10/beta-catenin inhibitor, MCI-048, suppresses lung tumorigenesis to block metastasis [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 2731.
Weight Gain After Smoking Cessation and Cardiovascular Events in Young Adults
Authors: Kyuwoong Kim, Seulggie Choi, Gyeongsil Lee, Su-Min Jeong, Sung Min Kim, Joung Sik Son, Jae Moon Yun, Yeon-Yong Kim, Seong Yong Park, Sang Min Park
Journal: Journal of the American College of Cardiology (2019)
Hormonal adjuvant treatment plus radiotherapy versus exclusive radiotherapy in locally advanced prostate cancer: Pooled analsys of 6 randomized trials
Authors: P. Carlini, E. Bria, M. Ciccarese, M. Milella, G. Arcangeli, M. Gallucci, E. Ruggeri, E. Terzoli, F. Cognetti, D. Giannarelli
Journal: Journal of Clinical Oncology (2006)

4642 Background: The magnitude of the benefit of adding adjuvant hormonal treatment to radiotherapy for locally advanced prostate cancer is still unclear. We performed a pooled-analysis of phase III trials, to quantify the eventual benefit in recurrence decrease. Methods: All prospective phase III trials were considered eligible. A pooled analysis was accomplished, and event-based relative risk ratios (RR) with 95% confidence interval (CI) were derived through both a fixed- (FEM) and a random-effect model (REM) approach. Significant differences in primary outcome (recurrence rate), and secondary outcomes (overall survival), were explored. Magnitude outcome measures were: absolute benefits and number of patients needed to treat (NNT) for 1 patient to benefit. Heterogeneity test was applied as well. Results: Six trials designed to look if hormonal treatment plus radiotherapy decreases recurrence rate (3,571 patients) were gathered. In the primary outcome, the combined approach significantly improves the recurrence rate when applying the FEM (RR 0.72, 95% CI 0.68, 0.77, p &lt; 0.0001), with an absolute benefit of 10.7%. The NNT was 9 patients. Although significant heterogeneity was found (p = 0.00001), the benefit remains significant at the REM as well (RR 0.67, 95% CI 0.54, 0.82, p &lt; 0.0001). Although significant at FEM (RR 0.93, 95% CI 0.86, 1.00, p = 0.039) but heterogeneous (p = 0.0007), the overall survival demonstrated a not-significant trend in favour of the combined strategy at REM (RR 0.90, 95% CI 0.75, 1.10, p = 0.263). Conclusions: Considered all the available phase III trials, the combination of adjuvant hormonal treatment with radiotherapy over standard exclusive radiotherapy significantly decreases the recurrence rate in patients affected by localized prostate cancer. The significant heterogeneity in the analysis underscores the existing difference in patient’ characteristics. No significant benefit in overall survival was found. No significant financial relationships to disclose.
Selection of topically applied non-steroidal anti-inflammatory drugs for oral cancer chemoprevention
Authors: Sandeep Sood, Steven J. Shiff, Chung S. Yang, Xiaoxin Chen
Journal: Cancer Research (2005)

746   Topical delivery of non-steroidal anti-inflammatory drugs through the oral mucosa has been used for oral cancer chemoprevention. Local permeability of these agents is one of the major concerns. Here we propose an approach to predict the permeability of topically applied agents for oral cancer chemoprevention. There are two routes of drug transport into the oral mucosa, paracellular and transcellular, with the paracellular route being the major one. Absorption of the topically applied agents into the oral mucosa is a process of passive diffusion. In theory, the total flux through the oral mucosa (J max ) can be estimated by adding the transcellular flux (J TC ) and the paracellular flux (J PC ). To target the Cox-2 enzyme in oral epithelial cells, it is desirable to maximize the theoretical activity index, the ratio of J TC  to IC 50  of a Cox-2 inhibitor (J TC /IC 50-Cox-2 ) .  Since we are unable to calculate J TC  of a drug in oral mucosa, skin J max  was calculated with aqueous solubility and log P , which are predicted by the ACD Suite (Version 8.0, Advanced Chemical Development Inc., Toronto, Canada). Theoretical activity indices were then calculated based on the IC 50  values in the literature. Among the 12 commonly used drugs, celecoxib, nimesulide and ibuprofen had the highest theoretical activity indices, and may be the agents of choice to target Cox-2 in oral epithelial cells through topical application. Based on these calculations, a long-term chemopreventive experiment using celecoxib (3% or 6%) through topical application was performed in a DMBA-induced hamster oral cancer model. Both 3% and 6% reduced the incidence of squamous cell carcinoma at the post-initiation stage. Such a cancer preventive effect was correlated with inhibition of prostaglandin E 2 biosynthesis. (Supported by NIH grant CA101235)
Stearoyl-CoA Desaturase 1 Protects Ovarian Cancer Cells from Ferroptotic Cell Death
Authors: Lia Tesfay, Bibbin T. Paul, Anna Konstorum, Zhiyong Deng, Anderson O. Cox, Jingyun Lee, Cristina M. Furdui, Poornima Hegde, Frank M. Torti, Suzy V. Torti
Journal: Cancer Research (2019)

Abstract Activation of ferroptosis, a recently described mechanism of regulated cell death, dramatically inhibits growth of ovarian cancer cells. Given the importance of lipid metabolism in ferroptosis and the key role of lipids in ovarian cancer, we examined the contribution to ferroptosis of stearoyl-CoA desaturase (SCD1, SCD), an enzyme that catalyzes the rate-limiting step in monounsaturated fatty acid synthesis in ovarian cancer cells. SCD1 was highly expressed in ovarian cancer tissue, cell lines, and a genetic model of ovarian cancer stem cells. Inhibition of SCD1 induced lipid oxidation and cell death. Conversely, overexpression of SCD or exogenous administration of its C16:1 and C18:1 products, palmitoleic acid or oleate, protected cells from death. Inhibition of SCD1 induced both ferroptosis and apoptosis. Inhibition of SCD1 decreased CoQ10, an endogenous membrane antioxidant whose depletion has been linked to ferroptosis, while concomitantly decreasing unsaturated fatty acyl chains in membrane phospholipids and increasing long-chain saturated ceramides, changes previously linked to apoptosis. Simultaneous triggering of two death pathways suggests SCD1 inhibition may be an effective component of antitumor therapy, because overcoming this dual mechanism of cell death may present a significant barrier to the emergence of drug resistance. Supporting this concept, we observed that inhibition of SCD1 significantly potentiated the antitumor effect of ferroptosis inducers in both ovarian cancer cell lines and a mouse orthotopic xenograft model. Our results suggest that the use of combined treatment with SCD1 inhibitors and ferroptosis inducers may provide a new therapeutic strategy for patients with ovarian cancer. Significance: The combination of SCD1 inhibitors and ferroptosis inducers may provide a new therapeutic strategy for the treatment of ovarian cancer patients. See related commentary by Carbone and Melino, p. 5149
Abstract 1919: Molecularly annotation of mouse avatar models derived from patients with colorectal cancer liver metastasis
Authors: Jingyuan Wang, Wei Liu, Jing Gao, Baocai Xing, Lin Shen
Journal: Cancer Research (2019)

Abstract Background: Liver is the most common metastatic site in advanced colorectal cancer. Most patients with colorectal cancer liver metastasis (CRLM) do not benefit from current treatment. Patient-derived xenograft (PDX) with defined molecular signatures are attractive models for preclinical studies. Methods: Successfully established PDXs were evaluated to elucidate their fidelity of patients’ biologic characteristics (pathologic, genetic and protein properties, together with chemosensitivity). The genomic variations of PDXs were analyzed by next-generation sequencing to explore the underlying molecular mechanism of metastasis and potential therapeutic targets. Results: CRLM (N=73) showed a significantly higher successful PDX establishment rate than primary specimens (N=26; 76.7% vs. 57.7%). CRLM PDXs recapitulated the pathologic, genetic and protein properties of parental tumors, as well as chemosensitivity. Frequent altered genes in PDXs showed high consistency compared to patients’ genomic alterations and were enriched in MAPK, ErbB, cell cycle, focal adhesion pathways for CRLM PDXs, whereas primary tumor-derived PDXs only exhibited genomic variations involving ErbB and cell cycle. The genetic alterations showed high concordance between paired PDXs from primary and metastatic tissues, except for recurrent gene mutations (ARID1A, CDK8, ETV1, STAT5B and WNK3) and common copy number gains in chromosomes 20q (e.g., AURKA/TPX2). Several potential drug targets such as KRAS, HER2, and FGFR2 were validated using corresponding inhibitors. Additionally, PDX models could also be used in screening efficient regimens for patients with no druggable alterations. Conclusion: This study has successfully established and validated a large panel of molecularly annotated platforms from patients with CRLM for preclinical studies. Note: This abstract was not presented at the meeting. Citation Format: Jingyuan Wang, Wei Liu, Jing Gao, Baocai Xing, Lin Shen. Molecularly annotation of mouse avatar models derived from patients with colorectal cancer liver metastasis [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 1919.
Abstract 1433: NeoTCR-P1, a novel neoepitope-specific adoptive cell therapy, consists of T cells with ‘younger’ phenotypes that rapidly proliferate and kill target cells upon recognition of cognate antigen
Authors: Barbara Sennino, Andrew Conroy, Bhamini Purandare, Adam Litterman, Kyle Jacoby, Robert Moot, William Lu, Diana Nguyen, Fabrizia Urbinati, Susan Foy, Theresa Hunter, Olivier Dalmas, Michael Bethune, Tim Park, Songming Peng, Alex Franzusoff, Stefanie Mandl
Journal: Cancer Research (2019)

Abstract Clinical benefit observed with immuno-oncology trials often depends on the unleashing of a pre-existing intrinsic T cell immune response in each cancer patient. The targets of these intrinsic T cells are commonly ascribed to recognition of patient-specific neoantigens that arose from cancer mutations. PACT Pharma has developed the ability to selectively capture neoantigen-specific CD8+ T cells from peripheral blood of the patient. Leveraging this technology, PACT Pharma is developing personalized, autologous neo-epitope specific TCR-engineered T cell therapies for the eradication of solid tumors. Briefly, using PACT's proprietary TCR isolation technology neoepitope-specific TCRs are cloned and autologous CD8+ and CD4+ T cells from the same patient with cancer are precision genome engineered (using a DNA-mediated (non-viral) method) to express the neoTCR. NeoTCR expressing T cells are then expanded in a manner that preserves a “younger” T cell phenotypes, resulting in a NeoTCR-P1 product in which the majority of the T cells exhibit T memory stem cell and T central memory phenotypes. Upon cognate antigen encounter, NeoTCR-P1 rapidly differentiate into potent effector T cells. Engineered NeoTCR-P1 cells rapidly expand, secrete effector molecules such as perforin and granzyme B, and cytokines such as interferon-gamma (IFN-γ), IL-2 and TNF-alpha (TNF-α). Single cell secretome analysis demonstrates that NeoTCR-P1 cells are highly polyfunctional (secretion of two or more cytokines or effector proteins). These results demonstrate that PACT’s autologous ex vivo engineered NeoTCR-P1 T cells represent a highly personalized adoptive T cell therapy with potential to provide significant clinical benefit to subjects with solid tumors. Citation Format: Barbara Sennino, Andrew Conroy, Bhamini Purandare, Adam Litterman, Kyle Jacoby, Robert Moot, William Lu, Diana Nguyen, Fabrizia Urbinati, Susan Foy, Theresa Hunter, Olivier Dalmas, Michael Bethune, Tim Park, Songming Peng, Alex Franzusoff, Stefanie Mandl. NeoTCR-P1, a novel neoepitope-specific adoptive cell therapy, consists of T cells with ‘younger’ phenotypes that rapidly proliferate and kill target cells upon recognition of cognate antigen [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 1433.
Abstract 1706: Elevation of Pericardial Fluid Active Matrix Metalloproteinase-9 (MMP-9) Level Is Closely Associated With Left Ventricular Remodeling
Authors: Shoichi Miyamoto, Moriaki Inoko, Kunihiko Nagai, Eisaku Nakane, Tomomi Abe, Kenichi Sasaki, Junji Nakashima, Nozomi Tanaka, Kyokun Uehara, Koji Ueyama, Ryohei Hosokawa, Ryuji Nohara, Masatoshi Fujita
Journal: Circulation (2007)

Background: The development of congestive heart failure (CHF) is associated with left ventricular (LV) remodeling. However, fundamental mechanisms that contribute to this remodeling process remain unclear. The matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) have been demonstrated to play a significant role in tissue remodeling through a number of pathological processes. Objectives: The purpose of this study was to investigate whether MMPs and TIMPs represent autocrine/paracrine factors and are accumulated in pericardial fluid. We previously reported that active MMP-2 levels in pericardial fluid served as more sensitive and accurate indicators of LV remodeling than did active MMP-2 levels in plasma. Methods: We measured the concentrations of the enzyme (active MMP-9) in both plasma and pericardial fluid in 20 patients during coronary artery bypass graft surgery. Results: The active MMP-9 level was significantly higher in pericardial fluid than in plasma (4.68 ± 1.17 vs. 2.58 ± 0.29 ng/ml, p&lt;0.0001). Interestingly, the pericardial fluid levels of active MMP-9 were significantly higher in patients with impaired LV function than in those with normal LV function (5.25 ± 0.57 vs. 2.96 ± 0.65 ng/ml, p&lt;0.0001). Pericardial fluid active MMP-9 levels had closer relations with LVEDVI (r=0.459, p=0.047) and LVESVI (r=0.490, p=0.0321) than did plasma active MMP-9 levels (LVEDVI: r=0.065, p=NS; LVESVI: r=0.254, p=NS). Active MMP-9 levels in pericardial fluid but not in plasma inversely correlated with LV ejection fraction (r=−0.626, p=0.0033). Conclusions: Active MMP-9 levels in pericardial fluid serve as more sensitive and accurate indicators of LV remodeling than did active MMP-9 levels in plasma. Thus, active form of MMP-9 may be also secreted from the heart into the pericardial space with the progression of CHF, and it may have a pathophysiologic role in LV remodeling process as an autocrine/paracrine factor.
ZUMA-8: A phase 1/2 multicenter study evaluating KTE-X19 in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).
Authors: Ian Flinn, Michael Marris, William G. Wierda, Steven Coutre, John M. Pagel, John C. Byrd, Lovely Goyal, Krista Goodman, Yan Zheng, Francesca Milletti, Swaminathan Murugappan, Jennifer R. Brown
Journal: Journal of Clinical Oncology (2019)

TPS7566 Background: Despite treatment advances, CLL is largely incurable. First-line targeted therapy with ibrutinib mostly produces durable remissions, but high-risk disease or many prior therapies increases relapse risk (Ghia P, et al. Haematologica. 2014). Relapse after ibrutinib is associated with a poor outcome (Maddocks KJ, et al. JAMA Oncol. 2015). Allogeneic stem cell transplantation potentially offers long-term remissions but has a high risk of morbidity/mortality (Shustik C, et al. Ann Hematol. 2017). Autologous T cells expressing a CD19-specific chimeric antigen receptor (CAR) with a CD28 costimulatory domain may be efficacious against CLL (Kochenderfer JN, et al. Blood. 2012). KTE-X19 is an autologous anti-CD19 CAR T cell therapy under investigation for R/R hematologic malignancies and may offer longer durable remissions with manageable safety in pts with R/R CLL. ZUMA-8 is a Phase 1/2 multicenter study for pts with R/R CLL. Methods: Adult pts must have R/R CLL with ≥ 2 prior treatment regimens, disease progression on ibrutinib, ECOG 0-1, and adequate organ function. Phase 1 will enroll 12-18 pts to assess dose-limiting toxicities (DLTs) with a 6 + 3 dose escalation/de-escalation design; 30 more pts may be enrolled to further assess safety. Phase 2 will enroll ≈60 pts to evaluate efficacy and safety. Pts will undergo leukapheresis followed by optional bridging therapy. Cyclophosphamide (500 mg/m 2 ) and fludarabine (30 mg/m 2 ) conditioning chemotherapy will be given on Days -5, -4 and -3. KTE-X19 will be given on Day 0 at 0.5, 1 or 2 × 10 6 KTE-X19 cells/kg. The primary endpoint is incidence of DLTs for Phase 1 and independent review committee-assessed objective response rate (ORR) per iwCLL 2018 criteria for Phase 2. Secondary endpoints include complete remission (CR) rate, investigator-assessed ORR, minimal residual disease (MRD) negativity rate, MRD-negative CR rate, duration of response, progression-free survival, overall survival, safety, and patient-reported outcomes (Phase 2). Serum cytokine and blood KTE-X19 cell levels over time and level of anti-KTE-X19 antibodies are exploratory endpoints. Accrual is ongoing. Clinical trial information: NCT03624036.
Abstract 1099: Organotypic tumor tissue slices provide versatile platform for immuno-oncology
Authors: Ramya Sivakumar, Marina Chan, Raymond Yeung, Taranjit S. Gujral
Journal: Cancer Research (2019)

Abstract Organotypic tissue slices represent one of the most physiologically-relevant culture systems for studying the tumor microenvironment. The thin slices of tumor cut out using automated vibratome retain the original architecture and cellular composition of the tumor from several days up to weeks depending on the investigated tumor model. The slice culture has been emerging as a versatile platform for studying cancer cell-host cell interactions. However, a thorough characterization of the multicellular organotypic culture system, particularly its immune component, is still unresolved to allow a better understanding of its potential applications. Here, we carried out a comprehensive characterization of immune cell composition in organotypic tumor slices prepared from several different syngeneic mouse tumor models. We generated several syngeneic mouse tumor models and harvested the primary tumors to make tumor slices. We then immunophenotyped the major tumor infiltrating leukocytes (TILs) by flow cytometry to understand the immune makeup of these slices immediately after the harvest, over a period of 7 days and upon treatment of various immuno-modulators. We found that the immune compositions of tumor slices do not deviate from that of the tumor cores, immediately after harvest, across all the syngeneic tumor models. During the 7-day follow-up, despite an initial decline in the overall cell viability which stabilized on day 3, we observed a consistent percentage of TILs out of total viable cells, suggesting that the relative composition of tumor and immune populations can be maintained in the tumor slice over time. Among the TILs, macrophages were the predominant immune cell type detected, similar to that observed in many human solid tumors. Macrophages remained viable till day 7 while other cell types were mostly viable till day 5, providing a window of time sufficient to support many short-term perturbation studies. Further, we found that these immune cell populations were responsive to the treatment with immunomodulators. For example, we observed an upregulation of co-stimulatory markers, CD86 and MHC-II, on macrophages and DCs upon stimulation with the pro-inflammatory cytokine IFN γ, further supporting the application of tumor slice in the study of immuno-oncology. Overall, these data support the approach of utilizing tumor slice culture as a platform for studying tumor microenvironment and evaluating efficacy of immune modulatory drugs. Citation Format: Ramya Sivakumar, Marina Chan, Raymond Yeung, Taranjit S. Gujral. Organotypic tumor tissue slices provide versatile platform for immuno-oncology [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 1099.
Hundreds of NHS consultants have financial conflicts with private hospitals
Authors: Elisabeth Mahase
Journal: BMJ (2019)

A significant number of NHS consultants have financial interests in private hospitals and many have failed to declare them, according to a report from the Centre for Health and Public Interest (CHPI).1

The report, which looked at how private hospitals use financial incentives to win the business of medical consultants, said that a significant number of NHS consultants (546) own shares and equipment in private hospitals, giving them a potential financial incentive to refer patients to these hospitals for treatment.

Private hospitals were also found to give consultants who referred patients to them “substantial amounts of corporate hospitality,” with an estimated £1.5m (€1.7m; $1.9m) worth of gifts given …