tbuckley/cabot-search huggingface dataset:
Abstract 1811: A novel OX40 humanized mouse model for efficacy assessment of OX40-targeting therapies
Authors: Fabiane Sônego, Gaëlle Martin, Audrey Beringer, Chloé Beuraud, Yacine Cherifi, Alexandre Fraichard, Patricia Isnard Petit, Kader Thiam
Journal: Cancer Research (2021)

Abstract Immunotherapies through targeting of activating and inhibitory immune checkpoints (ICP) has revolutionized the treatment of cancers. To facilitate the translation of basic research into clinical application of these immunotherapies, we developed a pipeline of immunocompetent mouse models expressing humanized ICP instead of their mouse counterparts, thus compounds can be tested in the absence of endogenous cross-reacting mouse targets. The humanization strategy is target-dependent but ensures that the biology of the target, its physiological regulation and interacting partners are preserved. Herein, we describe a novel OX40 humanized mouse model (hOX40 model), designed to assess the efficacy and mechanism of action of compounds targeting human OX40 (hOX40). The expression of the fully human OX40 protein (human extracellular, transmembrane and intracellular domains) did not alter the distribution of immune cells in spleen, blood and bone marrow. hOX40 was expressed on CD4 and CD8 T cells upon activation and the kinetic of expression mirrored the expression of mouse OX40 in WT cells activated under the same conditions. Treg cells isolated from hOX40 mice expressed hOX40 and this expression was upregulated upon activation, also recapitulating the expression of mouse OX40 in WT cells, and suggesting that the regulation of OX40 expression was kept in the hOX40 mice. hOX40 was also found to be functional on CD4 T cells, as evidenced by the increased proliferation and cytokine production upon stimulation with human OX40 ligand. Importantly, hOX40 mice bearing MC38 tumors showed a tumor growth inhibition upon treatment with an anti-human OX40 therapy with agonist activity. This model should also enable the investigation of mechanism of action as well as tumor immunological memory, as a similar design of the hOX40 model was used for the assessment of a bispecific therapy targeting OX40 and CTLA-4 (Kvarnhammar et.al, 2019). The hOX40 mouse model is currently being crossed with other models expressing humanized immune checkpoint to enable the assessment of bispecifics and combo therapies. Citation Format: Fabiane Sônego, Gaëlle Martin, Audrey Beringer, Chloé Beuraud, Yacine Cherifi, Alexandre Fraichard, Patricia Isnard Petit, Kader Thiam. A novel OX40 humanized mouse model for efficacy assessment of OX40-targeting therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1811.
Abstract 2558: Understanding the shared roles of obesity and genetic mutation in the development of endometrial cancer
Authors: Mike R. Wilson, Jake J. Reske, Ronald L. Chandler
Journal: Cancer Research (2021)

Abstract Up to 20% of all cancer deaths in women can be attributed to excess body weight. Endometrial cancer was the first cancer identified with an increased risk among obese populations, and incidence of endometrial cancer is rising steadily due to the obesity epidemic. Obesity is associated with over 60% of endometrial cancer occurring in the United States, but like many cancers, the causes of endometrial cancer are multi-faceted. Increased estrogen abundance in obese women is considered the primary driver, but obesity-linked complications, including hyperinsulinemia, are also known to contribute to endometrial cancer. However, obesity alone is not sufficient for tumorigenesis. Genetic mutations driving endometrial cancer are well characterized, but these mutations alone are not sufficient for EC pathogenesis as they exist in uteri without cancer. In normal cells, the PI3K pathway maintains metabolic homeostasis, but in cancer the PI3K pathway is activated to promote cell survival. There is an urgent need to understand the mechanisms by which obesity and genetic mutation interact to promote EC. Metabolic signaling influences protein production and folding. The unfolded protein response pathway acts to maintain protein quality control, and is activated upon endoplasmic reticulum stress. During endoplasmic reticulum stress, if proteostasis cannot be achieved, the unfolded protein response is activated, resulting in cell death. Obesity results in systemic endoplasmic reticulum stress, with overabundant estrogen and hyperinsulinemia likely as contributing factors. In our preliminary studies, we have identified a role for PI3K pathway mutations in regulating endoplasmic reticulum stress in the endometrial epithelium. By antagonizing endoplasmic reticulum stress, PI3K pathway mutations may promote survival of endometrial epithelium through resistance to unfolded protein response-mediated cell death mechanisms. Through understanding endoplasmic reticulum stress resistance in the endometrial epithelium, we hope to develop preventative interventions for obese women at risk for endometrial cancer. Citation Format: Mike R. Wilson, Jake J. Reske, Ronald L. Chandler. Understanding the shared roles of obesity and genetic mutation in the development of endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2558.
Abstract 2950: Humanized C5AR1 mouse model (B-hC5AR1 mice) for evaluation of anti-C5AR1 mAb <i>in vivo</i> efficacy
Authors: Yanhui Nie, Xiaofei Zhou, Jing Zhang, Veronika Chromikova, Yuelei Shen
Journal: Cancer Research (2021)

Abstract C5AR1 (complement C5a receptor 1) is a classical G protein-coupled receptor that is mainly expressed on granulocytes, monocytes, dendritic cells and MDSCs (Myeloid-derived suppressor cells) in several cancer types. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immature cells that play a significant role in inhibiting T cell-related responses. C5a can directly bind and activate MDSCs to upregulate C5AR1 expression, and that in turn leads to an increased stimulation of MDSCs by C5a, which further increases immunosuppression. The enhancement of cancer cell invasion and growth by the C5a-C5AR1 system suggests that this system is a possible target for cancer therapy. Currently, there is a lot of focus on research and development of antibody drugs targeting C5AR1. In order to generate a suitable animal model in which to evaluate the in vivo activity of humanized anti-C5AR1 antibodies, we have developed C5AR1 humanized mice (B-hC5AR1 mice) in which the murine C5ar1 gene is replaced with the human C5AR1 gene by homologous recombination. The viability of this model is supported by previous studies showing that mouse and human C5a bind human C5AR1 with comparable affinities. Our analysis shows that human C5AR1 was detectable in dendritic cells, granulocytes and macrophages isolated from spleen and dendritic cells isolated from bone marrow in homozygous B-hC5AR1 mice but not in wild type mice. Percentage of T cells, B cells, NK cells, DCs, granulocytes, monocytes, macrophages, CD8+ T cells, CD4+ T cells and Tregs in homozygous B-hC5AR1 mice were similar to those in the wild type mice, demonstrating that introduction of human C5AR1 in place of its mouse counterpart does not change the overall development, differentiation or distribution of these cell types. Following these results, we performed an in vivo efficacy evaluation of an anti-human C5AR1 antibody using the humanized mice. Mouse pancreatic ductal adenocarcinoma Panc02 cells were subcutaneously implanted into homozygous B-hC5AR1 mice (female, 6-7 week-old, n=5). Mice were grouped when tumor volume reached approximately 100 mm3, at which time they were treated with anti-human C5AR1 antibodies. We observed that anti-human C5AR1 antibodies were efficacious in controlling tumor growth in B-hC5AR1 mice. Mouse C5AR1 and human C5AR1 was detectable on MDSCs from TILs isolated of wild type mice and B-hC5AR1 mice, respectively. In conclusion, B-hC5AR1 mice are a promising model for preclinical in vivo pharmacodynamic assessment of anti-C5AR1 antibodies. Citation Format: Yanhui Nie, Xiaofei Zhou, Jing Zhang, Veronika Chromikova, Yuelei Shen. Humanized C5AR1 mouse model (B-hC5AR1 mice) for evaluation of anti-C5AR1 mAb in vivo efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2950.
Abstract 1644: Targeting type I IFN-regulated secretory profiles to overcome acquired anti-PD-L1 resistance
Authors: Yuhao Shi, Melissa Dolan, Michalis Mastri, James W. Hill, Kevin Eng, John M. Ebos
Journal: Cancer Research (2021)

Abstract Therapeutic inhibition of PD-L1 has led to durable benefits for many cancer patients; however, acquired resistance is common. Dysregulated type I and II interferon (IFN) signalling on tumor cells can contribute to resistance via altered expression of IFN stimulated genes (ISGs) leading to immune-suppression and tumor promotion. In this study, we examined the role of type I IFN signaling following acquired resistance to PD-L1 blockade using an EMT6 mouse breast orthotopic tumor model that was initially responsive to treatment, but that later relapsed. Following selection of PD-L1 drug resistant (PDR) tumor cells, transcriptomic and proteomic analysis was used to identify a unique signature of secreted proteins associated with IFN signaling that was then validated using published preclinical and clinical datasets. Using genetic and therapeutic approaches to block PD-L1 in vitro, we found PDR secretory signatures to be enhanced after type I IFN stimulation. In vivo, inhibition of specific ISGs (IL-6) or ISG regulators (IFNAR1) led to enhanced anti-tumor effects in PDR models, compared to parental controls. Together, these results identify a secretory profile associated with acquired resistance to PD-L1 blockade that may be modulated, in part, by a tumor-intrinsic PD-L1/IFN signaling crosstalk and suggest that selective targeting of secreted ISGs may provide benefit for patients after anti-PD-L1 treatment failure. Citation Format: Yuhao Shi, Melissa Dolan, Michalis Mastri, James W. Hill, Kevin Eng, John M. Ebos. Targeting type I IFN-regulated secretory profiles to overcome acquired anti-PD-L1 resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1644.
Genome-scale screens identify factors regulating tumor cell responses to natural killer cells
Authors: Michal Sheffer, Emily Lowry, Nicky Beelen, Minasri Borah, Suha Naffar-Abu Amara, Chris C. Mader, Jennifer A. Roth, Aviad Tsherniak, Samuel S. Freeman, Olga Dashevsky, Sara Gandolfi, Samantha Bender, Jordan G. Bryan, Cong Zhu, Li Wang, Ifrah Tariq, Govinda M. Kamath, Ricardo De Matos Simoes, Eugen Dhimolea, Channing Yu, Yiguo Hu, Olli Dufva, Marios Giannakis, Vasilis Syrgkanis, Ernest Fraenkel, Todd Golub, Rizwan Romee, Satu Mustjoki, Aedin C. Culhane, Lotte Wieten, Constantine S. Mitsiades
Journal: Nature Genetics (2021)
Abstract 2054: Characterization of TQB3823, a differentiated PARP inhibitor with anti-tumor activity in BRCA-deficiency cancer models
Authors: Hu Yanbin, Zhang Xiquan, Yang Ling, Tian Xin, Li Gang, Hu Lihong, Charles Z. Ding, Xia Yuanfeng, Li Wei, Yin Shanshan, Chen Ying, Wu Songliang, Chen Shuhui
Journal: Cancer Research (2021)

Abstract Objective: Homology-directed repair (HDR) pathway is the major DNA double-strand break repair pathway. BRCA-deficiency impairs this pathway, and combination with Poly(ADP-ribose) polymerase (PARP) inhibition results in cell death. This process is known as “synthetic lethality”. A proportion of breast cancer, ovarian cancer and other solid tumor patients carrying BRCA-mutated gene receive benefits from PARP inhibitors. In this study, we present in vitro activity and in vivo efficacy data of a novel small molecule PARP inhibitor, TQB3823 to support it as our clinical candidate. Method: Enzyme inhibition activities of TQB3823 were determined in PARP1/PARP2/Tankyrase 1 assays. Cellular anti-proliferative activity and selectivity were evaluated in MDA-MB-436 cell line with BRCA1 mutation and BRCA wild type MDA-MB-231 cell line. Antitumor efficacy of TQB3823 was investigated in BRCA1 mutated MDA-MB-436 breast cancer CDX model. Result: TQB3823 showed high potency and selectivity at both enzymatic and cellular level. IC50 of TQB3823 in PARP1/PARP2/Tankyrase 1 assays are 2.8/0.9/629.3 nM, respectively. It inhibited proliferation of BRCA1 mutant MDA-MB-436 cell with IC50 of 9.6 nM. In contrast, TQB3823 showed little anti-proliferative activity in BRCA-wild type MDA-MB-231 cell with IC50 &amp;gt;10 μM. TQB3823 demonstrated antitumor efficacy in dose dependent fashions with tumor regression was observed at 25 mg/kg in MDA-MB-436 CDX model. The level of antitumor effects was superior to niraparib at the same dose in the same study. DNA trapping experiments revealed similar potency to olaparib indicative of low toxicity. Conclusion: We have identified a novel, potent and selective PARP inhibitor TQB3823, which inhibits the proliferation of BRCA mutant cells but spares the wild type cells. In vivo study in a BRCA-deficiency tumor model confirms the high in vivo efficacy of this molecule. In conclusion, TQB3823 represents a promising differentiated clinical candidate for treating solid cancers with homology directed repair. Citation Format: Hu Yanbin, Zhang Xiquan, Yang Ling, Tian Xin, Li Gang, Hu Lihong, Charles Z. Ding, Xia Yuanfeng, Li Wei, Yin Shanshan, Chen Ying, Wu Songliang, Chen Shuhui. Characterization of TQB3823, a differentiated PARP inhibitor with anti-tumor activity in BRCA-deficiency cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2054.
Prediction of combination therapies based on topological modeling of the immune signaling network in multiple sclerosis
Authors: Marti Bernardo-Faura, Melanie Rinas, Jakob Wirbel, Inna Pertsovskaya, Vicky Pliaka, Dimitris E. Messinis, Gemma Vila, Theodore Sakellaropoulos, Wolfgang Faigle, Pernilla Stridh, Janina R. Behrens, Tomas Olsson, Roland Martin, Friedemann Paul, Leonidas G. Alexopoulos, Pablo Villoslada, Julio Saez-Rodriguez
Journal: Genome Medicine (2021)

Abstract Background Multiple sclerosis (MS) is a major health problem, leading to a significant disability and patient suffering. Although chronic activation of the immune system is a hallmark of the disease, its pathogenesis is poorly understood, while current treatments only ameliorate the disease and may produce severe side effects. Methods Here, we applied a network-based modeling approach based on phosphoproteomic data to uncover the differential activation in signaling wiring between healthy donors, untreated patients, and those under different treatments. Based in the patient-specific networks, we aimed to create a new approach to identify drug combinations that revert signaling to a healthy-like state. We performed ex vivo multiplexed phosphoproteomic assays upon perturbations with multiple drugs and ligands in primary immune cells from 169 subjects (MS patients, n=129 and matched healthy controls, n=40). Patients were either untreated or treated with fingolimod, natalizumab, interferon-β, glatiramer acetate, or the experimental therapy epigallocatechin gallate (EGCG). We generated for each donor a dynamic logic model by fitting a bespoke literature-derived network of MS-related pathways to the perturbation data. Last, we developed an approach based on network topology to identify deregulated interactions whose activity could be reverted to a “healthy-like” status by combination therapy. The experimental autoimmune encephalomyelitis (EAE) mouse model of MS was used to validate the prediction of combination therapies. Results Analysis of the models uncovered features of healthy-, disease-, and drug-specific signaling networks. We predicted several combinations with approved MS drugs that could revert signaling to a healthy-like state. Specifically, TGF-β activated kinase 1 (TAK1) kinase, involved in Transforming growth factor β-1 proprotein (TGF-β), Toll-like receptor, B cell receptor, and response to inflammation pathways, was found to be highly deregulated and co-druggable with all MS drugs studied. One of these predicted combinations, fingolimod with a TAK1 inhibitor, was validated in an animal model of MS. Conclusions Our approach based on donor-specific signaling networks enables prediction of targets for combination therapy for MS and other complex diseases.
Abstract 2759: Reprogramming of PD1+ M2-like tumor-associated macrophages with anti-PD-L1 and Lenalidomide in cutaneous T cell lymphoma
Authors: Zhen Han, Chingyu Su, Xiwei Wu, Hanjun Qin, Steven T. Rosen, Christiane Querfeld
Journal: Cancer Research (2021)

Abstract M2-like tumor-associated macrophages (TAMs) are abundant and influence cutaneous T cell lymphoma (CTCL) development by inducing immunosuppression. Although it is well established that depletion of M2-like TAMs delays CTCL development, little is known about the underlying mechanisms that shape programmed cell death 1+ (PD1+) M2-like TAMs phenotype in CTCL. Here we identified PD1+ M2-like TAMs accumulated in CTCL lesional skin. Moreover, RNA-seq analysis of human CTCL tissues revealed an up-regulation of the TLR/NF-κB and JAK/STAT signaling pathways. In vitro, PD1+ TAMs exhibited an M2-like profile, with a significant increase in the expression of CD163, CD206, and IL-10, and a clear decrease in the expression of CD80, IL-1β, CXCL-10, and CXCL-11, and the activation of TLR/NF-κB and JAK/STAT signaling pathways. To determine whether PD1+ M2-like TAMs could be reprogrammed, anti-PD-L1 (durvalumab) and lenalidomide were used for treatment of MyLa-conditioned media induced human peripheral blood monocyte-derived PD1+ M2-like TAMs. The results show that anti-PD-L1 and lenalidomide synergistically reshaped M2-like TAMs to M1-like TAMs in vitro through ablation of the TLR/NF-κB and JAK/STAT signaling pathways, which was linked with functional changes in phagocytic activity and cell migration. In conclusion, TLR/NF-κB and JAK/STAT signaling pathways may drive PD1+ M2-like TAMs programming in the CTCL tumor microenvironment, anti-PD-L1 and lenalidomide may reshape PD1+ M2-like TAMs and induce functional changes through ablation of these specific pathways in CTCL. Corresponding author: Christiane Querfeld, MD, PhD. Div. of Dermatology and Beckman Research Institute, City of Hope. 1500 E. Duarte Road, Duarte, CA 91010. Email: cquerfeld@coh.org Phone: 626-634-4436 Fax: 626-218-6190 Citation Format: Zhen Han1,5, Chingyu Su1,5, Xiwei Wu2,5, Hanjun Qin2,5, Steven T. Rosen3,5, Christiane Querfeld1,3,4,5. Reprogramming of PD1+ M2-like tumor-associated macrophages with anti-PD-L1 and Lenalidomide in cutaneous T cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2759.
Orchestration of myeloid-derived suppressor cells in the tumor microenvironment by ubiquitous cellular protein TCTP released by tumor cells
Authors: Sho Hangai, Takeshi Kawamura, Yoshitaka Kimura, Ching-Yun Chang, Sana Hibino, Daisuke Yamamoto, Yousuke Nakai, Ryosuke Tateishi, Masanobu Oshima, Hiroko Oshima, Tatsuhiko Kodama, Kyoji Moriya, Kazuhiko Koike, Hideyuki Yanai, Tadatsugu Taniguchi
Journal: Nature Immunology (2021)
Covid 19: We need a full open independent investigation into its origins
Authors: Fiona Godlee
Journal: BMJ (2021)

When news first broke that a contagious and deadly new virus had emerged in Wuhan, many were struck by the coincidence of the city being the home of one of the world's top virus research laboratories.But any suggestion that the virus originated in a laboratory was quickly labelled a conspiracy theory, dismissed by mainstream media, and even banned from Facebook.Donald Trump's support helped the theory on its way to being something that no progressive thinking person could entertain.
Evaluation of Insurance Coverage and Cancer Stage at Diagnosis Among Low-Income Adults With Renal Cell Carcinoma After Passage of the Patient Protection and Affordable Care Act
Authors: Juan F. Javier-DesLoges, Julia Yuan, Shady Soliman, Kevin Hakimi, Margaret F. Meagher, Fady Ghali, Walter Hsiang, Devin N. Patel, Simon P. Kim, James D. Murphy, J. Kellogg Parsons, Ithaar H. Derweesh
Journal: JAMA Network Open (2021)

<h3>Importance</h3> The association of the Patient Protection and Affordable Care Act (ACA) with insurance status and cancer stage at diagnosis among patients with renal cell carcinoma (RCC) is unknown. <h3>Objective</h3> To test the hypothesis that the ACA may be associated with increased access to care through expansion of insurance, which may vary based on income. <h3>Design, Setting, and Participants</h3> This retrospective cohort analysis included patients diagnosed with RCC from January 1, 2010, to December 31, 2016, in the National Cancer Database. Data were analyzed from July 1 to December 31, 2020. The periods from 2010 to 2013 and from 2014 to 2016 were defined as pre- and post-ACA implementation, respectively. Patients were categorized as living in a Medicaid expansion state or not. <h3>Exposures</h3> Implementation of the ACA. <h3>Main Outcomes and Measures</h3> The absolute percentage change (APC) of insurance coverage was calculated before and after ACA implementation in expansion and nonexpansion states. Secondary outcomes included change in stage at diagnosis, difference in the rate of insurance change, and change in localized disease between expansion and nonexpansion states. Adjusted difference-in-difference modeling was performed. <h3>Results</h3> The cohort included 78 099 patients (64.7% male and 35.3% female; mean [SD] age, 54.66 [6.46] years), of whom 21.2% had low, 46.2% had middle, and 32.6% had high incomes. After ACA implementation, expansion states had a lower proportion of uninsured patients (adjusted difference-in-difference, −1.14% [95% CI, −1.98% to −1.41%];<i>P</i> = .005). This occurred to the greatest degree among low-income patients through the acquisition of Medicaid (APC, 11.0% [95% CI, 8.6%-13.3%];<i>P</i> &lt; .001). Implementation of the ACA was also associated with an increase in detection of stage I and II disease (APC, 4.0% [95% CI, 1.6%-6.3%];<i>P</i> = .001) among low-income patients in expansion states. <h3>Conclusions and Relevance</h3> Among patients with RCC, ACA implementation was associated with an increase in insurance coverage status in both expansion and nonexpansion states for all income groups, but to a greater degree in expansion states. The proportion of patients with localized disease increased among low-income patients in both states. These data suggest that ACA implementation is associated with earlier RCC detection among lower-income patients.
Development of novel criteria to identify the optimal candidates for active surveillance among men with low-risk prostate cancer and a positive family history. Results from a large, single institution series
Authors: R. Leni, G. Gandaglia, L. Nocera, A. Stabile, N. Fossati, M. Bandini, L. Toneatto, G. Basile, A. Martini, F. Pellegrino, E. Mazzone, G. Rosiello, F. De Cobelli, F. Montorsi, A. Briganti
Journal: European Urology (2021)