tbuckley/cabot-search huggingface dataset:
Abstract 3452: Pre-clinical development of next generation selective estrogen receptor degrader - SAR439859
Authors: Fangxian Sun, Jane Cheng, Amy Sullivan, Natalia Malkova, Maysoun Shomali, Jesseca McManus, Mikhail Levit, Dinesh Bangari, Youssef El-Ahmad, Sukhvinder Sidhu, Laurent Debussche, Monsif Bouaboula
Journal: Cancer Research (2020)

Abstract Abstract: Nearly 70% or more of newly diagnosed cases of breast cancer (BC) are estrogen receptor positive (ER+) where endocrine therapy is a primary treatment. However, substantial evidence describes a continued role of ER signaling in tumor progression, where approximately 40% of patients on endocrine therapy develop resistance that include mutations in ER that drive a constitutively active receptor. SAR439859 is a novel next generation SERD (selective estrogen receptor degrader) with potent antagonist and degradation activity against ER both wild type and mutant and currently evaluated as a single agent and in combination with palbociclib in a Phase I/II clinical trial (NCT03284957). Here we describe the preclinical development of this molecule in multiple xenografts and demonstrated significant anti-tumor efficacy/regression in ER+ BC models including MCF7-ESR1 mutant-Y537S and endocrine therapy resistant patient-derived xenograft tumor models. The molecule also demonstrated strong synergistic activity with CDK4 inhibitor palbociclib. SAR439859 has a favorable safe profile and no uterotrophic activities. Collectively, these results show that SAR439859 is an oral, selective estrogen receptor antagonist and degrader that could provide therapeutic benefit to ER+ breast cancer patients. In conclusion, SAR439859 demonstrates broad anti-tumor activity in ER+ breast cancer cell line/PDX models. Anti-tumor efficacy correlates with PK exposure/PD modulation in target tissue. SAR439859 also has synergistic activity with CDK4 inhibitor Palbociclib. Citation Format: Fangxian Sun, Jane Cheng, Amy Sullivan, Natalia Malkova, Maysoun Shomali, Jesseca McManus, Mikhail Levit, Dinesh Bangari, Youssef El-Ahmad, Sukhvinder Sidhu, Laurent Debussche, Monsif Bouaboula. Pre-clinical development of next generation selective estrogen receptor degrader - SAR439859 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3452.
Abstract 5050: Novel TNFR2 humanized mouse model for human TNFR2 antibody evaluation
Authors: Yanan Guo, Yanan Li, Xiaofei Zhou, Youhong Su, Qingcong Lin
Journal: Cancer Research (2020)

Abstract In recent years, immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. Tumor necrosis factor receptor 2 (TNFR2), also known as tumor necrosis factor receptor superfamily member 1B (TNFRSF1B), is a transmembrane receptor that has been linked into immune modulation and tissue regeneration. TNFR2 is mainly expressed on the surface of a subset of potent regulatory T cells (Tregs) and promote the proliferation of Tregs through nuclear factor kappa B (NF-κB). Anti-TNFR2 antibodies have been developed to inhibit NF-κB driven growth and have revived excitement for the use of anti-TNFR2 antibodies in the clinic. To investigate the role of TNFR2, Biocytogen generated TNFR2 humanized mouse for both in vitro function validation of signaling pathway and in vivo efficacy evaluation of TNFR2 antibodies. In this model, the exon 2~6 of mouse Tnfr2 gene which encode the extracellular was replaced by human TNFR2 counterparts. Human TNFR2 is detectable on the Tregs in spleen and the TNFR2 antibodies bind well to the splenocytes of the TNFR2 humanized mice. Basal leukocyte subpopulations of TNFR2 humanized mice are comparable to that of wild-type mice, including T/B cells, NK cells, DC, granulocytes and monocytes/macrophages. Anti-human TNFR2 antibodies can repress the growth of colon cancer cells engrafted on TNFR2 humanized mice. The TNFα/TNFR2 signaling pathway is under validation on TNFR2 humanized mice and TNFα/TNFR2 double humanized mice due to the uncertain cross-reactivity between mouse and human TNFα/TNFR2. Taken together, TNFR2 humanized mice is a useful tool for in vivo efficacy evaluation of human TNFR2 antibodies that can be advanced to human clinical trials. Citation Format: Yanan Guo, Yanan Li, Xiaofei Zhou, Youhong Su, Qingcong Lin. Novel TNFR2 humanized mouse model for human TNFR2 antibody evaluation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5050.
Abstract 2204: Enhancing anti-tumor efficacy of MART-1-specific TCR-T cells by CRISPR-Cas9-based PD-1 disruption
Authors: Qianqian Gao, Renpeng Ding, Huanyi Chen, Qumiao Xu, Linnan Zhu, Xuan Dong, Ying Gu, Cheng-chi Chao
Journal: Cancer Research (2020)

Abstract T cell function can be compromised when continuously exposed to tumor antigens by immune checkpoint signaling. Immunotherapies with T cells and inhibitors of repressive checkpoint molecules such as PD-1, CTLA-4, etc. have been shown promising results in cancer clinical trials. Inhibitors of checkpoint molecules have been solely used to block or suppress the corresponding pathways to improve the functionality of T cells and enhance the anti-tumor immunity. However, few reports combined disruption of repressive checkpoint molecules with TCR-T cell therapy for the treatment of cancer patients. In our study, new TCR sequence was attained from T cells stimulated by Melan-A (aa27-35) peptide, but the cytotoxicity of MART-1-specific TCR-T cells was found to be inhibited by expression of PD-L1 in target cells. To overcome this PD(L)-1-mediated suppression, Cas9 mRNA and gRNA were electroporated into primary T cells infected by MART-1 TCR lentivirus. CRISPR/Cas9-mediated PD-1 disruption in MART-1 TCR-T cells recovered T cell cytotoxicity inhibited by PD-L1 overexpression in target cells. In addition, secretion of IFNγ and IL-2 was also increased in PD-1-damaged TCR-T cells. Furthermore, the differences between wild-type and PD-1-disrupted TCR-T cells were characterized by single-cell RNA (scRNA) sequencing. In summary, our study illustrates enhanced therapeutic efficacy and different features of PD-1-eliminated TCR-T cells compared to the control, providing an alternative strategy for current cell therapy. Citation Format: Qianqian Gao, Renpeng Ding, Huanyi Chen, Qumiao Xu, Linnan Zhu, Xuan Dong, Ying Gu, Cheng-chi Chao. Enhancing anti-tumor efficacy of MART-1-specific TCR-T cells by CRISPR-Cas9-based PD-1 disruption [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2204.
Abstract 2790: Evaluation of S100A9 targeted nanoparticles containing rapamycin to treat pancreatic adenocarcinoma
Authors: Karl Thomas, Molly McNally, Abhilash Samykutty, Lacey R. McNally
Journal: Cancer Research (2020)

Abstract Despite Pancreatic cancer being expected to contribute to only 3% of new cancer cases in both males and females in 2019, it is expected to cause an estimated 45,750 deaths making it the third highest contributor to cancer deaths. This is due to the low survivability associated with pancreatic cancer which has a 5-year survival rate of only 9%. In order to address the poor prognosis common with pancreatic cancer, biomarkers are being used to create therapies targeted to specific cancer cells. The S100A8/A9 complex is a heterodimer, known for modulating the inflammatory response, and it is upregulated in a variety of cancers including pancreatic cancers. For this reason, we selected it as a targeting agent to deliver Rapamycin to pancreatic cancer cells via a mesoporous silica-encased gold nanorod (MS-GNR). The use of this nanoparticle allows an anticancer molecule to be encapsulated within the mesoporous silica matrix by further encapsulation of the nanoparticle with the pH sensitive polymer chitosan. A low pH tumor microenvironment induces relaxation of the chitosan surrounding this chitosan-capped mesoporous silica gold nanorod (CMG) allowing for the anticancer molecule to be released only in cancer cells. The gold nanorod at the core of this enables these nanoparticles to be imaged in real time via Multispectral Optoacoustic Tomography (MSOT). Using these tools, we linked S100A9 to a mesoporous silica-encased gold nanorod which contained Rapamycin held in via the chitosan polymer (S100A9-Rap-CMG). MSOT imaging revealed a strong uptake in S2013Q and MiaPaca pancreatic cancer cells. Further tests showed that at a pH 6.8 S100A9-Rap-CMG treatment resulted in an increase in cell death by 69% compared to treatment at physiologic pH of 7.4 by the S100A9-Rap-CMG's which did not induce cell death. This data indicates the feasibility of S100A9 as a targeting agent for pancreatic cancer cells and the potential benefits of nano-drug delivery of Rapamycin to treat pancreatic adenocarcinoma. The ultimate benefit of the nano-drug delivery includes both increased tumor targeting and mitigating premature drug release and offsite delivery. Citation Format: Karl Thomas, Molly McNally, Abhilash Samykutty, Lacey R. McNally. Evaluation of S100A9 targeted nanoparticles containing rapamycin to treat pancreatic adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2790.
Abstract 472: What electric field strength is necessary for maximum tumor-treating fields efficacy
Authors: Kristen W. Carlson, Jack A. Tuszynski, Socrates Dokos, Nirmal Paudel, Zeev Bomzon
Journal: Cancer Research (2020)

Abstract Why Is 4 V/cm Electric Field Strength Necessary for Maximum Tumor-Treating Fields Efficacy? INTRODUCTION: Tumor Treating Fields (TTFields) extend overall survival in glioblastoma patients. Threshold field strength for TTFields is typically cited as 2V/cm. Yet plots of cell death vs. field strength in vitro indicate a power law relationship asymptotic to 4 V/cm for 100% efficacy. The mechanisms of action (MoA) of TTFields underlying this relationship are currently under investigation. TTFields are suspected of disrupting critical mitotic processes performed by large polar cellular molecules such as microtubules (MT). METHODS: Using the power law relationship for the energy (intensity, I) carried by an electric field and its amplitude (Eq. 1), we calculated energy vs. TTFields amplitude. (1) RESULTS: We suggest Eq. 1 is a likely source of the relationship between TTFields' amplitude and cell death proportion that has been demonstrated empirically. Further, Table 1 shows energy transmitted per unit MT surface area per TTFields cycle, specifically, the energy per MT dimer band around an MT helix per TTFields period of 5 µs. TTFields Field Strength (V/cm)Radiant Flux Density (W/nm2)Energy/(Cycle-Area) (J/nm2)Energy/MT Dimer/Cycle (J)Energy/MT Dimer Band/Cycle (J)113.3 × 10−186.63 × 10−234.01 × 10−224.17 × 10−20253.1 × 10−1826.6 × 10−231.60 × 10−211.67 × 10−193119 × 10−1859.7 × 10−233.61 × 10−213.75 × 10−194212 × 10−18106 × 10−236.42 × 10−216.67 × 10−195332 × 10−18166 × 10−231.00 × 10−201.04 × 10−186478 × 10−18239 × 10−231.44 × 10−201.50 × 10−18 A metric for disruption of cellular processes is 1-2 orders of magnitude greater than the thermal background energy in the cell, kT = 4.3 × 10−21 J. Table 1 shows that the energy absorbed by a MT dimer is insufficient to disrupt cellular processes at 2 V/cm, while due to energy increasing with square of field strength, at 5 V/cm it may be disruptive. For an entire dimer band around the MT helix, 2 V/cm appears to be sufficient, while 4 V/cm seems amply strong to disrupt MT function, in accordance with in vitro experiments. CONCLUSION: Assuming the power law of energy vs. electric field strength and the resulting energy absorbed by microtubule components, we found a correlation between typical TTFields' amplitudes and estimated disruption thresholds of MT function. TTFields MoA. 4 V/cm, not 2V/cm, should be the target field strength to realize the full efficacy of TTFields. Citation Format: Kristen W. Carlson, Jack A. Tuszynski, Socrates Dokos, Nirmal Paudel, Zeev Bomzon. What electric field strength is necessary for maximum tumor-treating fields efficacy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 472.
Abstract 6096: Bladder cancer microbiome and its association with chemoresponse
Authors: Rashida Ginwala, Erika Nachman, Suraj Peri, Jodie Franklin, Leigh Greathouse, Molly Ingersoll, Alexander Kutikov, James R. White, Philip H. Abbosh
Journal: Cancer Research (2020)

Abstract Background: The microbiome is widely known to cause cancer, modify its behavior, and alter the way therapies interact with tumors. Despite the urinary microbiome being one of the most clinically significant microbiomes in human health, is one of the least well-described. Results: To begin to annotate the urinary microbiome present in bladder cancers, we analyzed raw sequencing data from the Cancer Genome Atlas (TCGA) from 116 tumors (duplicates from 22 tumors), 22 adjacent normal bladder tissues, and 99 blood samples to identify reads originating from known microbiota. Twenty-seven viral and bacterial species were found to be enriched in the tumor samples. Bacterial species such as B. thetaiotamicron, A. mucinaphila and Bifidobacterium spp. with known positive association with immune checkpoint blockade therapy against CTLA-4 and PD-L1 were frequently found in these tumor samples. We also found sex-specific enrichment of genera such as Lactobacillus and Prevotella in female bladder cancer patients which also are prevalent in the normal female genitourinary tract. A. prevotii and F. magna were also enriched in females. We also found a correlation between Prevotella and TCGA subtypes III and IV (basal expression subtypes), suggesting a link between enrichment of certain microbial species and bladder cancer subtypes. Finally, single sample gene set enrichment analysis using the Hallmark and KEGG gene sets revealed the association of Mycoplasma with the Hallmark DNA repair gene set and with the KEGG pyrimidine metabolism pathway that can be further studied to ascertain its effects on DNA damaging chemotherapeutic agents. To corroborate these findings, we performed 16S metagenomics from urine pellets of 40 bladder cancer patients undergoing radical cystectomy on a prospective clinical trial (NCT02968732). We found one predominant genus consistent with prior urinary metagenomics studies in samples from most of the patients. Thirty eight of the 58 genera identified in the TCGA analyses were also present in these urine samples. Further correlation with response to clinical metadata is ongoing. Conclusions: Description of the bladder cancer microbiome is the first step in approaches to manipulate it for therapeutic gain. Citation Format: Rashida Ginwala, Erika Nachman, Suraj Peri, Jodie Franklin, Leigh Greathouse, Molly Ingersoll, Alexander Kutikov, James R. White, Philip H. Abbosh. Bladder cancer microbiome and its association with chemoresponse [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6096.
Genomic risk scores for juvenile idiopathic arthritis and its subtypes
Authors: Rodrigo Cánovas, Joanna Cobb, Marta Brozynska, John Bowes, Yun R Li, Samantha Louise Smith, Hakon Hakonarson, Wendy Thomson, Justine A Ellis, Gad Abraham, Jane E Munro, Michael Inouye
Journal: Annals of the Rheumatic Diseases (2020)

Objectives Juvenile idiopathic arthritis (JIA) is an autoimmune disease and a common cause of chronic disability in children. Diagnosis of JIA is based purely on clinical symptoms, which can be variable, leading to diagnosis and treatment delays. Despite JIA having substantial heritability, the construction of genomic risk scores (GRSs) to aid or expedite diagnosis has not been assessed. Here, we generate GRSs for JIA and its subtypes and evaluate their performance. Methods We examined three case/control cohorts (UK, US-based and Australia) with genome-wide single nucleotide polymorphism (SNP) genotypes. We trained GRSs for JIA and its subtypes using lasso-penalised linear models in cross-validation on the UK cohort, and externally tested it in the other cohorts. Results The JIA GRS alone achieved cross-validated area under the receiver operating characteristic curve (AUC)=0.670 in the UK cohort and externally-validated AUCs of 0.657 and 0.671 in the US-based and Australian cohorts, respectively. In logistic regression of case/control status, the corresponding odds ratios (ORs) per standard deviation (SD) of GRS were 1.831 (1.685 to 1.991) and 2.008 (1.731 to 2.345), and were unattenuated by adjustment for sex or the top 10 genetic principal components. Extending our analysis to JIA subtypes revealed that the enthesitis-related JIA had both the longest time-to-referral and the subtype GRS with the strongest predictive capacity overall across data sets: AUCs 0.82 in UK; 0.84 in Australian; and 0.70 in US-based. The particularly common oligoarthritis JIA also had a GRS that outperformed those for JIA overall, with AUCs of 0.72, 0.74 and 0.77, respectively. Conclusions A GRS for JIA has potential to augment clinical JIA diagnosis protocols, prioritising higher-risk individuals for follow-up and treatment. Consistent with JIA heterogeneity, subtype-specific GRSs showed particularly high performance for enthesitis-related and oligoarthritis JIA.
Abstract 622: Rapid non-uniform adaptation to conformation-specific KRAS G12Cinhibition
Authors: Jenny Y. Xue, Yulei Zhao, Jordan Aronowitz, Trang T. Mai, Alberto Vides, Besnik Qeriqi, Dongsung Kim, Chuanchuan Li, Elisa de Stanchina, Linas Mazutis, Davide Risso, Piro Lito
Journal: Cancer Research (2020)

Abstract KRAS GTPases are activated in one-third of cancers and KRAS G12C is the most common activating alteration in lung adenocarcinoma. KRAS G12C-specific inhibitors (G12Ci) are in Phase-I clinical trials and early data show only partial responses in lung cancer patients. How cancer cells bypass inhibition, to prevent maximal responses to therapy, is not understood. Because KRAS G12C cycles between an active and inactive conformation, and the covalent G12Ci only bind to the latter, we tested whether isogenic cell populations respond non-uniformly by studying the effect of treatment at a single-cell resolution. Using single-cell RNA sequencing and a fluorescent quiescence biosensor, we show that shortly after treatment, most cancer cells are sequestered in a quiescent state with low KRAS activity, while a small population reactivates KRAS to resume proliferation. This rapid divergent response is due to synthesis of new, drug-free KRAS protein, resulting from increased KRAS transcription in response to suppressed MAPK signaling. Combining cell fate-specific gene expressions and results from a CRISPR-Cas9 screen, we identified that adaptive signals such as epidermal growth-factor receptor and aurora kinase A signaling modulate the heterogeneous response to treatment with G12Ci. These upstream signals help to maintain new KRAS G12C protein in its active, drug-insensitive state, which restores KRAS signaling and transcriptional output in a subset of cells to allow escape from G12Ci-induced quiescence. Cells without these adaptive changes (or cells where they are pharmacologically inhibited) remain sensitive to G12Ci treatment, because new KRAS G12C is either not available, or it exists in its inactive, drug-sensitive state. Combined inhibition of these adaptive signals along with KRAS G12C produced more potent antitumor effects in xenograft models. The direct targeting of KRAS oncoproteins has been a longstanding objective in precision oncology. Our study uncovers a flexible non-uniform fitness mechanism that enables groups of cells within a population to rapidly bypass the effect of treatment. This adaptive process must be overcome to maximize the therapeutic potential of conformation-specific KRAS G12C inhibitors in the clinic. Citation Format: Jenny Y. Xue, Yulei Zhao, Jordan Aronowitz, Trang T. Mai, Alberto Vides, Besnik Qeriqi, Dongsung Kim, Chuanchuan Li, Elisa de Stanchina, Linas Mazutis, Davide Risso, Piro Lito. Rapid non-uniform adaptation to conformation-specific KRAS G12Cinhibition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 622.
Abstract 1521: New roles of ATP in metastasis: Extracellular and macropinocytosis internalized ATP work together to induces epithelial to mesenchymal transition and other early steps of metastasis
Authors: Yanyang Cao, Xuan Wang, Maria Evers, Yunsheng Li, Haiyun Zhang, Xiaozhuo Chen
Journal: Cancer Research (2020)

Abstract Metastasis is estimated to be responsible for more than 90% of all cancer-related deaths. Metastasis is initiated by induction of epithelial-mesenchymal transition (EMT) of cancer cells, but factors and mechanisms involved in EMT are far from being fully elucidated. Intratumoral extracellular ATP (eATP), at levels of 100-700 μM or 103 to 104 times higher than in normal tissues, has been known to induce epithelial-mesenchymal-transition (EMT) of cancer cells via purinergic receptor signaling. However, the exact induction mechanisms are far from fully known. We previously described that eATP is internalized by cancer cells in vitro and in vivo by macropinocytosis in human non-small cell lung cancer cells, drastically elevates intracellular ATP levels, enhances cell proliferation and resistance to anticancer drugs. In this study, we tested the hypothesis that eATP and macropinocytosis-internalized eATP also induces EMT and other early steps of metastasis. Here we report that eATP, at the concentrations reported in tumors, potently induces expression of matrix metallopeptidases (MMPs), detachment, EMT, migration, and invasion of lung cancer cells. The induction was independent of TGF-β and semi-independent of P2X7 activation. eATP performs these functions not only extracellularly, but also intracellularly after being macropinocytically internalized to further enhance P2X7-mediated EMT, filopodia formation and other early steps of metastasis. The knockout of the macropinocytosis-associated SNX5 gene significantly reduces macropinocytosis and slows down tumor growth in nude mice. Collectively, these results show that eATP functions on these processes not only from outside of cancer cells but also inside after being macropinocytotically internalized. These findings which shed light on eATP's initiator and effector roles in almost every step in early metastasis call for rethinking and rebalancing energy equations of intracellular biochemical reactions and the Warburg effect, and identify eATP and macropinocytosis as novel targets for potentially slowing down EMT, preventing metastasis, and reducing metastasis-related death in cancer patients. Citation Format: Yanyang Cao, Xuan Wang, Maria Evers, Yunsheng Li, Haiyun Zhang, Xiaozhuo Chen. New roles of ATP in metastasis: Extracellular and macropinocytosis internalized ATP work together to induces epithelial to mesenchymal transition and other early steps of metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1521.