tbuckley/cabot-search huggingface dataset:
Bioactive atropisomers: Unraveling design strategies and synthetic routes for drug discovery
Authors: Shuai‐Jiang Liu, Qian Zhao, Xiao‐Chen Liu, Allan B. Gamble, Wei Huang, Qian‐Qian Yang, Bo Han
Journal: Medicinal Research Reviews (2024)

Atropisomerism, an expression of axial chirality caused by limited bond rotation, is a prominent aspect within the field of medicinal chemistry. It has been shown that atropisomers of a wide range of compounds, including established FDA-approved drugs and experimental molecules, display markedly different biological activities. The time-dependent reversal of chirality in atropisomers poses complexity and obstacles in the process of drug discovery and development. Nonetheless, recent progress in understanding atropisomerism and enhanced characterization methods have greatly assisted medicinal chemists in the effective development of atropisomeric drug molecules. This article provides a comprehensive review of their special design thoughts, synthetic routes, and biological activities, serving as a reference for the synthesis and biological evaluation of bioactive atropisomers in the future.
Targeting refractory/recurrent neuroblastoma and osteosarcoma with anti-CD3×anti-GD2 bispecific antibody armed T cells
Authors: Maxim Yankelevich, Archana Thakur, Shakeel Modak, Roland Chu, Jeffrey Taub, Alissa Martin, Dana Schalk, Amy Schienshang, Sarah Whitaker, Katie Rea, Daniel W Lee, Qin Liu, Anthony F Shields, Nai-Kong V Cheung, Lawrence G Lum
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background The survival benefit observed in children with neuroblastoma (NB) and minimal residual disease who received treatment with anti-GD2 monoclonal antibodies prompted our investigation into the safety and potential clinical benefits of anti-CD3×anti-GD2 bispecific antibody (GD2Bi) armed T cells (GD2BATs). Preclinical studies demonstrated the high cytotoxicity of GD2BATs against GD2+cell lines, leading to the initiation of a phase I/II study in recurrent/refractory patients. Methods The 3+3 dose escalation phase I study ( NCT02173093 ) encompassed nine evaluable patients with NB (n=5), osteosarcoma (n=3), and desmoplastic small round cell tumors (n=1). Patients received twice-weekly infusions of GD2BATs at 40, 80, or 160×10 6 GD2BATs/kg/infusion complemented by daily interleukin-2 (300,000 IU/m 2 ) and twice-weekly granulocyte macrophage colony-stimulating factor (250 µg/m 2 ). The phase II segment focused on patients with NB at the dose 3 level of 160×10 6 GD2BATs/kg/infusion. Results Of the 12 patients enrolled, 9 completed therapy in phase I with no dose-limiting toxicities. Mild and manageable cytokine release syndrome occurred in all patients, presenting as grade 2–3 fevers/chills, headaches, and occasional hypotension up to 72 hours after GD2BAT infusions. GD2-antibody-associated pain was minimal. Median overall survival (OS) for phase I and the limited phase II was 18.0 and 31.2 months, respectively, with a combined OS of 21.1 months. A phase I NB patient had a complete bone marrow response with overall stable disease. In phase II, 10 of 12 patients were evaluable: 1 achieved partial response, and 3 showed clinical benefit with prolonged stable disease. Over 50% of evaluable patients exhibited augmented immune responses to GD2+targets post-GD2BATs, as indicated by interferon-gamma (IFN-γ) EliSpots, Th1 cytokines, and/or chemokines. Conclusions This study demonstrated the safety of GD2BATs up to 160×10 6 cells/kg/infusion. Coupled with evidence of post-treatment endogenous immune responses, our findings support further investigation of GD2BATs in larger phase II clinical trials.
Digital spatial proteomic profiling reveals immune checkpoints as biomarkers in lymphoid aggregates and tumor microenvironment of desmoplastic melanoma
Authors: David G Su, David A. Schoenfeld, Wael Ibrahim, Raysa Cabrejo, Dijana Djureinovic, Raymond Baumann, David L Rimm, Sajid A Khan, Ruth Halaban, Harriet M Kluger, Kelly Olino, Anjela Galan, James Clune
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Desmoplastic melanoma (DM) is a rare melanoma subtype characterized by dense fibrous stroma, a propensity for local recurrence, and a high response rate to programmed cell death protein 1 (PD-1) blockade. Occult sentinel lymph node positivity is significantly lower in both pure and mixed DM than in conventional melanoma, underscoring the need for better prognostic biomarkers to inform therapeutic strategies. Methods We assembled a tissue microarray comprising various cores of tumor, stroma, and lymphoid aggregates from 45 patients with histologically confirmed DM diagnosed between 1989 and 2018. Using a panel of 62 validated immune-oncology markers, we performed digital spatial profiling using the NanoString GeoMx platform and quantified expression in three tissue compartments defined by fluorescence colocalization (tumor (S100+/PMEL+/SYTO+), leukocytes (CD45+/SYTO+), and non-immune stroma (S100−/PMEL−/CD45−/SYTO+)). Results We observed higher expression of immune checkpoints (lymphocyte-activation gene 3 [LAG-3] and cytotoxic T-lymphocyte associated protein-4 [CTLA-4]) and cancer-associated fibroblast (CAF) markers (smooth muscle actin (SMA)) in the tumor compartments of pure DMs than mixed DMs. When comparing lymphoid aggregates (LA) to non-LA tumor cores, LAs were more enriched with CD20+B cells, but non-LA intratumoral leukocytes were more enriched with macrophage/monocytic markers (CD163, CD68, CD14) and had higher LAG-3 and CTLA-4 expression levels. Higher intratumoral PD-1 and LA-based LAG-3 expression appear to be associated with worse survival. Conclusions Our proteomic analysis reveals an intra-tumoral population of SMA+CAFs enriched in pure DM. Additionally, increased expressions of immune checkpoints (LAG-3 and PD-1) in LA and within tumor were associated with poorer prognosis. These findings might have therapeutic implications and help guide treatment selection in addition to informing potential prognostic significance.
SITC Clinical Immuno-Oncology Network (SCION) commentary on measurement and interpretation of essential biomarkers in early clinical trials
Authors: Michael T Lotze, Tricia Cottrell, Carlo Bifulco, Laura Chow, Leslie Cope, Sacha Gnjatic, Holden T Maecker, Joe Yeong Poh Shen
Journal: Journal for ImmunoTherapy of Cancer (2024)

Abstract
Improvements in Posttransplant Outcomes Over Two Decades in Older Patients with Acute Myeloid Leukemia in the EBMT ALWP Study
Authors: Ali Bazarbachi, Myriam Labopin, Nour Moukalled, Nicolaus Kröger, Christina Rautenberg, Johannes Schetelig, Jürgen Finke, Igor Wolfgang Blau, Didier Blaise, Matthias Stelljes, Matthias Eder, Uwe Platzbecker, Peter Dreger, Wolfgang Bethge, Johanna Tischer, David Burns, Henrik Sengeloev, Eolia Brissot, Sebastian Giebel, Arnon Nagler, Fabio Ciceri, Mohamad Mohty
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Acute myeloid leukemia (AML) is a disease of older patients. Progress in allogeneic hematopoietic cell transplantation (allo-HCT) allowed the delivery of allo-HCT to older patients. We assessed changes over time in transplant characteristics and outcomes in patients with AML ages 65 years and above. Patients and Methods: We identified 7,215 patients with AML (median age 68 years, range 65–80) allografted between 2000 and 2021 in first complete remission (CR1; 64%), second or subsequent remission (CR2+; 14%), or active disease (22%). Results: Median follow-up was 40 months. The 3-year cumulative relapse incidence (RI) gradually and significantly decreased from 37% to 31%, then to 30% (P = 0.001) over the three time periods (2000–2009; 2010–2014; 2015–2021), whereas nonrelapse mortality (NRM) decreased from 31% and 31% to 27% (P = 0.003). The 3-year leukemia-free survival (LFS) and overall survival (OS) gradually and significantly improved from 32% to 38%, and then to 44% (P = 0.001) and from 37% to 42%, and then to 49% (P = 0.001), respectively. In multivariate analysis, significant improvement in the RI, LFS, and OS were noted after 2015, whereas NRM was not significantly affected. This improvement was observed regardless of disease status at transplant. Conclusions: In older patients with AML, we observed an impressive improvement over time in posttransplant outcomes, mostly attributed to decreased RI rather than decreased NRM, and regardless of disease status at transplant. These large-scale, real-world data can serve as a benchmark for future studies in this setting and indicate that the opportunity for transplant for the elderly should be mandatory and no longer an option.
Abstract 2756: Single cell analysis reveals treatment response-associated plastic cell state and lineage switching in aggressive variant prostate cancer
Authors: Shuai Guo, Elavarasan Subramani, Daniel E. Frigo, Patrick G. Pilié, Sangeeta Goswami, Rama Soundararajan, Ana Aparicio, Wenyi Wang
Journal: Cancer Research (2024)

Abstract Prostate cancer (PCa) is a common malignancy in men over 65, ranking as the second leading cause of cancer-related deaths among men in the United States. While most prostate cancers respond to androgen receptor (AR) targeting therapies, Aggressive Variant Prostate Cancers (AVPCs), characterized by RB1, Tp53, and/or PTEN alterations, do not. AVPCs exhibit lineage plasticity in preclinical models, enabling the expression of non-prostate epithelial lineage markers to adapt to therapeutic pressures. However, a measurable definition of lineage plasticity as a potential therapeutic target for clinical trials is currently lacking. To arrive at said definition, we perform single-nuclei RNA sequencing (snRNA-seq) on lymph node metastases from twelve AVPC patients with matched sample pairs of both pre- and post-treatment. Additionally, we include snRNA-seq data from eight non-AVPC patients as a baseline. Expanding upon our prior establishment of tumor-specific total mRNA expression (TmS) as an indicator of tumor cell lineage plasticity (Nature Biotechnology, PMID: 35697807), we employ unique molecular identifier (UMI) counts from individual cells to quantify this plasticity. We reveal a distinct cluster of tumor cells with notably high UMI counts in resistant samples, indicative of a less differentiated state and increased transcriptional diversity. This high-UMI cluster is marked by significant enrichment in pathways associated with epithelial-mesenchymal transition (EMT), stemness, one-carbon metabolism, and arginine metabolism pathways. Concurrently, there is a reduction in activity within the androgen receptor (AR) and DNA damage repair pathways. These characteristics suggest an enhanced capacity for lineage switching in AVPC tumor cells, potentially contributing to evasion from targeted therapies. Moreover, immune components within resistant samples consistently display lower UMI counts, indicating a diminished propensity for lineage plasticity. In conclusion, we present a better understanding of lineage switching in therapeutic resistance in AVPCs, paving the way for novel treatment strategies in PCa management. Citation Format: Shuai Guo, Elavarasan Subramani, Daniel E. Frigo, Patrick G. Pilié, Sangeeta Goswami, Rama Soundararajan, Ana Aparicio, Wenyi Wang. Single cell analysis reveals treatment response-associated plastic cell state and lineage switching in aggressive variant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2756.
Abstract 5843: Exploring the implications of LPAR-1 expression in TKI-resistant NSCLC
Authors: Varsha Srinivasan, Zhaohui Li, Raghuraman Kannan, Anandhi Upendran
Journal: Cancer Research (2024)

Abstract Introduction: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer in the United States with a 5-year survival rate hovering between 20-30%. Mutations in EGFR can initially cause the tumors to respond to tyrosine kinase inhibitors (TKI). Osimertinib, a third generation TKI, is the preferred first or second line of treatment and despite being effective, recent reports indicate that patients develop resistance within 10-18 months of treatment. TKI resistance limits therapeutic options for patients and therefore, alternative strategies are being explored. In this context, Lysophosphatidic acid receptors (LPARs), a family of G-protein coupled receptors consisting of LPARs 1-6 expressed differentially in prostate, breast, ovarian, pancreatic, and brain cancers are being explored as potential targets for drug resistant cancers. Specifically, LPAR-1 has been shown to play a role in tumor cell clonogenicity, migration, and response to therapy in EGFR mutant NSCLC cells. Pharmacological inhibition or CRIPSR based deletion of LPAR-1 in EGFR mutant NSCLC cell lines HCC827 and NCI-H3255, increased TKI sensitivity by reducing clonogenic potential. Further, detailed pathway analysis in TKI sensitive and resistant EGFR mutant cell lines suggests that LPAR-1 expression influences drug sensitivity. Surprisingly, the role of LPAR-1 in TKI sensitivity is not well understood. In the present study, we have performed detailed investigation on the implications of LPAR-1 expression in the development of Osimertinib resistance. Methods: Osimertinib resistant EGFR mutant cell lines (OR) were generated using dose-escalation method and drug-tolerant persisters (DTPs) were generated using a short-term high exposure method. Gene and protein expressions were examined using qPCR and western blotting. Subcutaneous tumor cell derived xenografts were generated for in vivo studies. Results: LPAR-1 is downregulated in Osimertinib resistant NSCLC cells. Further, we also observe that LPAR-1 levels are lower in DTP cells, confirming a progressive loss of LPAR-1 with Osimertinib treatment. In vivo studies in cell derived xenografts correlated with the in vitro studies. Conclusion: Our studies indicate LPAR-1 downregulation correlates to Osimertinib resistance in EGFR mutant NSCLC cell lines. LPAR-1 downregulation has a key role in development of Osimertinib resistance. Future studies will focus on delineating LPAR-1 signaling pathways related to TKI resistance and investigating the effect of LPAR-1 overexpression using CRISPR technology. Citation Format: Varsha Srinivasan, Zhaohui Li, Raghuraman Kannan, Anandhi Upendran. Exploring the implications of LPAR-1 expression in TKI-resistant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5843.
Abstract 3840: Can serum exosomal content predict response to immunotherapy in hepatocellular carcinoma
Authors: Niramol Savaraj, Pablo Puente, Ying-Ying Li, Chunjing Wu, Jonathan D. Nguyen, Medhi Wangpaichitr, Peter J. Hosein, Lynn G. Feun
Journal: Cancer Research (2024)

Abstract While atezolizumab and bevacizumab combination has received FDA approval for the treatment of unresectable hepatocellular carcinoma (HCC), and recently durvalumab + tremelimumab also showed activity over sorafenib, there is no biomarker which can guild which patients can benefit from these regimens. The traditional PD-L1 positivity in the tumor by immunohistochemical staining which can predict possible response to immune checkpoint inhibitor in other solid tumors, such as melanoma and NSCLC, does not appear to apply to HCC. Thus, we attempt to explore whether exosomal content can be useful to predict response. HCC tumors exist in a complex microenvironment and serum exosomes can be generated from either tumor cells, macrophages, or other immune cells. Exosome act as new mediators for cell-cell communication transporting molecules such as lipids, proteins, and RNAs in vivo. Exosomal PD1 and PD-L1 have been implicated for possible biomarkers for immune checkpoint sensitivity. We isolated exosome from serum of unresectable HCC patients who underwent treatment with atezolizumab and bevacizumab. Blood sample was obtained prior to treatment, and then on cycle 3 and at the time of disease progression. Exosomes were isolated using the kit from System BioScience. Twenty patients were entered into the study. Five patients were not treated (received SBRT or other regional treatment), one was lost to follow up and one had atezolizumab only. In terms of antitumor response, eight patients had stable disease, three patients had partial response and two patients had progressive disease. Serum exosomal content data was available in 16 patients. Both PD1 and PDL1 are lowest in the three patients who had response followed by the group who had stable disease. In the two patients who had progressive disease, both exosomal PD-L1 and PD1 appeared to be the highest and did not change during treatment. Unlike in melanoma patients we have studied, other proteins in the antiapoptotic family such as Bcl-2 do not show any differences. While the number of patients are small and accrual is still ongoing, it appears that exosomal PD-L1/PD1 may have clinical value in predicting response to atezolizumab + bevacizumab therapy. Supported by Sylvester Comprehensive Cancer Center grant. Citation Format: Niramol Savaraj, Pablo Puente, Ying-Ying Li, Chunjing Wu, Jonathan D. Nguyen, Medhi Wangpaichitr, Peter J. Hosein, Lynn G. Feun. Can serum exosomal content predict response to immunotherapy in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3840.
Abstract 5609: A WRN screening cascade to facilitate novel drug discovery
Authors: Aicheng Wang, Kejun Mao, Tao Li, Lizhao Guan, Yuhong Chen, Haiting Dai, Xian Wu, Jiabao Lv, Xu Wang, Cong Huang, Tiejun Bing
Journal: Cancer Research (2024)

Abstract Human RecQ deconjugating enzyme WRN is involved in DNA replication, DNA repair, recombination, transcription and telomere stabilization[1]. It plays a key role in nucleic acid metabolism as well. WRN defects lead to premature aging, type II diabetes, osteoporosis, atherosclerosis and cancer[2]. Hence it is of great interest of both pharmaceutical and academic field to develop the WRN inhibitors. Here we constructed an integrated experimental cascade, which contains both in vitro and in vivo assays, to conduct the high throughput hit-to-lead compound screen. WRN proteins of different length have been successfully purified and utilized to develop multiple biochemical assays such as unwinding assay and ATPase assay. We have also validated different cellular assays, including proliferation and immunofluorescence, to assess the cytotoxicity and the influence of downstream biomarkers of WRN inhibitors. A WRN knock-out cell line has been generated to better appreciate the inhibition mechanism. In addition, we have generated a WRN-HiBiT knock-in cell line to evaluate WRN degraders or target-compound interactions. Lastly, multiple CDX models utilizing different MSI or MSS cell lines have been validated to help determine the efficacy of WRN inhibitors thus shed light on the drug indications. Together our WRN screening cascade can provide comprehensive compound evaluation across in vitro and in vivo platforms, thus serve as an efficient screening platform for new drug discovery. [1] Kitano K. Structural mechanisms of human RecQ helicases WRN and BLM. Front Genet. 2014 Oct 29;5:366. [2]Hussain M, Krishnamurthy S, Patel J, Kim E, Baptiste BA, Croteau DL, Bohr VA. Skin Abnormalities in Disorders with DNA Repair Defects, Premature Aging, and Mitochondrial Dysfunction. J Invest Dermatol. 2021 Apr;141(4S):968-975. Citation Format: Aicheng Wang, Kejun Mao, Tao Li, Lizhao Guan, Yuhong Chen, Haiting Dai, Xian Wu, Jiabao Lv, Xu Wang, Cong Huang, Tiejun Bing. A WRN screening cascade to facilitate novel drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5609.
Abstract 1535: Differential immune microenvironments in triple-negative breast cancer and hormone receptor-positive HER2-negative breast cancer: A spatial analysis via multiplex immunofluorescence
Authors: Yoon Jin Cha, Inho Park, Su-Jin Shin
Journal: Cancer Research (2024)

Abstract Objective: To elucidate differences in immune cell (IC) composition and their spatial distribution between triple-negative breast cancer (TNBC) and hormone receptor-positive HER2-negative breast cancer (HR+HER2-BC), and to evaluate the effect of PD-L1 status on these parameters. Methods: We selected 32 patients with ≥60% tumor-infiltrating lymphocytes (TIL) (TNBC, n=18; HR+HER2- BC, n=14). Multiplex immunofluorescence was employed on resected tumor tissues. Using markers such as CK, CD20, CD8, CD4, and FOXP3, IC types and tumor cells (TC) were identified in both stromal and tumor areas. We analyzed and compared cellular density and proportional distribution of IC, and spatial interactions (both IC-TC and IC-IC) based on tumor subtype and PD-L1 status. Results: TNBC exhibited a unique IC composition with a higher proportion of CD8+IC (stroma: 27% vs 17%, p&amp;lt;0.001; tumor: 54% vs 31%, p&amp;lt;0.001) and CD4+FOXP3+IC (stroma: 3.9% vs 3.0%, p=0.036) than HR+HER2-BC. Among PD-L1 positive cases, TNBC had a denser stromal population of CD4+FOXP3+IC (146.4±67.1/mm2 vs 114.3±146.9/mm2, p=0.036). Both tumor subtypes displayed varied IC compositions based on PD-L1 status. Density plots revealed a pronounced clustering of IC near TC in TNBC, especially in PD-L1 positive cases. Analysis of cell-cell interactions showed diverse adjacency patterns between TC and various IC combinations with frequencies differing by tumor subtype and PD-L1 status. Conclusion: The immune landscape, typified by IC composition and spatial distribution, varies between TNBC and HR+HER2- BC, with PD-L1 status further modulating these patterns. Citation Format: Yoon Jin Cha, Inho Park, Su-Jin Shin. Differential immune microenvironments in triple-negative breast cancer and hormone receptor-positive HER2-negative breast cancer: A spatial analysis via multiplex immunofluorescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1535.