tbuckley/cabot-search huggingface dataset:
Abstract LB271: Synergistic anti-tumor efficacy in olaparib-sensitive and -resistant models via simultaneously inhibition of USP1 and PARP
Authors: Shuqun Yang, Zhengtao Li, Lei Zhou, Feng Zhou, Xiaokang Qin, Liting Xue, Piaopiao Xu, Jianxing Tang, Wendy Wang, Renhong Tang
Journal: Cancer Research (2024)

Abstract SIM0501 is a potent, orally bioavailable, specific inhibitor for USP1. We have explored its combination with olaparib, an approved PARP inhibitor, in both in vitro cancer cell lines and in vivo tumor models. Specifically, SIM0501 showed synergistic effect with olaparib on cell lines across different cancer types, including breast, ovarian, and prostate cancers. Most of these cell lines contain mutations in the homologous recombinational repair (HRR) pathway, which is likely the reason for their susceptibility to the combined inhibition on USP1 and PARP. In the in vivo efficacy studies, SIM0501 dose-dependently inhibited tumor growth when combined with olaparib, including BRCA1-mutated MDA-MB-436, BRCA-wildtype olaparib-resistant OVCAR3, and olaparib-resistant ovarian PDX models. Further, in the MDA-MB-436 model, delayed addition of olaparib to SIM0501 showed comparable efficacy with simultaneous combination treatment, suggesting the flexibility in add-on dosing strategy. Regarding the biomarker research, dose-dependent increase of Ub-PCNA was demonstrated by western blot (WB) following in vivo efficacy studies. Moreover, we have developed robust IHC detection method for Ub-PCNA, which correlated well with WB results. Since Ub-PCNA is a direct target of USP1, these results will facilitate the clinical assessment of target engagement by SIM0501. In summary, SIM0501 demonstrates strong synergistic anti-tumor growth effect in combination with PARP inhibitors in both in vitro and in vivo pharmacology studies, which supports the clinical testing of SIM0501, in combination with PARP inhibitors in patients harboring HRR mutations. Citation Format: Shuqun Yang, Zhengtao Li, Lei Zhou, Feng Zhou, Xiaokang Qin, Liting Xue, Piaopiao Xu, Jianxing Tang, Wendy Wang, Renhong Tang. Synergistic anti-tumor efficacy in olaparib-sensitive and -resistant models via simultaneously inhibition of USP1 and PARP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB271.
Abstract SY34-02: Age-related and organ-specific host mosaicism as a driver of dormant cancer cell awakening
Authors: Julio A. Aguirre-Ghiso, Michael Papanicolaou, Pablo Sánchez Vela, Julie Yang, Anton Safonov, Jacqueline Tao, Sebastia Franch Exposito, Vera Tiedje, Erica Dalla, Luis E. Valencia Salazar, Nicole Barth, Merve Sahin, Kevin Chen, Jinae Park, Matthew Wereski, Aishwarya Krishnan, Anthony Martinez Benitez, Ryan Ptashkin, Mark E. Robson, Elisa de Stanchina, Lior Z. Braunstein, Ahmet Zehir, Elizabeth Comen, Larry Norton, Michael Berger, Richard Koche, Pedram Razavi, Ross Levine
Journal: Cancer Research (2024)

Abstract Most BC patients succumb to metastatic relapse years to decades following primary tumor resection due to reactivation of dormant disseminated cancer cells (DCCs). Improved BC patient survival has led to metastatic relapse manifesting in an older patient population. This population carries somatic mosaicism in many organs including bone marrow. Age-specific somatic mutations (e.g., DNMT3A, ASXL1, TET2) in hematopoietic stem and progenitor cells (HSPCs) results in CH, which is associated with increased inflammatory myeloid cells and risk of leukemia and intriguingly with BC-specific mortality. In this presentation I will discuss new data from a team effort to test the hypothesis that CH myeloid cells could shape target organs niches that harbor dormant DCCs to be pro-metastatic. This hypothesis has been explored in clinical trials data where the presence of CH in ER+ and HER2+ metastatic BC patient cohorts (MSK-IMPACT) was associated with the response to first line CDK4/6i/endocrine therapy or taxol/herceptin/pertuzumab, respectively. We also tested whether CH can accelerate dormant DCC awakening in a murine model of CH carrying mutations in DNMT3A (KO or point mutation) and HER2+ mammary cancer. We propose our work may provide unprecedented insights into how a traceable age-related-mosaicism in the bone marrow (CH) may shape distant organs to be drive metastatic relapse. Citation Format: Julio A. Aguirre-Ghiso, Michael Papanicolaou, Pablo Sánchez Vela, Julie Yang, Anton Safonov, Jacqueline Tao, Sebastia Franch Exposito, Vera Tiedje, Erica Dalla, Luis E. Valencia Salazar, Nicole Barth, Merve Sahin, Kevin Chen, Jinae Park, Matthew Wereski, Aishwarya Krishnan, Anthony Martinez Benitez, Ryan Ptashkin, Mark E. Robson, Elisa de Stanchina, Lior Z. Braunstein, Ahmet Zehir, Elizabeth Comen, Larry Norton, Michael Berger, Richard Koche, Pedram Razavi, Ross Levine. Age-related and organ-specific host mosaicism as a driver of dormant cancer cell awakening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY34-02.
Improving the healthcare experiences of transgender and gender-diverse youths: a mixed-methods systematic review of interventions
Authors: Ryan Goulding, John Goodwin, Mohamad M. Saab, Megan McCarthy, Brenda Happell, Aine O’Donovan
Journal: International Journal of Transgender Health (2024)

Introduction Health disparities are commonly identified within the transgender and gender-diverse community. Gender minority stress theory expands the existing minority stress theory to identify the unique stressors of this community. The outcomes of these stressors and disparities are recurring negative experiences among transgender and gender-diverse youths and subsequent care avoidance. This mixed-methods systematic review aims to identify and critically analyze the effect of interventions to improve the healthcare experiences of transgender and gender-diverse youths.
Quantitative Biofabrication Platform for Collagen‐Based Peripheral Nerve Grafts with Structural and Chemical Guidance (Adv. Healthcare Mater. 9/2024)
Authors: Heran Wang, Yiming Hao, Kai Guo, Lianqing Liu, Bing Xia, Xue Gao, Xiongfei Zheng, Jinghui Huang
Journal: Advanced Healthcare Materials (2024)
Abstract CT055: Efficacy of YK-029A, a novel EGFR TKI, in advanced NSCLC patients with acquired T790M mutation
Authors: Rui Wan, Yi Fung Chau, Jun Zhao, Zhe Liu, Mingfang Zhao, Yanqiu Zhao, Xiumei Dai, Yueyin Pan, Zhihong Zhang, Yu Yao, Kunyu Yang, Lin Wu, Yanyan Xie, Bi Chen, Yixuan Yang, Yongqi Guo, Jie Wang, Jianchun Duan
Journal: Cancer Research (2024)

Abstract In the multicenter, dose-escalation and dose-expansion phase 1 clinical trial (NCT05767866), we evaluated safety and tolerability of YK-029A in various EGFR mutated non-small-cell lung cancer (NSCLC). We have reported efficacy of YK-029A in untreated NSCLC with EGFR ex20ins mutation[1]. This time we report efficacy of YK-029A in patients with acquired EGFR T790M mutation after failure of first or second generation EGFR tyrosine kinase inhibitors (TKIs). Method: This dose-escalation and dose-expansion phase 1 trial recruited previously treated NSCLC patients with EGFR T790M mutation or patients with EGFR ex20ins or EGFR rare mutations. In dose-escalation phase, patients with EGFR T790M mutation were enrolled. YK-029A was given at doses of 50, 100, 150, 200 to 250 mg/day (3+3 design). In dose-expansion phase, patients with EGFR T790M, EGFR ex20ins, or EGFR rare mutations were enrolled. The primary objective was safety. Dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) were explored. Efficacy of YK-029A in EGFR T790M mutated NSCLC was assessed by the investigators. Results: A total of 114 patients were recruited into the study. Safety profile of the first 108 patients was reported previously[1]. By the cut-off date on Sep 12, 2023, 38 patients harbored EGFR T790M mutation were included in efficacy analysis. All these patients were previously treated with first or second generation EGFR-TKIs. The objective response rate (ORR; RECIST 1.1) was 65.8% (95%CI: 48.6%-80.4%) and disease control rate (DCR) was 84.2% (95%CI: 68.7%-94.0%). With a median follow-up time of 8.2 months,the median progression free survival (PFS) was 11.0 months (95%CI: 7.75-NR). The median overall survival (OS) was not reached. Among the 8 patients with measurable brain metastases, intracranial ORR was 75% (95%CI: 35.6%-95.6%) . Conclusions: YK-029A has promising activity in previously treated NSCLC patients harboring EGFR T790M mutation. Reference[1] DUAN J, WU L, YANG K, et al. Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of YK-029A in Treatment-Naive Patients With Advanced NSCLC Harboring EGFR Exon 20 Insertion Mutations: A Phase 1 Trial [J]. J Thorac Oncol, 2023. Citation Format: Rui Wan, Yi Fung Chau, Jun Zhao, Zhe Liu, Mingfang Zhao, Yanqiu Zhao, Xiumei Dai, Yueyin Pan, Zhihong Zhang, Yu Yao, Kunyu Yang, Lin Wu, Yanyan Xie, Bi Chen, Yixuan Yang, Yongqi Guo, Jie Wang, Jianchun Duan. Efficacy of YK-029A, a novel EGFR TKI, in advanced NSCLC patients with acquired T790M mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT055.
Abstract LB110: Impact of circulating tumor cell-expressed prostate-specific membrane antigen and prostate-specific antigen transcripts in various stages of prostate cancer
Authors: Hyungseok Cho, Seok-Soo Byun, Nak-Hoon Son, Jae Il Chung, Won Ik Seo, Chan Ho Lee, Todd M Morgan, Ki-Ho Han, Jae-Seung Chung
Journal: Cancer Research (2024)

Abstract PurposeProstate-specific membrane antigen (PSMA)-based images, which visually quantify PSMA expression, are used to determine prostate cancer (PCa) micrometastases. This study evaluated whether a circulating tumor cell (CTCs-based transcript platform, including PSMA mRNA, could help identify potential prognostic markers in PCa. Experimental design We prospectively enrolled 21 healthy individuals and 247 patients with PCa (localized PCa [LPCa]: 94; metastatic hormone-sensitive PCa [mHSPC]: 44; and metastatic castration-resistant PCa [mCRPC]: 109). The mRNA expression of six transcripts (PSMA, prostate-specific antigen [PSA], AR, AR-V7, EpCAM, and KRT 19) from CTCs was measured, and their relationship with biochemical recurrence (BCR) in LPCa and mCRPC progression-free survival (PFS) rate in mHSPC was assessed. PSA-PFS and radiological-PFS were also calculated to identify potential biomarkers for predicting androgen receptor signaling inhibitor (ARSI) and taxane-based chemotherapy resistance in mCRPC. Results CTC detection rates were 75.5%, 95.3%, and 98% for LPCa, mHSPC, and mCRPC, respectively. In LPCa, PSMA (hazard ratio [HR]: 3.35; P=0.028) and PSA mRNA (HR: 1.42; P=0.047) expression was associated with BCR. mHSPC patients with high PSMA (HR: 4.26; P=0.020) and PSA mRNA (HR: 3.52; P=0.042) expression showed significantly worse mCRPC-PFS rates than those with low expression. Increased PSA and PSMA mRNA expression was significantly associated with shorter PSA-PFS and radiological PFS in mCPRC, indicating an association with drug resistance. Conclusion PSMA and PSA mRNA expression is associated with BCR in LPCa. In advanced PCa, PSMA and PSA mRNA can also predict rapid progression from mHSPC to mCRPC and ARSI or taxane-based chemotherapy resistance. Citation Format: Hyungseok Cho, Seok-Soo Byun, Nak-Hoon Son, Jae Il Chung, Won Ik Seo, Chan Ho Lee, Todd M Morgan, Ki-Ho Han, Jae-Seung Chung. Impact of circulating tumor cell-expressed prostate-specific membrane antigen and prostate-specific antigen transcripts in various stages of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB110.
Local Spinal Cord Injury Treatment Using a Dental Pulp Stem Cell Encapsulated H<sub>2</sub>S Releasing Multifunctional Injectable Hydrogel (Adv. Healthcare Mater. 9/2024)
Authors: Abdullkhaleg Ali Albashari, Yan He, Yu Luo, Xingxiang Duan, Jihea Ali, Mingchang Li, Dehao Fu, Yangfan Xiang, Youjian Peng, Song Li, Lihua Luo, Xingjie Zan, Tushar Kumeria, Qingsong Ye
Journal: Advanced Healthcare Materials (2024)
Abstract LB060: Engineering KRAS mutation-specific affinity binders: A new frontier in cancer research
Authors: Ramon Serrano, Ryan Wallace, Sergei Bibikov, Michael Weiner, Kevin J. Harvey
Journal: Cancer Research (2024)

Abstract Cancer is a complex disease involving genetic and proteomic dysregulation. Better understanding of this disease requires precise tools to analyze how cells change from a normal to a diseased state. Among the genes implicated in cancer, the checkpoint inhibitor KRAS is notable for its frequent cancer causing mutations. These mutations, especially in glycine codon 12, are a driving force in several cancers, including those of the pancreas, lung, and colon. Recently, researchers have made significant strides in treating one variant, targeting G12C, using small molecules. However, other mutations, including the G12D and G12V variants, which are more common in disease, still lack targeted treatments. To overcome this challenge, we are using a unique immunization and screening strategy to identify a series of KRAS mutant-specific binders. These affinity binders, targeting the wild-type glycine and variants like G12D, G12S, G12C, G12A, G12R, and G12V, are being designed for research purposes to dissect cancer pathways and understand the spatial organization of cancer cells. They may also hold potential for clinical use as tools for prognosis and therapy. Deep characterization of these and other potentially widely used tools will be critical for advancing their uptake in the laboratory and clinic. Citation Format: Ramon Serrano, Ryan Wallace, Sergei Bibikov, Michael Weiner, Kevin J. Harvey. Engineering KRAS mutation-specific affinity binders: A new frontier in cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB060.
Abstract LB245: Single cell guided identification of logic-gated cell surface combinations for selective and safe CAR therapy design
Authors: Sanna Madan, Tiangen Chang, Binbin Wang, Saugato Rahman Dhruba, Alejandro A. Schäffer, Eytan Ruppin
Journal: Cancer Research (2024)

Abstract The advancement of chimeric antigen receptor (CAR) T-cell therapy has been groundbreaking in the treatment of hematological malignancies. However, its application in solid tumors is constrained by antigen variability and unintended off-tumor, on-target toxicities. Addressing these issues, we introduce a genetic algorithm to analyze single-cell transcriptomics data from patient tumors. This method pinpoints sets of surface antigens exclusive to cancer cells, utilizing the logical operators "AND," "OR," and "NOT." Our technique scales to gene combinations of any size and exhibits robust performance across diverse parameter settings. When applied to five breast cancer datasets, this algorithm successfully uncovered triplet antigen combinations superior to current clinical single antigen targets in distinguishing between cancerous and healthy cells. This strategy offers a promising pathway toward the design of more selective and safe CAR therapies. Citation Format: Sanna Madan, Tiangen Chang, Binbin Wang, Saugato Rahman Dhruba, Alejandro A. Schäffer, Eytan Ruppin. Single cell guided identification of logic-gated cell surface combinations for selective and safe CAR therapy design [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB245.
Abstract CT287: LINNOVATE: A Phase 1/2 study of safety/efficacy using lurbinectedin, combined with ipilimumab, and nivolumab for advanced soft tissue sarcomas <i>(NCT05876715)</i>
Authors: Erlinda M. Gordon, Nadezhda Omelchenko, Samantha Jeffrey, Vaishali Kumar, Neal S. Chawla, Mahesh Seetharam, Victoria Chua, Ania Moradkhani, Doris Quon, Steven Wong, Sant Chawla
Journal: Cancer Research (2024)

Abstract Background: Sarcoma cells are most immunogenic earlier in the course of the disease. Therefore, immune checkpoint inhibitors such as ipilimumab (ipi) and nivolumab (nivo), that promote sustained T-cell activation by suppressing T regs would be most effective when given as first line therapy, together with a tumoricidal agent, such as lurbinectedin, whose plausible mechanism of action is not only to destroy the cancer cells and expose the tumor neoantigens for immune recognition, but also to destroy growth promoting factors in the tumor microenvironment. In the SAINT phase 2 study using ipi, nivo and trabectedin as first line therapy for advanced soft tissue sarcomas (STS; n=79), there were 6 complete responses, 14 partial responses, 49 stable disease, 25.3% best response rate, 87.3% disease control rate; median PFS, 6.7 months, median OS, 24.6 months (Gordon et al, Cancers vol. 15, 906, 2023). Lurbinectedin is a synthetic marine-derived agent and an analog of trabectedin. Therefore, we expect that lurbinectedin will be as effective as trabectedin when used together with ipi and nivo as first line therapy for advanced STS. Methods: Objective 1: Assess MTD of lurbinectedin. Objective 2: Evaluate PFS, OS, incidence and severity of adverse events; Correlative: Correlate response with ctDNA using Signatera. This is an open label, dose-seeking phase 1/2 study. The phase 1 part employs standard “cohort of three” design with a DLT window of 6 weeks. Treatment schedule: Ipi 1 mg/kg IV q 12 weeks; Nivo 3 mg/kg IV q 2 weeks; escalating doses of lurbinectedin from 2.6 mg/m2 to 3.2 mg/m2 IV q 3 weeks. Phase 2 part follows completion of phase 1 part wherein additional 28-34 participants will receive lurbinectedin at the MTD with fixed doses of Ipi and Nivo. Participants may continue treatment until significant disease progression or unacceptable toxicity occurs. Eligible patients are 18 years of age or older, previously treated in phase 1 and previously untreated in phase 2 with confirmed diagnosis of advanced STS, adequate hematologic and organ function, and no history of autoimmune disorder. To date, 6 patients in phase 1 have been dosed. Citation Format: Erlinda M. Gordon, Nadezhda Omelchenko, Samantha Jeffrey, Vaishali Kumar, Neal S. Chawla, Mahesh Seetharam, Victoria Chua, Ania Moradkhani, Doris Quon, Steven Wong, Sant Chawla. LINNOVATE: A Phase 1/2 study of safety/efficacy using lurbinectedin, combined with ipilimumab, and nivolumab for advanced soft tissue sarcomas (NCT05876715) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT287.
Abstract CT116: Preclinical antitumor activity and first-in-human phase I study of NB004/GDC-0570, a novel pan-PIM kinase inhibitor, in patients with advanced solid tumors
Authors: Siqing Fu, Rachel E. Sanborn, Minxia Cai, Lijia Zhang, Yanhua Xu, Kui Lin
Journal: Cancer Research (2024)

Abstract PIM proto-oncogenes encode a family of three serine/threonine kinases (PIM1, PIM2, PIM3), which are frequently overexpressed in human hematological malignancies and solid cancers. PIM kinases are promising cancer therapeutic targets for pharmacological inhibition. NB004 (aka GDC-0570) is a novel, potent, selective, orally available small molecule pan-PIM inhibitor, which exhibits antiproliferative activity as a single agent in a variety of preclinical models and can augment the activity of standard of care or targeted therapies, both in vitro and in vivo. In multiple patient-derived xenograft (PDX) models of human solid tumors, NB004 demonstrates both single agent and combination activity with agents targeting the RTK/RAS/MAPK pathways, including synergistic effects with KRAS inhibitors (KRASis). Remarkably, in NSCLC PDX models with acquired resistance to KRASis, strong combination efficacy was observed between NB004 and sotorasib, resulting in complete tumor regression. Based on the promising preclinical data, NB004 is currently being assessed in an open-label, first-in-human phase I clinical trial as monotherapy or combination therapy in patients with advanced solid tumors. The primary objective is to characterize the safety and tolerability and to recommend the phase 2 dose (RP2D). Secondary objectives include PK characterization and preliminary antitumor activity evaluation. In the phase I monotherapy dose escalation part, NB004 was administered daily in 5 dose levels, ranging from 75mg to 600mg, following a standard 3+3 design. As of December 22, 2023, a total of 18 patients were treated. Of the 13 patients (72.2%) who reported any treatment-related adverse events (TRAEs), 12 (66.7%) had Grade 1 or 2 TRAEs, 1 patient (5.6%) experienced Grade 3 neutrophil count decrease and white blood cell count decrease. No dose-limiting toxicity (DLT) or treatment-related serious adverse event (SAE) was reported, and PK exposure is in general dose proportional. These results warrant further evaluation of this drug in combination with other therapeutic agents. The combination part of the trial is currently open for enrollment (NCT05036291). Citation Format: Siqing Fu, Rachel E. Sanborn, Minxia Cai, Lijia Zhang, Yanhua Xu, Kui Lin. Preclinical antitumor activity and first-in-human phase I study of NB004/GDC-0570, a novel pan-PIM kinase inhibitor, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT116.