tbuckley/cabot-search huggingface dataset:
Abstract SY31-02: Nociceptor neurons control anti-tumor immunity
Authors: Tuany Eichwald, Mohammad Balood, Maryam Ahmadi, Karine Roversi, Dylan Wong, Judith Mandl, Moutih Rafei, Nader Ghasemlou, Paola Vermeer, Moran Amit, Sébastien Talbot
Journal: Cancer Research (2024)

Abstract Cancer is the top cause of death in the USA, responsible for 30% of deaths. A cure remains undiscovered. Therapy effectiveness varies by patient and tumor type and can have negative side effects. The immune system, designed to eliminate abnormal cells, including cancer cells, is often impaired. For example, in skin cancer, extended activation of certain receptors can exhaust immune cells, reducing their cancer-fighting ability. Our lab found that cancer cells trigger nociceptor neurons in tumors, leading to neuropeptide release that exhausts CD8+ T cells. To explore their interactions, we conducted single-cell RNA sequencing on tumor-related sensory neurons, leukocytes, and cancer cells. We found a distinct group of tumor-related neurons expressingATF3, Sox10, Sprr1a, and galanin. In our study, mice with injury-resistant nociceptor neurons (NaV1.8ΔATF3) developed smaller melanoma tumors and had reduced galanin levels compared to controls. These mice also showed stronger anti-tumor immune responses, especially in cytotoxic CD8+ T-cells. Restoring galanin in mice with ATF3-deficient nociceptor neurons resulted in tumor growth similar to normal mice. We observed that galanin increases exhaustion, reduces the cytotoxic capacity of CD8+ T-cells, and leads the cells to a state of immunoparalysis. Higher galanin levels in melanoma patients were linked to worse outcomes. Using single-cell RNA sequencing from melanoma patients, we also found that cytotoxic CD8+ T cells with the galanin receptor 1(GALR1) were more exhausted than those without it. In summary, ATF3-modifiedtumor-related sensory neurons that release galanin can weaken anti-tumor immunity, suggesting cancer cells may use this aspect of neuro-immunity to promote tumor growth. Citation Format: Tuany Eichwald, Mohammad Balood, Maryam Ahmadi, Karine Roversi, Dylan Wong, Judith Mandl, Moutih Rafei, Nader Ghasemlou, Paola Vermeer, Moran Amit, Sébastien Talbot. Nociceptor neurons control anti-tumor immunity [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 SY31-02.
Abstract LB212: Transcriptional dosage of oncogenic KRAS drives lung adenocarcinoma cell states, progression and metastasis
Authors: Michela Serresi, Sonia Kertalli, Yuliia Dramaretska, Matthias Jürgen Schmitt, Heike Naumann, Maria Zschummel, Gaetano Gargiulo
Journal: Cancer Research (2024)

Abstract Metastasis is the endpoint of tumorigenesis and is generally diagnosed at an untreatable stage. The molecular mechanisms underlying metastasis and biomarkers for early intervention are largely unknown. Here, combining a mouse model of aggressive Kras-driven non-small-cell lung cancer with in vivo fate mapping and CRISPR activation screens, we show that transcriptional amplification of oncogenic Kras promotes orthotopic lung cancer lesions growth as well as oligoclonal and polyclonal metastasis to distal organs. Mild Kras transcriptional up-regulation by CRISPRa is sufficient to fuel competitive advantage in vitro and in vivo. Parallel CRISPR activation and transcriptome sequencing show that KrasG12D amplification cooperates with sterile inflammation to drive tumor progression and with the TGFß pathway to promote metastasis. Chromatin profiling of Kras-amplifying cells uncovers transcriptional regulators potentially collaborating with oncogenic Kras to drive lung cancer and metastasis in vivo. Transcriptional modulation of KRAS dosage in mouse cell and pharmacological inhibition in human PDXs affect cell stress and differentiation programs. These observations are corroborated by bulk and single-cell RNA-seq analysis in patients. Collectively, our data on a model oncogene advance our current understanding of how KRAS drives tumor evolution, with implications for prognosis and treatment of patients. Citation Format: Michela Serresi, Sonia Kertalli, Yuliia Dramaretska, Matthias Jürgen Schmitt, Heike Naumann, Maria Zschummel, Gaetano Gargiulo. Transcriptional dosage of oncogenic KRAS drives lung adenocarcinoma cell states, progression and metastasis [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 LB212.
Abstract LB082: A high-throughput immune-oncology screen identifies immunostimulatory properties of low dose chemotherapy in triple negative breast cancer
Authors: Kennady K. Bullock, Thomas Hasaka, Emily Days, Joshua Bauer, Ann Richmond
Journal: Cancer Research (2024)

Abstract Triple-negative breast cancer (TNBC) is a heterogeneous subtype broadly characterized by the lack of hormone receptor (HR) and HER2 expression. Compared to HR+ breast cancers, TNBCs typically have a greater immune cell infiltrate and are more likely to respond to immune checkpoint inhibition (ICI). The results from KEYNOTE-355 and KEYNOTE-522 trials led to the approvals of anti-PD-1 in combination with physician’s choice chemotherapy for the treatment of TNBC in adjuvant and neoadjuvant settings. However, few patients achieve a durable response, and there remains a need to optimize combination strategies to enhance the benefits of ICI in TNBC. Therefore, we developed a high-throughput co-culture screening assay to identify compounds enhancing T-cell-mediated cytotoxicity. Co-cultures included three cell types: mKate2-labeled PyMT tumor cells expressing the OVA antigen, BPF-labeled PyMT cells, and CD8+ OT-1 T-cells. The screening library included over 400 FDA-approved compounds or agents under investigation for oncology indications. Each compound was evaluated at five concentrations (3µM-12nM) and across three-time points (24hr, 48hr, and 72hr) to provide insight into the kinetics. Cell viability was assessed via image analysis at each time point, and enhanced cell death in the PyMT-OVA cells compared to the non-OVA PyMT cells was considered evidence of enhanced T-cell mediated cytotoxicity. Five chemotherapy agents were chosen as priority hits for mechanistic follow-up due to their ability to enhance T-cell mediated cytotoxicity at multiple doses and multiple timepoints: paclitaxel, bleomycin sulfate, kinesin-inhibitor, ABT-751, and etoposide. We are exploring the dose dependency of MHC-I and MHC-II induction, as well as the minimum dose required to cause immunogenic cell death. We further found that low doses of these agents do not negativity affect CD8+ T-cell proliferation, whereas high doses may have deleterious effects on CD8+ T-cell functioning. The results of these studies provide mechanistic insight into potential new chemotherapy partners to enhance anti-PD-1 efficacy in TNBC patients and suggest benefit to further investigating the immunostimulatory potential of low dose chemotherapy. Citation Format: Kennady K. Bullock, Thomas Hasaka, Emily Days, Joshua Bauer, Ann Richmond. A high-throughput immune-oncology screen identifies immunostimulatory properties of low dose chemotherapy in triple negative breast 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 LB082.
Increased DNA methylation contributes to the early ripening of pear fruits during domestication and improvement
Authors: Bobo Song, Jinshan Yu, Xiaolong Li, Jiaming Li, Jing Fan, Hainan Liu, Weilin Wei, Lingchao Zhang, Kaidi Gu, Dongliang Liu, Kejiao Zhao, Jun Wu
Journal: Genome biology (2024)

Abstract Background DNA methylation is an essential epigenetic modification. However, its contribution to trait changes and diversity in the domestication of perennial fruit trees remains unknown. Results Here, we investigate the variation in DNA methylation during pear domestication and improvement using whole-genome bisulfite sequencing in 41 pear accessions. Contrary to the significant decrease during rice domestication, we detect a global increase in DNA methylation during pear domestication and improvement. We find this specific increase in pear is significantly correlated with the downregulation of Demeter-like1 ( DML1 , encoding DNA demethylase) due to human selection. We identify a total of 5591 differentially methylated regions (DMRs). Methylation in the CG and CHG contexts undergoes co-evolution during pear domestication and improvement. DMRs have higher genetic diversity than selection sweep regions, especially in the introns. Approximately 97% of DMRs are not associated with any SNPs, and these DMRs are associated with starch and sucrose metabolism and phenylpropanoid biosynthesis. We also perform correlation analysis between DNA methylation and gene expression. We find genes close to the hypermethylated DMRs that are significantly associated with fruit ripening. We further verify the function of a hyper-DMR-associated gene, CAMTA2 , and demonstrate that overexpression of CAMTA2 in tomato and pear callus inhibits fruit ripening. Conclusions Our study describes a specific pattern of DNA methylation in the domestication and improvement of a perennial pear tree and suggests that increased DNA methylation plays an essential role in the early ripening of pear fruits.
Abstract LB177: Discovery of HC-4955, a novel AR-V7-targeting PROTAC for the treatment of mCRPC
Authors: Jing Li, Zhilin Tu, Wu Du, Xi Xiang, Zeyu Wen, Yang You, Lijuan Zhao, Yin Chen, Chengcheng Yang, Hongwei Yuan, Xinghai Li
Journal: Cancer Research (2024)

Abstract Prostate cancer is the second most commonly diagnosed cancer and the second leading cause of cancer death among men worldwide. Androgens play an important role in the development and progression of prostate cancers and targeting androgen receptor (AR) signaling axis over decades has remained a mainstay of prostate cancer therapy. Next generation hormonal agents (NHAs) enzalutamide and abiraterone have brought clinical benefits for metastatic castrate-resistant prostate cancer (mCRPC) patients, AR axis-targeted therapy resistance is inevitable due to AR gene amplification or mutations. AR-V7 is the most clinically relevant AR splice variant associated with endocrine resistance and poor prognosis. AR-V7 constitutively activates AR signaling and lacks the ligand binding domain (LBD) where hormones and AR antagonists interact, resulting in resistance to AR signaling inhibitors (ARSi). Thus, AR-V7 is a promising therapeutic target to address ARSi resistance in mCRPC. We have discovered a highly potent AR-V7 proteolysis targeting chimera (PROTAC), HC-4955 that degrades both the wild-type AR (WT-AR) and AR-V7 mutant. HC-4955 degrades AR-V7 with DC50 &amp;lt; 5 nM. In silico molecular docking analysis predicts the binding of HC-4955 to the N-terminal domain of AR and then the essential amino acids contributed to HC-4955 binding are validated by mutational analysis studies. HC-4955 also potently degrades mutants of AR-LBD mutations including L702H and T878A and these mutations are also associated with ARSi resistance. HC-4955 strongly inhibits proliferation of ARSi-resistant prostate cancer cell lines with IC50 &amp;lt; 10 nM. HC-4955 shows a robust anti-tumor activity in the AR-V7-bearing 22Rv1 cell line derived tumor xenograft (CDX) and patient-derived xenograft (PDX) mouse models, with majority of the tumors completely regressed and &amp;gt; 90% AR-V7 expression decreased at 1-5 mg/kg (QD, PO) in these models. The pre-clinical results support the clinical development of HC-4955 for the treatment of mCRPC. Selected pre-clinical data along with the chemical structure of HC-4955 will be presented. Citation Format: Jing Li, Zhilin Tu, Wu Du, Xi Xiang, Zeyu Wen, Yang You, Lijuan Zhao, Yin Chen, Chengcheng Yang, Hongwei Yuan, Xinghai Li. Discovery of HC-4955, a novel AR-V7-targeting PROTAC for the treatment of mCRPC [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 LB177.
Abstract LB339: Transient EZH2 suppression by tazemetostat during <i>in vitro</i> expansion maintains T cell stemness and improves adoptive T cell therapy
Authors: Yingqin Hou, Peng Wu
Journal: Cancer Research (2024)

Abstract The histone methyltransferase enhancer of zeste homolog 2 (EZH2) plays important roles in T cell differentiation, proliferation and function. Previous studies demonstrated that genetic deletion of EZH2 in CD8+ or total T cells impairs their antiviral and antitumor activity, cytokine production and expansion upon rechallenge. Contrary to the detrimental role of deleting T cell-intrinsic EZH2, here we demonstrate that transient inhibition of EZH2 in T cells prior to the phenotypic onset of exhaustion with a clinically approved inhibitor, Tazemetostat, delays their dysfunctional progression and preserves T cell stemness and polyfunctionality while having no negative impact on cell proliferation. Tazemetostat induces T-cell epigenetic reprogramming and increases the expression of the self-renewal T cell transcription factor TCF1 by reducing its promoter H3K27 methylation preferentially in rapidly dividing T cells. In a murine melanoma model, T cells depleted of EZH2 induce poor tumor control, whereas T cells pretreated with tazemetostat exhibited superior anti-tumor immunity, especially when used in combination with anti-PD-1 blockade after adoptive transfer. Collectively, these data highlight the potential of transient epigenetic reprogramming by EZH2 inhibition to enhance adoptive T cell immunotherapy. Citation Format: Yingqin Hou, Peng Wu. Transient EZH2 suppression by tazemetostat during in vitro expansion maintains T cell stemness and improves adoptive T cell therapy [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 LB339.
Abstract LB178: HP518, an oral AR-targeting PROTAC for the treatment of AR positive triple negative breast cancer with a novel mechanism of action
Authors: Jing Li, Hongwei Yuan, Kefan Chen, Yongxu Huo, Guoqing Liu, Wu Du, Xinghai Li
Journal: Cancer Research (2024)

Abstract Triple negative breast cancer (TNBC) accounts for 15-20% of all breast carcinomas and has poor prognosis. Chemotherapy is the mainstay treatment for TNBC patients, yet with limited clinical benefit. Androgen receptor (AR) is expressed in approximately 50% of TNBC tumors and thus the anti-androgen therapy could be a promising solution for the treatment of AR+ TNBC. Nevertheless, AR inhibitors including enzalutamide and bicalutamide or the androgen biosynthesis inhibitor abiraterone have failed to demonstrate satisfying anti-tumor activity in clinical trials. We have discovered HP518, an AR-targeting PROTAC (proteolysis targeting chimera) that induces potent degradation of both the wild-type AR and AR mutants. HP518 is currently under the clinical development for the treatment of mCRPC. Here we report the preclinical data on HP518 for the treatment of AR+ TNBC. HP518 robustly degrades AR in multiple TNBC cell lines with a half-maximal degradation concentration (DC50) &amp;lt; 1 nM. HP518 strongly inhibits AR+ TNBC cell growth, whereas the AR inhibitor enzalutamide does not show significant anti-proliferative effect on these cells in the presence or absence of androgen. Consistent with the in vitro results, HP518 significantly and dose-dependently inhibits tumor growth in MDA-MB-453 cell line derived tumor xenograft (CDX) and patient-derived xenograft (PDX) mouse models. PI3KCA activating mutations are frequently expressed in AR+ TNBC. HP518 in combination with alpelisib, a PI3Kα inhibitor shows a synergistic anti-tumor activity. Mechanistically, HP518, but not AR inhibitor enzalutamide downregulates the mRNA expression levels of a set of DNA replication-related genes in AR+ TNBC cells, indicating a novel and ligand-independent role for AR in regulating growth of AR+ TNBC cells. Therefore, HP518, an AR-targeting PROTAC degrader holds great potential to fulfill the unmet clinical needs for the AR+ TNBC therapy. Selected pre-clinical data will be presented. HP518 structure will not be disclosed. Citation Format: Jing Li, Hongwei Yuan, Kefan Chen, Yongxu Huo, Guoqing Liu, Wu Du, Xinghai Li. HP518, an oral AR-targeting PROTAC for the treatment of AR positive triple negative breast cancer with a novel mechanism of action [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 LB178.
Abstract SY05-03: Circular extrachromosomal DNA promotes tumor heterogeneity and enhancer rewiring
Authors: Lukas Chavez
Journal: Cancer Research (2024)

Abstract Circular extrachromosomal DNA (ecDNA) in patient tumors is an important driver of oncogenic gene expression, evolution of drug resistance and poor patient outcomes. Applying computational methods for the detection and reconstruction of ecDNA across a retrospective cohort of 481 medulloblastoma tumors from 465 patients, we identify circular ecDNA in 82 patients (18%). Patients with ecDNA-positive medulloblastoma were more than twice as likely to relapse and three times as likely to die within 5 years of diagnosis. Multimodal sequencing, imaging and CRISPR inhibition experiments in medulloblastoma models reveal intratumoral heterogeneity of ecDNA copy number per cell and frequent ‘enhancer rewiring’ events on ecDNA. This study reveals the frequency and diversity of ecDNA in medulloblastoma, stratified into molecular subgroups, and suggests copy number heterogeneity and enhancer rewiring as oncogenic features of ecDNA. Citation Format: Lukas Chavez. Circular extrachromosomal DNA promotes tumor heterogeneity and enhancer rewiring [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 SY05-03.
Abstract CT288: Brightline-4: A phase 3 open-label, single-arm, multicenter study to assess the safety and efficacy of brigimadlin (BI 907828) treatment in patients with treatment-naïve or pretreated advanced dedifferentiated liposarcoma
Authors: Scott Schuetze, Girish Jayadeva, Michael Santoro
Journal: Cancer Research (2024)

Abstract Background Current treatment options for dedifferentiated liposarcoma (DDLPS) are associated with suboptimal efficacy and substantial toxicities. Purpose Brigimadlin (BI 907828) is a highly potent, orally available MDM2-p53 antagonist that binds to MDM2 and blocks its interaction with p53, thereby restoring p53 function, leading to cell cycle arrest and apoptosis in TP53 wild-type tumors. Brigimadlin has been evaluated in a phase 1a/1b study in patients with solid tumors (NCT03449381) and has shown encouraging preliminary efficacy in patients with DDLPS. Based on these data, brigimadlin is being investigated for the first-line treatment of advanced DDLPS in the randomized phase 2/3 Brightline-1 trial (NCT05218499). The Brightline-4 trial will generate additional safety and efficacy data in a broader DDLPS patient population. Experimental design Brightline-4 (NCT06058793) is an open-label, single-arm, global, multicenter phase 3 study that aims to assess the safety and efficacy of brigimadlin in patients with treatment-naïve or pretreated advanced DDLPS. Approximately 240 patients with treatment-naïve (Cohort A) or pre-treated (Cohort B) advanced DDLPS will be enrolled. All patients will receive brigimadlin 45 mg orally once every 3 weeks. Key inclusion criteria include: ≥18 years of age; locally advanced/metastatic, unresectable, histologically confirmed DDLPS; tumor MDM2 expression by immunohistochemistry or MDM2 amplification (via fluorescence in situ hybridization or next-generation sequencing); ≥1 measurable target lesion (RECIST v1.1); and ECOG PS 0/1. Key exclusion criteria include: prior treatment with an MDM2-p53 antagonist; known mutation in TP53; receiving treatment for brain metastases or leptomeningeal disease. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoints are the occurrence of treatment-emergent adverse events (TEAEs) and grade ≥3 TEAEs according to NCI CTCAE v5. Secondary endpoints include objective response, progression-free survival, overall survival, duration of response, disease control and further assessment of safety. All analyses will be descriptive; no hypothesis testing is planned. Citation Format: Scott Schuetze, Girish Jayadeva, Michael Santoro. Brightline-4: A phase 3 open-label, single-arm, multicenter study to assess the safety and efficacy of brigimadlin (BI 907828) treatment in patients with treatment-naïve or pretreated advanced dedifferentiated liposarcoma [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 CT288.