tbuckley/cabot-search huggingface dataset:
Abstract 6026: A novel lutetium-177 radioligand therapy targeting FAP has potent antitumor activity in xenograft cancer model
Authors: Spencer Lindeman, Jack Higgins
Journal: Cancer Research (2024)

Abstract Fibroblast Activation Protein (FAP) is an attractive target for cancer therapy due to its overexpression in most solid tumors, predominantly localized on cancer associated fibroblasts. Unfortunately, trials with first generation FAP-targeted radioligand therapies (RLTs) have produced only modest clinical responses, indicating the need for improvements. We developed a library of over 40 fully synthetic, novel FAP-targeted RLTs comprising a FAP inhibitor with a stable linker to an albumin binding domain and a DOTA-lutetium-177 payload. Screening this library for binding, biodistribution and pharmacology properties identified a 177Lu-FAP RLT lead molecule. The novel 177Lu-FAP RLT demonstrates high selectivity and binds to FAP with a sub-nanomolar binding affinity. Biodistribution of the 177Lu-FAP RLT was evaluated in mice bearing U87MG tumors, demonstrating delivery and retention of a high tumor absorbed dose. In vivo efficacy of the 177Lu-FAP RLT at 150 µCi or 500 µCi was evaluated in mice bearing U87MG tumors. The 177Lu-FAP RLT elicits potent and dose-dependent antitumor activity with &amp;gt;80% reduction in tumor volume of 8/10 mice following a single 500 µCi dose. The treatment was well-tolerated, with no significant weight loss or deaths. The outstanding antitumor activity and high selectivity for FAP support further evaluation of this investigational RLT in patients with solid tumors. Citation Format: Spencer Lindeman, Jack Higgins. A novel lutetium-177 radioligand therapy targeting FAP has potent antitumor activity in xenograft cancer model [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 6026.
Abstract 3522: Application of large language models to nucleotide sequences for profiling signaling pathway disruptions in ovarian cancer patients
Authors: Dmitrii K. Chebanov, Nadezhda S. Tatevosova
Journal: Cancer Research (2024)

Abstract Ovarian cancer is a challenging disease, often exhibiting recurrence after initial treatment. The complexity arises from simultaneous disruptions in multiple signaling pathways within tumor cells, rendering targeted inhibitors ineffective in providing sustained therapeutic impact. While targeted sequencing panels can identify specific therapeutically relevant events, they often fail to capture the complete picture of targetable tumor driving aberrations, and provide biomarkers relevant to disease resistance and/or recurrence. A potential solution lies in comprehensively defining the landscape of signaling pathway alterations by identifying molecular triggers underlying their dysregulation. While individual DNA mutations sometimes may not lead to carcinogenesis or changes in tumor cell behavior, combination of deactivating mutations in suppressor genes, can influence tumor development and prognosis, warranting a comprehensive delineation of their effect on the broad signaling network level. To this end, we propose the Large Language Models (LLMs), which have been successful in natural language processing, particularly in understanding context. Such tools are essential for discerning the effect of mutation combinations, their physical proximity to other mutations, and functional gene regions. We obtained mutation annotation files for 177 ovarian cancer patients from the TCGA database, reconstructing consensus nucleotide sequences using a reference genome. To input this data into LLMs, we generated embeddings for these sequences using the Nucleotide Transformer algorithm, pre-trained on 500 million variants of the reference genome. Additionally, we extracted data on detected disruptions in 10 signaling pathways (Cell Cycle, HIPPO, MYC, NOTCH, NRF2, PI3K, RTK RAS, TP53, TGF-Beta, WNT) for these patients from TCGA. Each pathway was associated with the percentage of its alteration. We trained a deep learning algorithm on these data to predict a combination of 10 numerical values, each corresponding to the percentage of disruption for a given signaling pathway. Our findings revealed that nearly half of the patients exhibited disruptions in 5 or more signaling pathways. The algorithm developed enables the determination of the extent of disruption in each pathway based on whole exome sequencing results. This approach facilitates more informed treatment strategy planning and enhances the efficient development of new drugs for ovarian cancer treatment. Citation Format: Dmitrii K. Chebanov, Nadezhda S. Tatevosova. Application of large language models to nucleotide sequences for profiling signaling pathway disruptions in ovarian cancer patients [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 3522.
Abstract 5414: BDNF/TrKB signaling may lead to higher incidence of perineural invasion in men with prostate cancer
Authors: Gabrielle Joy Edwards, Valerie Odero-Marah
Journal: Cancer Research (2024)

Abstract Perineural invasion (PNI) is a crucial mechanism facilitating prostate cancer metastasis. PNI encompasses perineural, circumferential, and intraneural invasion, with cancer cells closely interacting with nerves. Evidence suggests that cancer cells utilize the nervous system for metastasis through signaling pathways. PNI is associated with poor prognoses in various cancers, but its role in prostate cancer remains unclear. PCa primarily metastasizes through systemic routes, such as lymphatic and circulatory systems. Metastasizing cancer cells undergo epithelial-mesenchymal transition (EMT), enhancing their motility. SNAIL1, a transcriptional repressor, induces EMT and promotes cancer cell migration, including towards nerves, termed neurite outgrowth. Neurite outgrowth involves intricate signaling between tumor cells and nerves, possibly facilitating cancer cell infiltration into nerve sheaths and PNI. Our lab has shown SNAIL1 in interactions with neurotrophic factors like Brain-Derived Neurotrophic Factor (BDNF) and Tyrosine Kinase Receptor Beta (TrkB), modulating cancer cell behavior. TrkB is overexpressed in various cancers, while BDNF signaling contributes to EMT via the Twist-Snail axis. BDNF may also play a role in PNI pathogenesis. Our hypothesis posits the BDNF-TrkB axis drives aggressive prostate cancer and PNI. This study employed prostate cancer cell lines for comprehensive analysis. We assessed BDNF expression in different cell lines, particularly those with high Snail levels, and analyzed BDNF transcript levels via real-time quantitative PCR following RNA extraction and reverse transcription. We explored whether BDNF overexpression enhanced cancer cell migration towards nerves, employing migration assays. Our findings indicated heightened migration in BDNF-high cell lines, C42, PC3, and MDA-2b, compared to BDNF knockdown cells. Additionally, a TrkB inhibitor, K252a, attenuated migration due to BDNF-induced TrkB phosphorylation. Our study establishes that BDNF/TrkB signaling promotes prostate cancer cell migration towards nerves, a phenomenon reversible with K252a, offering a potential strategy to impede prostate cancer progression and metastasis. Citation Format: Gabrielle Joy Edwards, Valerie Odero-Marah. BDNF/TrKB signaling may lead to higher incidence of perineural invasion in men with 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 5414.
Abstract 5556: An vascularized melanoma model for with unidirectional perfusion of circulating immune cells for advancing immune-oncology research
Authors: Manuel Caro Torregrosa, Sander de Ruiter, Todd Burton, Karla Queiroz, Will Allen, Job Komen, Sebastiaan Trietsch, Lenie van den Broek
Journal: Cancer Research (2024)

Abstract Understanding the interactions between the tumor the vascular systems and circulating immune cells is crucial for elucidating mechanisms of immune cell recruitment in cancer and in exploring potential immunotherapeutic approaches. However, current in vitro models often lack the fidelity to replicate these intricate dynamics observed in vivo. The OrganoPlate Graft has been developed for perfusion of peripheral blood mononuclear cells (PBMCs) through a vascular bed with a melanoma monolayer (A375) to study aspects such as immune cell adhesion, extravasation and interaction with the tumor. The OrganoPlate Graft comprises 48 chips per plate, each designed to simulate the conditions of vascular beds. The device achieves flow through passive leveling, utilizing gravity to induce a pressure drop and unidirectional flow across the vascular bed in both positive and negative inclines. This approach avoids the complications and potential artifacts introduced by external pump, reduces complexity, and increases the throughput with up to 16 plates (768 chips) served by each OrganoFlow rocker. In experimental settings, formation of the vascular bed was seen to be consistent in plates and the introduction of the chemokine CXCL-12 led to the establishment of a gradient. Subsequently, PBMCs were observed to localize in clusters as a result of extravasation towards this gradient and the A375 monolayer. This behavior is consistent with known chemotactic responses in more complex in vivo environments. A notable observation was the sustained activity of PBMCs within the system. Cells continued to perfuse through the vascular bed for up to three days after seeding. In summary, the OrganoPlate Graft provides a platform for studying immune interactions in an immunocompetent vascular bed model. Its design and functionality allow for the exploration of immune cell behaviors in proximity to tumor cells, offering potential insights for immune-oncology research. The system's ability to mimic immune cell migration and extravasation in a controlled environment, and future potential to observe tumour killing makes it a valuable tool for advancing our understanding of immune-tumor interactions and may contribute to the development of novel immune-oncology therapeutic strategies. Citation Format: Manuel Caro Torregrosa, Sander de Ruiter, Todd Burton, Karla Queiroz, Will Allen, Job Komen, Sebastiaan Trietsch, Lenie van den Broek. An vascularized melanoma model for with unidirectional perfusion of circulating immune cells for advancing immune-oncology research [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 5556.
Abstract 3505: Classification of cancer subtypes by cfDNA fragmentomics analysis
Authors: Lisha Zhu, Chao Dai, Shuang Gan, Shidong Jia, Pan Du
Journal: Cancer Research (2024)

Abstract Introduction Fragmentation patterns of cell-free DNA (cfDNA) from whole genome sequencing offer insights into nucleosome occupancy, providing a tool to infer epigenomic and transcriptomic information. The nucleosome complex, the primary protector of cfDNA, is reflected in the size distribution of cfDNA fragments, with a mode fragment size of 167 bp corresponding to the wrapping of DNA around a single nucleosome. Nucleosome occupancy patterns at transcription factor binding sites (TFBS) exhibit differences between circulating tumor DNA in cancer patients and normal plasma controls, as well as among different tumor subtypes. Therefore, cfDNA fragmentomics can be employed for cancer subtyping analysis. Methods We utilized the Griffin framework to classify tumor subtypes based on nucleosome profiling of cancer-specific TFBS and tumor subtype-specific chromatin accessibility regions from low-pass whole genome sequencing data of cfDNA. For prostate cancer subtyping, AR and ASCL1 binding sites were used to distinguish between androgen receptor-dependent prostate cancer (ARPC) and neuroendocrine prostate cancer (NEPC). ER and ERBB2 were employed for breast cancer subtyping to differentiate between ER-positive and ER-negative tumor subtypes. Results Nucleosome profiling patterns at AR binding sites (ARBS) were compared among over 500 prostate cancer plasma samples and 42 normal plasma backgrounds. The ARBS nucleosome profiling abnormality score (ARBS score) was quantified by comparing its GC-corrected fragment central coverage with the normal background using a standard Z-score.Majority of prostate cancer samples with a high ARBS score could be classified as ARPC. For 12 samples with high tumor fraction but low ARBS score and no AR copy number amplification, we found that 8 had a high ASCL1 nucleosome profiling abnormality score. All these samples also exhibited RB1 copy number loss, suggesting that these 8 samples likely belong to NEPC. Nucleosome profiling of 171 breast cancer plasma samples at breast cancer-specific ER binding sites revealed that majority of samples had a high ERBS abnormality score, indicating likely ER-positive breast cancer. Conclusion Our results demonstrate that nucleosome profiling of tumor cfDNA exhibits distinct patterns across different tumor types. Integrating nucleosome profiling at cancer-specific transcription factor binding sites can facilitate cancer subtyping, highlighting its potential clinical utility for patient stratification. Citation Format: Lisha Zhu, Chao Dai, Shuang Gan, Shidong Jia, Pan Du. Classification of cancer subtypes by cfDNA fragmentomics analysis [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 3505.
Abstract 1813: Discovery, biomarker validation, and pre-clinical profiling of a novel PKMYT1 inhibitor
Authors: Alfie Brennan, Jan Lanz, Daniel S. Miller, Oliver Vipond, Noah Harrison, James Aaronson, Anna Hercot
Journal: Cancer Research (2024)

Abstract Protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) is a negative regulator of CDK1 activity and has been identified as a putative synthetic lethal target in cancers which upregulate cyclin E (CCNE1). We used high-throughput virtual screening to identify inhibitors of PKMYT1 with high lipophilic ligand efficiency (LLE), which were rapidly optimized to potent leads with exceptional selectivity over a key off target, WEE1. Machine learning-driven optimization rapidly reduced mouse hepatocyte clearance to acceptable levels, delivering a compound with best-in-class potency, selectivity, and pharmacokinetic profiles in relevant animal models. Tool compounds from this series were used to validate a differentiated biomarker for sensitivity to PKMYT1 inhibition in cellular models, which could significantly expand the potential patient population. In vivo proof-of-concept studies are ongoing in a variety of cell line- and patient-derived xenograft models which represent the novel biomarker previously identified, to further validate our therapeutic strategy. Citation Format: Alfie Brennan, Jan Lanz, Daniel S. Miller, Oliver Vipond, Noah Harrison, James Aaronson, Anna Hercot. Discovery, biomarker validation, and pre-clinical profiling of a novel PKMYT1 inhibitor [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 1813.
Abstract 7575: BPI-460372, a covalent, irreversible TEAD inhibitor in Phase I clinical development
Authors: Xiaohong Han, Jing Guo, Xiangyu Jin, Lingyin Zhu, Hongling Shen, Xiaofeng Xu, Mengjie Zhang, Xiaoyun Liu, Yanju Liu, Hongke Cheng, Shunna Guo, Lieming Ding, Jiabing Wang, Hong Lan, Mengzhao Wang
Journal: Cancer Research (2024)

Abstract The Hippo signaling pathway is critical for the regulation of organ development, tissue homeostasis, and tumorigenesis by controlling the activation status of yes-associated protein (YAP) or its homolog PDZ-binding motif (TAZ). As a major downstream effector, the transcription factor TEAD is activated by forming a complex with YAP/TAZ. Hippo pathway aberrations leading to TEAD activation have been reported in many cancers. Inhibiting TEAD function by directly blocking the palmitoylation pocket of TEAD is a potential therapeutic approach for cancer treatment. Betta Pharma has discovered a selective, covalent and irreversible TEAD inhibitor known as BPI-460372. The discovery of BPI-460372 was first reported in AACR 2023. Here we present additional preclinical and clinical data characterizing BPI-460372 as a promising candidate drug. In the dose-escalating part of the Phase Ι study, the exposure of BPI-460372 increased proportionally over 10 to 80 mg dose range after oral administration and exhibited linear pharmacokinetics, with a clearance rate suitable for once-daily dosing. The compound is generally well tolerated, with no drug-related Grade ≥3 adverse event observed. Remarkably, we have not seen renal toxicities that was perceived as a potential risk associated with certain TEAD inhibitors. Preliminary efficacy was observed in a few subjects. In preclinical studies, we found that intermittent dosing schedule of 3 days on/4 days off, compared with continuous dosing at equivalent weekly exposure, can ameliorate kidney damage and improve early renal injury biomarkers while maintaining anti- tumor activity. Thus, alternative dosing schedule could further improve the therapeutic window and enable combination studies in clinical development. Collectively, these results support further development of BPI-460372 for the treatment of cancers harboring Hippo pathway alterations. Citation Format: Xiaohong Han, Jing Guo, Xiangyu Jin, Lingyin Zhu, Hongling Shen, Xiaofeng Xu, Mengjie Zhang, Xiaoyun Liu, Yanju Liu, Hongke Cheng, Shunna Guo, Lieming Ding, Jiabing Wang, Hong Lan, Mengzhao Wang. BPI-460372, a covalent, irreversible TEAD inhibitor in Phase I clinical development [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 7575.
Abstract 7064: BRCA 1/2 haploinsufficiency-associated metabolic dysfunction in benign fallopian tube epithelia
Authors: Jovanka Ravix, Iru Paudel, Gauthami Pulivendala, Ramlogan Sowamber, Elizabeth Smith, Matthew Schlumbrecht, David Lombard, Sophia George
Journal: Cancer Research (2024)

Abstract In 3-17% of women with BRCA1/2 mutations who undergo risk-reducing surgery, pre-neoplastic and neoplastic lesions are found in their fallopian tubes that display differential loss of heterozygosity of BRCA1/2. Precisely how mutations in BRCA1/2 predispose women to develop high grade serous ovarian carcinoma (HGSC) is not completely understood. Although linked to various processes localized in the nucleus, BRCA1/2 may also have essential roles in the cytoplasm, specifically in the regulation of key processes associated with mitochondrial homeostasis and metabolism. Understanding how haploinsufficiency of BRCA1/2 contributes to the potential neoplastic transformation of fallopian tube epithelial cells should reveal new insights into BRCA1/2 function, and ultimately provide novel opportunities for preventative interventions in individuals with this mutation and new treatment opportunities for HGSC associated with BRCA1/2 heterozygosity. We have identified distinct metabolic and mitochondrial deficits in BRCA2 mutation carriers compared to BRCA1 carriers and non-carriers. Fallopian tube epithelial cell lines derived from BRCA2 mutation carriers showed increased levels of mitochondrial respiration and activity followed by BRCA1 mutation carriers and non-carriers. Western blot analysis of mitochondrial proteins regulating glycolysis and oxidative phosphorylation showed differential expression based on mutation status. Transmission electron microscopy of BRCA2 mutation carriers showed increased disrupted mitochondrial networks when compared to wild type, suggesting that mutation status may contribute to increased mitochondrial fission. These observations reveal an entirely new aspect of BRCA1 and BRCA2 biology and further studies will disaggregate the effects of BRCA1 and BRCA2 on mitochondrial function, versus DNA damage repair. Ultimately, this work will provide new insight into the adaptive changes within FT cells which promote neoplastic transformation and inform how high-grade serous carcinoma (HGSC) cells distinctively respond to microenvironmental stimuli. Citation Format: Jovanka Ravix, Iru Paudel, Gauthami Pulivendala, Ramlogan Sowamber, Elizabeth Smith, Matthew Schlumbrecht, David Lombard, Sophia George. BRCA 1/2 haploinsufficiency-associated metabolic dysfunction in benign fallopian tube epithelia [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 7064.
Abstract 6770: Acquired temozolomide resistance instructs patterns of glioblastoma cell motility and proteome expression within gelatin hydrogels
Authors: Viktoriia Kriuchkovskaia, Ela Eames, Rebecca Riggins, Brendan Harley
Journal: Cancer Research (2024)

Abstract Acquired drug resistance in glioblastoma (GBM) presents a major clinical challenge and is one of the key factors contributing to the abysmal prognosis with less than 15 months median overall survival. The aggressive chemotherapy with the frontline therapeutic, temozolomide (TMZ), ultimately fails to kill residual, highly invasive tumor cells after surgical resection and radiotherapy. Here, we present a robust three-dimensional (3D) in vitro hydrogel model of acquired temozolomide (TMZ) resistance using isogenically-matched glioblastoma (GBM) cell lines. We demonstrate distinct drug response patterns between TMZ-sensitive and TMZ-resistant GBM cells, emphasizing our model's promise for future pre-clinical investigations aimed at developing novel therapies targeting drug-resistant GBM. Importantly, our model detects apoptosis-related protein changes in response to TMZ, validating its ability to study drug-induced molecular changes. Furthermore, our study delves into the migratory potential of GBM cells within the 3D extracellular matrix environment. Additionally, we uncover significant alterations in cytokine expression associated with matrix remodeling and angiogenesis, providing new avenues for therapeutic investigation. Although our findings are derived from a specific set of isogenically-matched cell lines, this model highlights the potential to explore personalized treatment strategies. Ongoing research in our lab is dedicated to gaining a more profound understanding of matrix remodeling and the migratory potential of TMZ-resistant GBM cells. Moreover, our future work will aim to expand our study to include a wider range of cell lines and patient-derived xenografts within our advanced microphysiological systems that include key elements of GBM tumor microenvironment such as perivascular niche. This endeavor seeks to establish connections between observed therapeutic behaviors and clinical outcomes, ultimately contributing to the development of more effective treatments for GBM patients. Citation Format: Viktoriia Kriuchkovskaia, Ela Eames, Rebecca Riggins, Brendan Harley. Acquired temozolomide resistance instructs patterns of glioblastoma cell motility and proteome expression within gelatin hydrogels [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 6770.