tbuckley/cabot-search huggingface dataset:
Abstract 6062: Potent and orally bioavailable BCL6 protein degraders demonstrate efficacy in pre-clinical models of diffuse large B-cell lymphoma (DLBCL)
Authors: Jun Xu, Yangguang Li, Ju Wang, Pingming Tang, Yuting Liao, Chen Zhang, Pangke Yan
Journal: Cancer Research (2024)

Abstract The B-cell lymphoma 6 (BCL6) transcription repressor protein is a protooncogene especially in diffuse large B-cell lymphoma (DLBCL), conferring survival, protection, and maintenance of lymphoma cells. BCL6 expression in normal B cells contributes to initiation and maintenance of the germinal centers (GC). Somatic mutations of the BCL6 gene including chromosome translocations have been shown to result in the deregulation of BCL6 expression and contributes to a subgroup of poor prognostic double- and triple-hit lymphomas. To solve this unmet clinical need, we have developed highly specific, potent, and orally bioavailable BCL6 protein degrader HSK43608 that demonstrates potent in vitro and in vivo efficacy in multiple pre-clinical DLBCL models. HSK43608 achieves &amp;gt;90% BCL6 degradation at 10 nM and DC50 of &amp;lt;1 nM in the OCI-Ly1 model following 24 hr treatment. Time-course studies showed &amp;gt;90% BCL6 degradation within 1 hr which could be maintained at 24 hrs. Importantly, medicinal chemistry efforts have resulted in the successful development of new-generation IMIDs to improve the oral bioavailability of BCL6 degrader for in vivo treatment. As expected, concentration of HSK43608 in tumor tissue was much higher than that in plasma in the DLBCL xenograft models. This tumor tissue enrichment of HSK43608 achieved &amp;gt;95% BCL6 degradation 48 hr after last dosing and convincing tumor growth inhibition. It is worth noting that BCL6 knockout mice suffer from myocarditis with eosinophils infiltration in heart muscle. The tissue distribution study demonstrated less HSK43608 in heart than in plasma, partially explained why there was no sign of myocarditis with eosinophils infiltration in the heart of the HSK43608 treated mice. Taking advantage of the new IMIDs structure, HSK43608 barely induce the degradation of the first generation IMIDs targets including GSPT1, SALL4, CK1α, Aiolos and Ikaros, indicating its safety. In summary, these results indicate HSK43608 as a potent and orally bioavailable BCL6 degrader and support further development. Citation Format: Jun Xu, Yangguang Li, Ju Wang, Pingming Tang, Yuting Liao, Chen Zhang, Pangke Yan. Potent and orally bioavailable BCL6 protein degraders demonstrate efficacy in pre-clinical models of diffuse large B-cell lymphoma (DLBCL) [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 6062.
Abstract 6621: Development of a melanocyte lineage-specific knockout system in zebrafish
Authors: Sarah Perlee, Yilun Ma, Jacob Swanson, Zhitao Ming, Julia Xia, Timothée Lionnet, Maura McGrail, Richard White
Journal: Cancer Research (2024)

Abstract Zebrafish have emerged as an ideal model organism for investigating melanocyte and melanoma biology. While CRISPR-Cas9 technology has significantly advanced our understanding of gene functions in zebrafish, two challenges remain: 1) how do we knock out embryonic lethal genes in adult melanocytes? and 2) how do we knock out tumor promoting genes (rather than tumor suppressors)? To address this, we have developed a new transgenic line in which Cas9 is knocked into the melanocyte-specific endogenous mitfa locus. To test this system in normal melanocytes, Tg(mitfa:Cas9) embryos were injected with a plasmid containing albino sgRNA. Cells with integration of this plasmid exhibited almost complete loss of pigmentation, demonstrating the high efficiency of our approach. This system can now be rapidly used to knock out embryonic essential genes specifically in melanocytes and evaluate the phenotype of adult fish. In melanoma, the commonly available zebrafish lines overexpress the oncogene BRAFV600E in melanocytes with germline knockout of tp53. This is not comparable to the situation in humans, where global p53 loss is rare. By utilizing our mitfa:Cas9 system, we have generated tumors with melanoma-specific loss of tp53 or ptena/b, thereby eliminating non-specific tumors that originate from knockout of tumor suppressors in other cell types. Using this system, we are now testing whether knockout of tumor promoting genes delays melanoma onset and progression, something that has previously been difficult to efficiently achieve in zebrafish. In addition to specificity, an additional advantage of our system is that we can create nearly complete knockout of genes in the melanocytes by the F1, rather than the F2 generation. This saves several months of time and reduces the number of uninformative animals without the relevant genotype. Collectively, our system provides a highly efficient mechanism to study essential genes in melanocytes and melanoma in the zebrafish system. Citation Format: Sarah Perlee, Yilun Ma, Jacob Swanson, Zhitao Ming, Julia Xia, Timothée Lionnet, Maura McGrail, Richard White. Development of a melanocyte lineage-specific knockout system in zebrafish [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 6621.
Abstract 696: Proton radiation and Seco-Duocarmycin SA: A synergistic strategy unveiling new frontiers in glioblastoma multiforme therapy
Authors: Ann Morcos, Antonella Bertucci, Ryan Nicholaus Fuller, Nathan Robert Wall, Marcelo Eduardo Vazquez
Journal: Cancer Research (2024)

Abstract Glioblastoma multiforme (GBM) is one of the most aggressive brain cancers with a 6.9% five-year survival rate. More effective therapies are needed as standard treatments, which include surgery, radiation, and chemotherapy are inefficient due to radio-chemo-resistance and relapse. The goal of this project is to investigate the efficacy of seco-duocarmycin SA (sDSA) as an anticancer drug, alone and the potential synergy of combining proton radiation and sDSA in human GBM cell lines. Proton therapy offers numerous advantages in treating cancers because of its superior dose distribution and biological effects. sDSA is an exceptionally potent agent that selectively alkylates DNA at the N3 position of adenine, making it of great interest as a therapeutic drug. We hypothesize that by pairing sDSA with proton radiation, a more dynamic effect will result, which will amplify their collective power, unleashing an enhanced cytotoxicity against human GBM cells. GBM cell lines (T98G and LN18) were exposed to graded doses and concentrations of protons and sDSA respectively in order to evaluate cellular changes in proliferation, survival, cell cycle, apoptosis/necrosis induction, and DNA damage. Results show that proton radiation and sDSA when used alone induce a dose-dependent decrease of cell proliferation, an increase in foci formation, and an increase in G2/M phase arrest in LN18 and T98G cells. The data also illustrates that the combination of proton radiation and sDSA synergistically enhances these effects. The utilization of proton radiation in conjunction with sDSA against GBM represents an innovative and previously unexplored approach. Currently, the cellular mechanisms of sDSA cytotoxicity are not well understood or studied, and even less is known regarding the effects when combined with proton radiation. This study serves as a vital cornerstone in unraveling the biological response of GBM cells when confronted with proton radiation and sDSA, paving the way for the future development of a more precise and potent combination therapy. Citation Format: Ann Morcos, Antonella Bertucci, Ryan Nicholaus Fuller, Nathan Robert Wall, Marcelo Eduardo Vazquez. Proton radiation and Seco-Duocarmycin SA: A synergistic strategy unveiling new frontiers in glioblastoma multiforme therapy [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 696.
Abstract 3745: Metabolomic profiling of lipid and metabolite in cirrhosis patients with and without hepatocellular carcinoma
Authors: Hannah Powell, Elisa Ruiz, Sandra L. Grimm, Omar Najjar, Luis Olivares, Michael Scheurer, Hashem B. El Serag, Cristain Coarfa, Salma Kaochar
Journal: Cancer Research (2024)

Abstract Early detection of hepatocellular carcinoma (HCC) is crucial for improving patient outcomes, as curative treatments are most effective at the early stages of the disease. The lack of robust biomarkers, particularly a non-invasive diagnostic tool, precludes significant improvement of clinical outcomes for HCC patients. Serum metabolites are one of the best non-invasive means for determining patient prognosis. Established biomarkers for HCC including alpha-fetoprotein (AFP), have shown suboptimal performance in early disease stages. This study aimed to develop a combined metabolite and lipid panel to differentiate early-stage HCC from cirrhosis. Unbiased metabolomic and lipidomic analyses of serum samples were performed for 28 and 30 patients with early HCC and cirrhosis, respectively. We developed an unbiased high-resolution liquid chromatography mass spectrometry (LC-MS) based metabolic profiling platform and evaluated differences in the serum global metabolome and lipidome. This method enabled the detection of over 1200 metabolites and up to 800 lipid molecules in this select cohort. We identified 124 metabolites and 246 lipids that were upregulated and 208 metabolites and 73 lipids that were downregulated in HCC compared to cirrhosis. Using multiomic integrative analysis, we identified the overlap between differentially expressed metabolites and lipid and previously published transcriptomic signatures and illustrate that the overlapping signature associates with clinical disease progression. Lastly, we leveraged machine learning models to identify a minimal panel of lipids and metabolites that accurately distinguish between cirrhosis patients with HCC and without HCC. The best performing classifier was derived using Support Vector Machines, achieving a median AUC of 0.98 over 100 cross-validation iterations, and we showed that we need as little as 12 metabolite and lipids for effective discrimination between cirrhosis and early HCC. Citation Format: Hannah Powell, Elisa Ruiz, Sandra L. Grimm, Omar Najjar, Luis Olivares, Michael Scheurer, Hashem B. El Serag, Cristain Coarfa, Salma Kaochar. Metabolomic profiling of lipid and metabolite in cirrhosis patients with and without 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 3745.
Abstract 6567: Affinity and cooperativity modulate ternary complex formation to drive degradation of SMARCA2
Authors: Ivonne Archibeque, Ken Dellamaggiore, Karen Rex, Sudipa Ghimire-Rijal, Kaylee Choi, Smither Kate, Albert Amegadzie, Ning Chen, Xiaofen Li, Ryan Wurz, Amit Vaish, Paul Hughes, Dane Mohl
Journal: Cancer Research (2024)

Abstract Small molecules that hijack the ubiquitin-proteasome system to degrade target proteins have gained traction as tools for chemical biology and as promising clinical candidates. Targeted degradation strategies encompass relatively large hetero-bifunctional small molecules (hSMs) that are built from target and effector ligands joined by a linker to much smaller molecular glues that have limited affinity for the target or effector proteins outside of a ternary complex. There is good reason for medicinal chemists to move from linkered hSMs toward glue-like scaffolds. Molecular glues can be considerably smaller, e.g., the IMiDs, and thus are less likely to possess atoms and functional motifs that add up to poor permeability and higher protein binding. Guided by the principle that hSMs with reduced molecular weight will have superior druglike properties, we have used SMARCA2, a potential therapeutic target in patients that have both copies of SMARCA4 inactivated, as a test of our own ability to drive rapid target degradation in relevant models. The hetero-bifunctional degraders that resulted from our work trade conventional linkers for chemical spacers that orient SMARCA2 and VHL to promote fortuitous protein-protein contacts in the ternary complex. Following in the footsteps of previously published works, we employed surface plasmon resonance (SPR), x-ray crystallography, and molecular modeling to understand the relationships between our cell-based metrics of degrader activity and the biophysical parameters that describe the ternary complex. Consequently, we found that cooperativity (α) and ternary complex affinity (KLPT) correlated well with both DC50 and initial rate of degradation. Within our series of novel SMARCA2 degraders, compound 1 exhibited exceptional cooperativity and ternary complex affinity, α = 12.8 and KLPT = 4.7 ± 1. The result of high cooperativity and enhanced affinity was rapid and near complete SMARCA2 degradation. Treatment of a cancer cell line with compound 1 resulted in 50% of SMARCA2 being degraded in under 30 minutes, and greater than 90% degradation in 2 hours. Most importantly, the near complete degradation of SMARCA2 resulted in potent effects on SWI/SNF dependent transcription in vitro and in inhibition of tumor cell growth both in vitro and in vivo. Citation Format: Ivonne Archibeque, Ken Dellamaggiore, Karen Rex, Sudipa Ghimire-Rijal, Kaylee Choi, Smither Kate, Albert Amegadzie, Ning Chen, Xiaofen Li, Ryan Wurz, Amit Vaish, Paul Hughes, Dane Mohl. Affinity and cooperativity modulate ternary complex formation to drive degradation of SMARCA2 [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 6567.
Abstract 2340: STRUMP-I: Structure-based binding prediction of MHC class I
Authors: Adam Voshall, Woongyang Park, Eunjung Alice Lee, Yoonjoo Choi
Journal: Cancer Research (2024)

Abstract The presentation of short peptides derived from endogenously expressed proteins within the Major Histocompatability Complex-I (MHC-I), together known as the pMHC, allows the adaptive immune system to monitor the internal functioning of a cell and surveil for foreign or mutated self-proteins. With the rising importance of immunotherapies targeting neoantigens in cancers, the ability to accurately predict which peptides will bind to the diverse population of MHC alleles is critically important. Computational methods for predicting MHC/peptide interactions fall into two broad categories: sequence-based methods that utilize machine learning or deep learning to predict binding from information about the MHC and peptide sequence alone, and structure-based methods that leverage the computed structure and energetics of the pMHC to predict binding. While sequence-based methods have outperformed structure-based methods, their performance varies with the quantity and quality of training data for each MHC allele. The pMHC structure also provides additional insights into downstream analyses, such as predicting the immunogenicity of cancer neoantigens, that cannot be determined from the sequence alone. We developed a STRUMP-I (STRUcture-based pMHC Prediction (for class I)), a novel pMHC binding prediction tool that combines structural modelling with a machine learning-based classifier to discriminate binders from non-binders. STRUMP-I has comparable performance to the state-of-the-art sequence-based methods on data taken from IEDB, the HLAthena training set, TESLA, PRIME, and an in-house cancer neoantigen dataset. However, it generalizes better to alleles with low representation or a lower proportion of positive examples in the training data than the sequence-based methods. Additionally, we demonstrate how STRUMP-I can be used in conjunction with PRIME, a sequence-based immunogenicity prediction method, to use structural information about the peptide to filter out false positive predictions and increase the precision of immunogenicity predictions, increasing the precision by up to 2-fold. Further, on a set of 10 experimentally validated peptides from the in-house cancer neoantigen dataset containing only a single immunogenic peptide, STRUMP-I filtered all false positive predictions and retained only the true positive prediction. By leveraging structural information about the pMHC, STRUMP-I provides robust binding predicting performance across MHC alleles and increases the precision of immunogenicity prediction for neoantigen screening. Citation Format: Adam Voshall, Woongyang Park, Eunjung Alice Lee, Yoonjoo Choi. STRUMP-I: Structure-based binding prediction of MHC class I [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 2340.
Abstract 105: Understanding the role of β2-adrenergic receptor signaling on type II innate lymphoid cells in cancer
Authors: Jee Eun Choi, Cameron R. MacDonald, Saeed Daneshmandi, Jianmin Wang, Nathan T. Roberts, Caitlin M. James, Philip L. McCarthy, Hemn Mohammadpour, Elizabeth A. Repasky
Journal: Cancer Research (2024)

Abstract Increased norepinephrine (NE) due to chronic stress can activate adrenergic receptors, specifically β2-adrenergic receptors (β2AR), to produce an immunosuppressive tumor microenvironment (TME). Previous work by our lab demonstrated that tumor burden can be reduced by blocking β2AR signaling. Immune cells express β2AR and we have shown that the increased β2AR signaling leads to increased T cell exhaustion and increased inhibitory activity of myeloid-derived suppressor cells (MDSCs). In general, the resulting immunosuppression leads to a modest but significant reduction in tumor growth. However, the lack of a dramatic reduction in tumor growth reveals the complex nature of adrenergic signaling dependent regulation of the cancer immune response. Recent literature revealed that innate lymphoid cells (ILCs), especially type II ILCs (ILC2s), express high levels of β2AR. Therefore, we evaluated whether β2AR regulates ILC2s within the TME and how that affects tumor prognosis. We generated a genetic conditional knockout murine model where β2AR expression in ILC2s was deleted by crossing IL5cre expressing mice to β2ARflox/flox mice (IL5creβ2ARf/f). AT3 breast cancer cell line was injected into the 4th mammary fat pad and tumor volume was measured every 2-3 days. Tumor infiltrating ILC2s (CD45+Lineage−CD90.2+CD127+ST2+) were analyzed by flow cytometry at D36 post-tumor implantation. Notably, IL5creβ2ARf/f mice had increased AT3 breast cancer tumor growth compared to control mice. Flow cytometric analysis of the tumor revealed an increased frequency of GATA3+ ILC2s within the TME. These GATA3+ ILC2s lacking β2AR expressed higher levels of the IL33 receptor, ST2, and a higher percentage of IL13+ cells compared to WT GATA3+ ILC2 cells. We also observe a trend toward increased MDSC population within the TME of mice lacking β2AR in ILC2s. These results reveal an anti-tumor function of β2AR signaling through the suppression of ILC2 activity within the TME that warrants further investigation. This work has been in part supported by NIH Grants F30 CA284763 (to J.C.), K99 HL155792 (to H.M.), and RO1 CA205246 (to E.R.) Citation Format: Jee Eun Choi, Cameron R. MacDonald, Saeed Daneshmandi, Jianmin Wang, Nathan T. Roberts, Caitlin M. James, Philip L. McCarthy, Hemn Mohammadpour, Elizabeth A. Repasky. Understanding the role of β2-adrenergic receptor signaling on type II innate lymphoid cells in 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 105.
Abstract 535: Resistant PDO models: Unraveling drug resistance mechanisms for discovering new drug targets
Authors: Yasmine Abouleila, Mayke Doorn, Roel Verkerk, Joris Maas, Carla Verissimo, Sylvia Boj
Journal: Cancer Research (2024)

Abstract Resistance to cancer treatment remains a significant obstacle in curing patients with cancer. Despite recent advancements in novel drug targets for cancer therapeutics, patients often develop treatment resistance even after initial disease remission, leading to tumor relapse. To investigate the mechanisms responsible for developing resistance to standard-of-care therapies, it is essential to gain insights into the stepwise progression leading to complete resistance. Recent research has revealed that cancer cells can evade the effects of chemotherapy and targeted therapy by entering a reversible and slow proliferation state known as the drug-tolerant persister (DTP) state. This DTP state allows cancer cells to survive drug therapy long enough for additional mechanisms of acquired drug resistance to develop. HUB Organoids® or patient-derived organoid (PDO) models are derived from patient tissues, making them more physiologically relevant than traditional cell lines. Thus, studying drug persistence and resistance in PDO models is more likely to reflect in vivo conditions. This study demonstrates the successful development of persistent and resistant CRC PDO models to standard-of-care therapies. All models were characterized using whole exome sequencing and RNA sequencing to confirm their persistent or resistant state and to identify possible pathways involved in developing therapy resistance, as well as potential new drug targets. In conclusion, developing persistent and resistant PDO models is crucial for understanding drug resistance mechanisms, enabling the development of more effective and personalized cancer treatments, and advancing our overall knowledge of how resistance develops in cancer patients. Citation Format: Yasmine Abouleila, Mayke Doorn, Roel Verkerk, Joris Maas, Carla Verissimo, Sylvia Boj. Resistant PDO models: Unraveling drug resistance mechanisms for discovering new drug targets [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 535.