tbuckley/cabot-search huggingface dataset:
Abstract 1067: Label free Raman spectroscopy of extracellular vesicles for early stage liquid biopsy cancer detection
Authors: Randy P. Carney, Maria Navas-Moreno, Andrew Birkeland
Journal: Cancer Research (2024)

Abstract Aim: To improve patient outcomes, there remains a critical need to develop faster, less invasive platforms capable of identifying biomarkers. Multi-omics approaches, while promising, are high in cost and complexity, low throughput, slow, and require large sample volumes, thus are impractical for many stages of clinical care. Raman spectroscopy (RS) addresses many of these needs: it requires little to no sample preparation, is non-destructive, does not need exogenous dyes or labelling agents, and can be performed directly in aqueous solutions. Surface enhanced Raman spectroscopy (SERS) offers further improvements in terms of sensitivity but increases complexity. In this study we carried out comprehensive RS and SERS measurements on a &amp;gt;100-person cohort of blood and saliva from head and neck cancer (HNC) patients and benign controls. Analyses were carried out on whole biofluids, in addition to extracellular vesicles (EVs) isolated from the biofluids to investigate the added value. EVs are emerging biomarkers of interest found in high numbers in circulating biofluids with great promise to increase the specificity of diagnostic platforms. Results: We analyzed a robust clinical dataset of HNC patient saliva and plasma to build a diagnostic model. We found distinct Raman and SERS signatures of metabolites in all cancer samples uniquely present compared to non-cancer controls. Raman spectral measurements fused together for EVs and whole biofluids across saliva and plasma delivered accuracies of &amp;gt;95% using a novel machine learning module based on convolutional neural networks. Our platform features an automated method to isolate EVs amenable to rapid clinical use. Conclusions: The results of this study indicate an exciting step in validating Raman as a robust diagnostic tool revealing that complementary chemical information spread out across biofluids and biomarkers of interest can strongly improve simple, quick Raman based diagnostics of whole biofluids and EVs. Citation Format: Randy P. Carney, Maria Navas-Moreno, Andrew Birkeland. Label free Raman spectroscopy of extracellular vesicles for early stage liquid biopsy cancer detection [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 1067.
Abstract 6909: KRASG12C inhibitor resistance in patient-derived non-small cell lung cancer models
Authors: Joshua C. Rosen, Nhu-An Pham, Quan Li, Pinjiang Cao, Katrina Hueniken, Takamasa Koga, Nikolina Radulovich, Alex Koers, Michael Niedbala, Sarah Ross, Adrian Sacher, Ming-Sound Tsao
Journal: Cancer Research (2024)

Abstract Introduction: One quarter of lung adenocarcinomas (LUAD) harbor KRAS-mutations, with KRASG12C accounting for the majority (40%). GDP-KRASG12C inhibitors (G12Ci) have been developed for this patient cohort, and two of these are approved for clinical use in the US. While response rates to G12Ci tested in clinical trials have been between 35-50%, studies have identified mechanisms of adaptive resistance to these novel agents, limiting their use as monotherapies. However, primary (intrinsic) resistance to these compounds has not been explored extensively. We leveraged our patient-derived xenograft (PDX) and xenograft-derived organoid (XDO) development programs to study primary resistance to the novel G12Ci, AZD4625. Methods: Twelve KRASG12C PDX models were established which recapitulated patient tumor histology, and genomic, transcriptomic, and methylome profiles. From these 12 PDX, six long-term (passage &amp;gt;10) XDO were generated. PDX were treated with AZD4625 chronically for four weeks as well as in an acute dosing pharmacodynamic study, where tumors were harvested for further analysis. Results: The AZD4625 drug screen in our PDX models reproduced the G12Ci response rate observed in clinical trials. Four of twelve tumor models reduced in size on treatment, while the remainder were considered resistant as these tumors increased in size on treatment. Sensitive tumors became necrotic while those resistant remained proliferative. XDO models recapitulated their originating PDX genomic alterations, histology, as well as responses to AZD4625. During the acute pharmacodynamic screen in our PDX models, we observed a decrease in pERK1/2 and pS6 protein expression in sensitive but not resistant models, despite acute DUSP6 gene expression decreases in every model. Global proteomic analysis highlighted differences between each model. Conclusion: PDX and XDO are useful models to study resistance to this novel class of inhibitor, with the KRASG12C NSCLC PDX models exhibiting a treatment response rate that is similar to those observed in clinical trials. Global proteomics suggests uniqueness of each model in our cohort, hinting that a universal combination of specific targeted agents to treat KRASG12C LUAD tumors may be insufficient. Citation Format: Joshua C. Rosen, Nhu-An Pham, Quan Li, Pinjiang Cao, Katrina Hueniken, Takamasa Koga, Nikolina Radulovich, Alex Koers, Michael Niedbala, Sarah Ross, Adrian Sacher, Ming-Sound Tsao. KRASG12C inhibitor resistance in patient-derived non-small cell lung cancer models [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 6909.
Abstract 7595: PRMT5 inhibitor synergizes with PARP inhibitors in triple-negative breast cancer cells
Authors: Samyuktha Suresh, Lisa A. McPherson, James M. Ford
Journal: Cancer Research (2024)

Abstract Background: Treating triple-negative breast cancer (TNBC) patients, an aggressive subtype of breast cancer, is an ongoing clinical challenge. Small-molecule inhibitors targeting the poly ADP-ribose polymerase (PARP) DNA repair enzymes, have been approved for treating only a subset of TNBC patients with a specific genetic landscape (BRCA1 mutation). However, TNBC patients with wildtype BRCA1 (BRCA1WT) are still lacking targeted therapy and chemotherapy remains their main treatment strategy. High expression of protein arginine methyltransferase 5 (PRMT5) is linked to poor prognosis in breast cancer and PRMT5 alone or via its interacting proteins plays an oncogenic role in breast cancer. Recent evidence suggests that PRMT5 is a key player in regulating the repair of DNA double strand breaks (DSBs) either through homologous recombination (HR) or non-homologous end joining (NHEJ) depending on the PRMT5 expression level within the cell. This dependency of cancer cells on PRMT5 expression levels in deciding the repair pathway of choice can be exploited for developing therapies. We hypothesize that in BRCA1 wildtype TNBC cells, inhibiting PRMT5 activity will force the cells to rely on NHEJ rather than HR to repair DNA DSBs, and introducing PARP inhibitors in this setting will inactivate NHEJ as well, causing synthetic lethality and cell death. In this study, we evaluated the pre-clinical benefit of combining PARP inhibitors with a PRMT5 inhibitor in TNBC cells. Methods: Human TNBC cell lines with wildtype BRCA1 (MDA-MB-468, HCC1806) and mutant BRCA1 (MDA-MB-436, SUM149-PT) were treated with varying doses of two PARP inhibitors (Olaparib, Talazoparib) and a PRMT5 inhibitor (GSK3326595) as single agents or in combination. MTT-based cell viability assay was used to determine cytotoxicity of the treatments. mRNA expression was determined by RT-qPCR after drug treatment. Results and Conclusion: We report that PRMT5 inhibition synergizes with both Olaparib and Talazoparib, to potentiate cell death in two BRCA1WT but not in BRCA1mut TNBC cell lines. Furthermore, we show that inhibiting PRMT5 in BRCA1WT cells upregulates the mRNA expression of RAD50, a DNA damage sensing gene in the HR pathway. Our ongoing study is to delineate the molecular mechanism of action for the observed synergy and whether PRMT5 inhibition can overcome resistance to PARP inhibitors. Through this study, we will identify a novel treatment strategy for the majority of TNBC patients (BRCA1WT) who currently lack targeted therapies. Citation Format: Samyuktha Suresh, Lisa A. McPherson, James M. Ford. PRMT5 inhibitor synergizes with PARP inhibitors in triple-negative breast cancer cells [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 7595.
Abstract 7611: Circulating blood RNAseq detects activation of immune system and predicts response to immunotherapy in bladder cancer
Authors: Corentin Richard, Sandy Chevrier, Aurélien Marabelle, Romain Boidot
Journal: Cancer Research (2024)

Abstract Background: Anti-PD(L)1 immunotherapies have revolutionized oncology by getting durable tumor responses in advanced cancers. Nevertheless, currently approved biomarkers (PD-L1, MSI, TMB) have suboptimal positive/negative predictive values for tumor responses and survival. Aims &amp; Methods: We sought to assess the value of gene expression on circulating blood to predict responses to immunotherapy. We performed total paired-end RNAseq at 20-million reads and analyzed differential gene expressions according to cancer outcomes on baseline frozen whole blood from a cohort of 186 patients prospectively enrolled in the IOPREDI study, a French ancillary cohort of the international multi-center STRONG Phase III trial testing the anti-PD-L1 durvalumab in advanced bladder cancers (NCT03084471). Results: One hundred and sixty four out of the 186 baseline samples generated valuable blood transcriptome data. Thanks to mathematical corrections, all samples were normalized, and the analysis was possible without introducing any bias despite the sample origin from 16 enrolling sites. We first observed that patients with a complete or partial response or a stable disease overexpressed 19 genes, 5 of which are markers of immune cell activation: CXCL8, EOMES, GBP5, GZMA, and GZMH. Conversely, patients with a progressive disease overexpressed 11 genes including CD177, a marker of neutrophil cells, recently associated to immunotherapy resistance. Next, patients with a PFS &amp;gt; 3 months showed an overexpression of 25 genes associated with immune cells activation such as CD8A, CXCL8, EOMES, FASLG, GZM genes, whereas patients with a shorter PFS highly expressed genes of immune cell inhibition: CD177, CD300LG, CD99, and CST7. Finally, patients with an OS &amp;gt; 7 months had also a higher expression of the same previous genes completed with 6 other genes, still indicators of immunity activation (CD3D, CD3E, CD3G, GZMM, IL2RB, and PTGDS). Conclusion: Total RNAseq from RNA directly extracted from whole blood can detect baseline activation of T-cells in patients who will subsequently benefit from anti-PD-L1 immunotherapy. This work shows that RNAseq can detect an immune activation state in circulating blood without specific cell selection. This technique could be used in clinical trials to select for patients prone to benefit from cancer immunotherapies. Citation Format: Corentin Richard, Sandy Chevrier, Aurélien Marabelle, Romain Boidot. Circulating blood RNAseq detects activation of immune system and predicts response to immunotherapy in bladder 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 7611.
Abstract 760: Alteration to transcriptional rhythmicity in mammary glands from pubertal MMTV-PyMT mice fed a high-fat diet
Authors: Lin Yan, Daniel G. Palmer, Huawei Zeng
Journal: Cancer Research (2024)

Abstract Biological clocks, existing in all human organ systems, cycle every 24 hours in a diurnal pattern and control the daily rhythms of human life (e.g., eating vs. fasting, sleep vs. wakefulness), which is essential for health and wellbeing. Disruption of the biological clocks, either by genetic or environmental alteration, disturbs circadian rhythms, which may lead to chronic diseases. Childhood obesity is a risk factor for breast cancer in adult women. Lifestyle changes in the modern world (e.g., energy-dense diets) serve as environmental factors that contribute to alterations in biological clocks and obesity. The present study examined transcriptional rhythmic changes in mammary glands from pubertal MMTV-PyMT mice fed a high-fat diet (HFD). Three-week-old female mice (FVB background) were randomly assigned into three groups - wild-type (WT) mice fed the AIN93G diet and MMTV-PyMT mice fed the AIN93G diet or an HFD for three weeks. At the end of the study, mammary glands were collected every 4 hours over a period of 24 hours (Zeitgeber time 0-24 hours) for RNA-sequencing analysis. The mammary weight was 0.45±0.02, 0.59±0.02, and 0.67±0.02 g for WT mice fed the AIN93G diet and MMTV-PyMT mice fed the AIN93G and HFD, respectively (means ± SEM, all p&amp;lt;0.05 when three groups were compared each other). The rhythmicity analysis using R showed that greater than 1,000 transcripts were classified as “loss of rhythm” when MMTV-PyMT mice (both AIN93G-fed and HFD-fed groups) were compared to WT mice fed the AIN93G diet. Eighteen transcripts were classified as “loss of rhythm” in MMTV-PyMT mice when the HFD was compared to AIN93G diet. Hierarchical clustering analysis showed differentially expressed genes that were significantly altered and KEGG enrichment analysis showed the most upregulated and downregulated metabolic pathways in treatment groups than in the control group at each time point over the 24-hour period. These findings indicates that genetic alterations may have a greater effect than dietary effects on transcriptional rhythmicity in mammary glands from pubertal mice. Citation Format: Lin Yan, Daniel G. Palmer, Huawei Zeng. Alteration to transcriptional rhythmicity in mammary glands from pubertal MMTV-PyMT mice fed a high-fat diet [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 760.
Abstract 6010: BRCA2 reversion alleles confer PARPi resistance via homology-directed repair, not fork protection
Authors: Ryan Jensen, Gemma Moore, Sudipta Lahiri
Journal: Cancer Research (2024)

Abstract BRCA2 reversion alleles have been identified in relapsed, treatment resistant cancer patients. The reversions restore the open reading frame of the BRCA2 protein often resulting in significant sequence deletions with unknown functional consequences. No reports to date have introduced patient reversion mutations into a BRCA2 null cell model to analyze which BRCA2 functions are re-established and whether all or a subset of activities are required for PARPi resistance. Our study utilized BRCA2 reversion alleles identified through sequencing of circulating tumor DNA (ctDNA) from PARPi resistant ovarian cancer patients. We rigorously evaluated whether altered BRCA2 reversion proteins restore homology-directed repair (HDR), fork protection, or gap suppression to determine the specific activities required for PARPi resistance. We found that reverted BRCA2 proteins are functional for HDR by assessing survival response to PARPi, analyzing RAD51 foci at DSBs, DR-GFP reporter assays, RAD51 binding, and CRISPR/Cas9 gene targeting assays. Surprisingly, using the DNA fibercombing approach to assess replication fork dynamics, we identify two separation-of-function mutants, T1974 and C1654_M1890, which are deficient in fork protection, yet confer PARPi resistance. The mutations are located within the BRC 5-8 domain of BRCA2 proposed to play an important role in RAD51 nucleoprotein filament stability. Biochemical analyses of the purified proteins using single molecule FRET (smFRET) indicate reduced filament stability potentially explaining the deficit in fork protection. In conclusion, these separation-of-function BRCA2 mutations provide new mechanistic insight into the underlying biology of BRCA2 and reveal the specific functions needed to overcome PARPi-mediated cell death. Citation Format: Ryan Jensen, Gemma Moore, Sudipta Lahiri. BRCA2 reversion alleles confer PARPi resistance via homology-directed repair, not fork protection [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 6010.
Abstract 6903: Treatment efficacy of transcatheter hepatic arterial infusion chemotherapy with cisplatin in a severe immunodeficient rat model with patient-derived primary pancreatic ductal adenocarcinoma xenografted into the liver
Authors: Ken Kageyama, Akira Yamamoto, Masanori Ozaki, Kenjiro Kimura, Shinpei Eguchi, Ryota Tanaka, Mizue Terai, Takami Sato, Yukio Miki
Journal: Cancer Research (2024)

Abstract Purpose: Liver metastases of pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease; most patients die within 5 years. There is a critical need to identify appropriate anticancer treatments for these patients. A patient-derived tumor xenograft (PDX) model in severe immunodeficient rat with primary PDAC xenografted into the liver is suitable for evaluating transcatheter hepatic arterial infusion chemotherapy. Materials and Methods: The purpose of this study was to develop a severe immunodeficient rat model with patient-derived primary PDAC xenografted into the liver, and to assess the treatment efficacy of hepatic arterial infusion chemotherapy with cisplatin in this model. Three patient-derived tumors of PDAC were transplanted into the liver of 21 rats each, totaling 63 rats. Four weeks after transplantation, the 21 rats were randomly assigned into three treatment groups of seven rats each: hepatic arterial infusion, systemic venous infusion, and control group. Tumor volumes were evaluated on CT twice at pre-treatment and 4-weeks post-treatment. Following euthanasia of the rats, resected tumor specimens were pathologically analyzed. Results: The liver-implanted PDAC PDX rat model was established in all 63 rats. hepatic arterial infusion chemotherapy and systemic venous infusion chemotherapy with cisplatin were able to be performed in the assigned rats. The hepatic arterial infusion group significantly inhibited tumor growth and reduced Ki67 expression, indicating lower cell proliferation, compared to the control group in three PDX tumors. Conclusion: A rat-based preclinical platform was established by liver-implanted PDAC PDX rat model. Arterial cisplatin infusion chemotherapy would be one of potential therapies for PDAC liver metastases. Citation Format: Ken Kageyama, Akira Yamamoto, Masanori Ozaki, Kenjiro Kimura, Shinpei Eguchi, Ryota Tanaka, Mizue Terai, Takami Sato, Yukio Miki. Treatment efficacy of transcatheter hepatic arterial infusion chemotherapy with cisplatin in a severe immunodeficient rat model with patient-derived primary pancreatic ductal adenocarcinoma xenografted into the liver [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 6903.
Abstract 1914: Amivantamab efficacy in wildtype EGFR NSCLC tumors correlates with levels of ligand expression
Authors: Ricardo Rivera-Soto, Benjamin Henley, Marian Pulgar, Stacey Lehman-Tenuto, Himanshu Gupta, Megan Weindorfer, Smruthi Vijayaraghavan, Tsun-Wen Yao, Sylvie Laquerre, Sheri Moores
Journal: Cancer Research (2024)

Abstract Amivantamab (RYBREVANT™) is an FDA-approved, low-fucose IgG1 bispecific antibody targeting EGF and Met receptor tyrosine kinases, with proven clinical activity against EGFR mutant non-small cell lung cancer (NSCLC). Preclinical studies demonstrated that three context-dependent mechanisms of action (MOA) contribute to amivantamab efficacy: immune cell-mediated killing by antibody-dependent cellular cytotoxicity and trogocytosis, receptor internalization and degradation, and inhibition of ligand binding to both EGF and Met receptors. In tumors lacking known cancer-driver genetic aberrations, ligand binding to wildtype EGFR (EGFRWT) and/or MetWT may activate downstream signaling pathways, inducing pro-tumorigenic processes. Among the EGFR ligands, we demonstrated that amphiregulin (AREG) is highly expressed in EGFRWT NSCLC primary tumors, with significantly higher circulating protein levels in NSCLC patients than in healthy volunteers, and induces EGFR phosphorylation, promoting downstream signaling and increasing cell proliferation. Importantly, treatment of AREG-stimulated EGFRWT cells/tumors with amivantamab, or an AREG-targeting antibody, inhibits ligand-induced signaling and cell/tumor proliferation/growth. Across 10 EGFRWT NSCLC patient-derived xenograft mouse models, amivantamab efficacy correlated with AREG RNA levels, suggesting AREG as a potential predictive marker for amivantamab activity in this population. Interestingly, in these xenograft models, amivantamab anti-tumor activity was independent of amivantamab's Fc engagement with immune cells, suggesting that, in this context, the amivantamab’s ligand-blocking function is sufficient for its efficacy. Juxtaposedly, we previously demonstrated that low fucose amivantamab, active Fc domain, was necessary for maximal anti-tumor activity against tumors with EGFR or Met activating mutations. Altogether, these results demonstrated amivantamab context-dependent MOA for efficacy. In conclusion, these data 1) highlight EGFR ligand AREG as a driver of tumor growth in some EGFRWT NSCLC models, 2) illustrate the preclinical efficacy of amivantamab in ligand-driven EGFRWT NSCLC, and 3) identify AREG as a potential predictive biomarker for amivantamab against anti-EGFRWT therapies. Citation Format: Ricardo Rivera-Soto, Benjamin Henley, Marian Pulgar, Stacey Lehman-Tenuto, Himanshu Gupta, Megan Weindorfer, Smruthi Vijayaraghavan, Tsun-Wen Yao, Sylvie Laquerre, Sheri Moores. Amivantamab efficacy in wildtype EGFR NSCLC tumors correlates with levels of ligand expression [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 1914.