tbuckley/cabot-search huggingface dataset:
Abstract 4720: Evaluation of lorlatinib efficacy using plasma DNA
Authors: Yasushi Goto, Tadaaki Yamada, Akehiro Nishiyama, Naoko Aragane, Minehiko Inomata, Hiroki Nagai, Satoshi Takahashi, Kazuhito Miyazaki, Yukari Tsubata, Hiroaki Akamatsu, Tetsuya Mitsudomi
Journal: Cancer Research (2025)

Abstract Background: Lorlatinib is approved globally as a second-line treatment for ALK-positive NSCLC following resistance to alectinib, with Japan being the first country to approve its use. This study is the first to analyze lorlatinib’s efficacy in such patients by integrating ctDNA analysis to explore predictive markers and resistance mechanisms. Methods: This multi-center prospective study enrolled patients with ALK-rearranged NSCLC resistant to alectinib, with no prior exposure to ALK-TKIs other than alectinib and brigatinib. Patient eligibility required documented ALK translocations, CT imaging within 56 days, and written consent. Blood and pathology samples were collected pre- and post-treatment. Clinical data were integrated using an Electronic Data Capture (EDC) system. ctDNA analysis was conducted via Guardant Health, focusing on mutation emergence, persistence, and correlation with treatment outcomes. Results: Among 27 evaluable patients, partial response (PR) was observed in 37% of cases, while stable disease (SD) was noted in 14.8%. The median progression-free survival (PFS) was 6.5 months (95% CI: 1.8-23.5), consistent with previously reported outcomes for lorlatinib-treated patients. Disease progression commonly involved the CNS (18.5% of cases). Genetic analysis of ctDNA revealed that patients with TP53 mutations had a reduced PFS of 2.9 months compared to 6.7 months in wild-type TP53 cases, suggesting a potential role as a poor prognostic marker. Additionally, persistent ALK fusions or new rearrangements were observed and correlated with reduced efficacy, indicating coactivation of other oncogenic pathways. Notably, two patients exhibited ALK secondary mutations (L1196M) following alectinib treatment, both of whom responded with a partial response (PR) to lorlatinib. Conclusions: This exploratory study highlights the complexity of resistance mechanisms in ALK-rearranged NSCLC treated with lorlatinib, demonstrating ctDNA’s potential as a predictive biomarker for treatment outcomes. The persistence and emergence of specific mutations, such as in TP53 and ALK, underscore the need for further investigation into combination or personalized therapeutic strategies. Despite the study’s limited sample size, these findings offer critical insights into the genomic landscape influencing lorlatinib efficacy following alectinib resistance. Citation Format: Yasushi Goto, Tadaaki Yamada, Akehiro Nishiyama, Naoko Aragane, Minehiko Inomata, Hiroki Nagai, Satoshi Takahashi, Kazuhito Miyazaki, Yukari Tsubata, Hiroaki Akamatsu, Tetsuya Mitsudomi. Evaluation of lorlatinib efficacy using plasma DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4720.
Abstract 5881: Transcriptomic profiling of extracellular vesicle subpopulations enables liquid biopsy-based brain tumor classification
Authors: Margie Kinnersley, Claire Seibold, Tre Blohm, Riley Kemp, Sean Lodmell, Amanda Mast, Tia Seibold, Rachel Short Miller, Kelley Van Vaerenberghe, Katie Havranek
Journal: Cancer Research (2025)

Abstract Liquid biopsies based on circulating tumor-derived cell-free DNA (ctDNA) have become an increasingly common tool for minimally invasive diagnostic testing. However, as ctDNA does not easily cross the blood-brain barrier, cell-free DNA tests for identifying and classifying brain tumors are of limited utility. Extracellular vesicles (EVs), which carry heterogeneous protein, nucleic acid, and metabolite cargos derived from various cell types including cancer cells, are an attractive alternative to ctDNA that can cross the blood-brain barrier. Because only a small fraction of circulating EVs are derived from diseased cells, current EV-based methods for cancer detection often suffer from low signal-to-noise ratios. To circumvent this issue, we have developed an extracellular vesicle subpopulation enrichment technology that specifically targets EVs derived from diseased cells. EV subpopulation transcriptomics interrogated using machine learning and gene network analyses can distinguish healthy patients, patients with benign tumors, and patients with glioma. Known tissue markers as well as novel features provide the basis for patient stratification. Coupled with a state-of-the-art multi-omics workflow, our novel EV enrichment platform allows us to capitalize upon the powerful diagnostic information contained within EV subpopulations to identify and characterize cancers from standard blood plasma samples. Citation Format: Margie Kinnersley, Claire Seibold, Tre Blohm, Riley Kemp, Sean Lodmell, Amanda Mast, Tia Seibold, Rachel Short Miller, Kelley Van Vaerenberghe, Katie Havranek. Transcriptomic profiling of extracellular vesicle subpopulations enables liquid biopsy-based brain tumor classification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5881.
Abstract 5862: Combining circular RNA and a silicon membrane-based cell engineering approach to create CAR-Ts with membrane bound IL-2 and IL-12
Authors: Zhihui Song, Andrew Larocque, Sophia Hirsch, Eleni Rogers, Darby Kreienberg, Jacquelyn Hanson, Alec Barclay, Armon Sharei
Journal: Cancer Research (2025)

Abstract Engineered immune cell therapies have great potential to revolutionize the treatment of many pathologies such as cancer, autoimmunity and infectious diseases. However, limitations remain in some areas including long manufacturing times, inability to engineer critical cell functions, potential for cell exhaustion, and limited access to the disease site as in the case for solid tumors. Portal has developed a novel implementation of mechanoporation technology using a silicon membrane with pores which enables deformation of the cell and poration of the cell membrane, allowing for diffusion of any cargo, charged or uncharged, into the cell. Mechanoporation is a gentle intracellular delivery technique that preserves cell viability and function (DiTommaso, et al., PNAS 2018). It can shorten manufacturing time and enable the introduction of key therapy-enhancing factors via transient modifications shortly before administration. Portal has established methodology for cytoplasmic introduction of many diverse cargo including mRNA, circular RNA, siRNA, proteins, peptides, and CRISPR RNPs to primary immune cells, including both unstimulated and activated T cells, B cells, NK cells, monocytes and iPSCs. In this work, we demonstrated simultaneous expression of a functional CD19 CAR, membrane bound IL-2 and membrane bound IL-12 through delivery of three circRNAs into activated T cells. They are highly expressed for multiple days while maintaining high viability and ensuring robust in vitro killing. The expression of mbIL2 and mbIL12 not only promotes T cell proliferation but also upregulates CD62L and enhances the cytotoxic function of CAR T cells. At clinical scale, we have demonstrated delivery of RNA to over 1 billion T cells while achieving over 90% expression. Portal’s technology and approach has the potential to further advance immune cell therapy developments, particularly in multiplexed engineering approaches involving simultaneous delivery of multiple cargos. Coupled with Portal’s compatibility with diverse immune cell types and next generation cargos. We believe this simple approach to intracellular delivery can dramatically reduce manufacturing time and cost, easily integrate into existing clinical equipment and enable unique enhancements that underpin a new generation of therapeutics. Citation Format: Zhihui Song, Andrew Larocque, Sophia Hirsch, Eleni Rogers, Darby Kreienberg, Jacquelyn Hanson, Alec Barclay, Armon Sharei. Combining circular RNA and a silicon membrane-based cell engineering approach to create CAR-Ts with membrane bound IL-2 and IL-12 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5862.
Abstract 5941: Impact of neoadjuvant treatment on the presence of perineural invasion in rectal cancer: a national analysis
Authors: Mohyeddine El Sayed, Sassine Youssef, Raymond N. Dubois
Journal: Cancer Research (2025)

Abstract Background: Perineural invasion (PNI) is an independent prognostic factor associated with lower overall and disease-free survival in rectal cancer patients. Several studies have established nomograms predicting PNI presence using clinical data and radiomics. These nomograms will help guide treatment for patients with high risk for PNI. There is limited data on the impact of neoadjuvant therapy on the presence of PNI in pathological specimens. This study assesses whether neoadjuvant treatment reduces the odds of PNI at the time of surgical resection. Methods: A retrospective analysis was conducted using the National Cancer Database, including patients aged ≥20 years diagnosed with rectal cancer from 2004 to 2020, with documented tumor stage and PNI status. Data collected encompassed demographics, tumor size and grade, TNM stage, and treatment sequences. Patients were categorized based on treatment sequence: surgical resection only (SRT), neoadjuvant treatment (NAT), adjuvant treatment (AT), and perioperative systemic therapy with neoadjuvant radiotherapy (PST/NART). Multivariable binary logistic regression analyzed the impact of neoadjuvant therapy on PNI presence, adjusting for significant covariates. Overall survival was assessed using multivariable Cox proportional hazards regression, adjusting for significant covariates. Results: Among 38, 537 patients, 25.3% received SRT, 38.7% NAT, 11.4% AT, and 24.6% PST/NART. In stage I, patients who received neoadjuvant treatment (NAT + PST/NART) were 50% less likely to have PNI compared to those who did not (SRT + AT) (P &amp;lt; 0.001). Stage II, III, and IV patients were 47%, 47%, and 40% less likely to have PNI with neoadjuvant treatment, respectively (all P &amp;lt; 0.001). In stage I, NAT patients had a 39% higher mortality risk compared to SRT patients (P &amp;lt; 0.001). In stages II and III, PST/NART patients had 38% and 34% lower mortality risks, respectively, compared to SRT patients (P = 0.003 and P &amp;lt; 0.001). In stage IV, AT patients had an 88% higher mortality risk compared to SRT patients (P = 0.049). Conclusion: Neoadjuvant treatment significantly reduces the presence of perineural invasion across all stages of rectal cancer, potentially improving survival outcomes, particularly in stages II and III. However, the increased mortality risk observed in stage I patients receiving neoadjuvant therapy indicates that benefits may not extend to early-stage disease, underscoring the need for careful patient selection and further prospective studies. Citation Format: Mohyeddine El Sayed, Sassine Youssef, Raymond N. Dubois. Impact of neoadjuvant treatment on the presence of perineural invasion in rectal cancer: a national analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5941.
Abstract 5894: Detection of a novel GNA11 processed pseudogene from cfDNA and implications for liquid biopsy
Authors: Jan Wignall, Wen Zhou
Journal: Cancer Research (2025)

Abstract Processed pseudogenes are messenger RNAs that have been reverse transcribed and inserted into the genome. While the functional implications of these processed pseudogenes remain unknown, their presence can lead to variants being mistakenly detected and classified as copy number amplifications and deletions in comprehensive genomic profiling (CGP) assays for cancer treatment selection. False positive amplifications run the risk of patients being prescribed ineffective therapies. Northstar Select is a liquid biopsy CGP assay which covers 84 genes. In this retrospective analysis of 1800 patients, amplification signals due to a pseudogene were observed in 4 patients on SMAD4 and 7 patients on GNA11 and confirmed via orthogonal methods. These samples showed abnormal exonic amplifications and intronic deletions in the SMAD4 and GNA11 genes. Splice site variants were present at low variant allele fraction (VAF) on either side of each exon. Notably, the copy number detected does not correlate with estimated tumor fractions or other ctDNA mutations detected in these samples. Whole genome sequencing (WGS) of selected patients harboring the SMAD4 amplifications revealed the presence of a poly-A tail and a breakpoint in SCAI on chromosome 9, consistent with a pseudogene previously described in the literature. WGS of GNA11 amplification-positive samples revealed the presence of a novel processed pseudogene in chromosome 20 that has not been previously described, which may have further implications on cancer-driving mutations as GNA11 is an oncogene. Northstar Select’s copy number calling algorithm measures a copy number of 3 for GNA11, indicating an additional copy from the pseudogene. qPCR of extracted buffy coat gDNA across the suspected breakpoint in chromosome 20 confirms the insertion and its germline nature. The presence of the same breakpoint in multiple patients suggests this is an ancestral integration event. Similar to the previously described SMAD4 pseudogene, false positive splice site variants are results of mismapping of reads. In conclusion, we have determined a framework to confirm pseudogene presence that is not tumor DNA derived. Bioinformatic analysis of CGP tests should carefully screen suspicious results for the possibility of as-yet undiscovered processed pseudogenes to avoid reporting such false positive amplifications and deletions. Citation Format: Jan Wignall, Wen Zhou. Detection of a novel GNA11 processed pseudogene from cfDNA and implications for liquid biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5894.
Abstract 2387: Characterizing HERV expression patterns across breast cancer subtypes: Implications for tumor biology and therapeutic targets
Authors: Nathália Da Roz D'Alessandre, Gabriela Der Agopian Guardia, Helena Beatriz da Conceição, Rafael Loch Batista, Pedro Alexandre Favoretto Galante
Journal: Cancer Research (2025)

Abstract Endogenous Retroviruses (ERVs) are remnants of ancient retroviral infections that have permanently integrated into host genomes, including humans. Human Endogenous Retroviruses (HERVs) are ‘fossil’ viral sequences, having lost their ability to generate infectious viruses due to mutations and deletions accumulated over millions of years. Although most HERVs are deemed non-functional, they constitute up to 8% of the human genome. Some HERVs have roles in gene expression regulation, and others are transcribed under specific conditions, such as in cancer. HERV-K is the most recently integrated class within our genome, with some members retaining relatively intact open reading frames (ORFs), suggesting their potential to encode proteins. In cancer, reactivation of HERV expression may impact gene expression, genomic stability, and cell signaling pathways.In this study, we investigated the expression of HERVs in breast cancer (BC) and non-tumor breast tissue using RNA sequencing (RNA-Seq) data from The Cancer Genome Atlas (TCGA). Specifically, we analyzed the expression profiles of HERVs across BC subgroups and their association with protein-coding gene expression profiles. We identified differentially expressed HERVs in BC subgroups (HR-/HER2-, HR+/HER2+, HR-/HER2+, HR+/HER2-) in comparison to non-tumor samples. Our analysis revealed 98 differentially expressed HERVs in HR-/HER2-, 51 in HR+/HER2+, 81 in HR-/HER2+, and 48 in HR+/HER2-. Distinct expression profiles across all subtypes were evident. Furthermore, we identified 45 differentially expressed protein-coding genes with transcription start sites within 5 kb of differentially expressed HERVs. This proximity suggests a potential regulatory influence of HERVs on these genes, indicating the need for further research to clarify the underlying mechanisms. In conclusion, the unique HERV expression profiles across BC subtypes suggest specific molecular characteristics and gene regulation patterns. These findings may aid in identifying new therapeutic targets and treatment strategies for breast cancer, emphasizing HERVs' importance in tumor biology. Citation Format: Nathália Da Roz D'Alessandre, Gabriela Der Agopian Guardia, Helena Beatriz da Conceição, Rafael Loch Batista, Pedro Alexandre Favoretto Galante. Characterizing HERV expression patterns across breast cancer subtypes: Implications for tumor biology and therapeutic targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2387.
Abstract 3925: <i>In vitro</i> and <i>in vivo</i> characterization of <i>Cdh1</i> CRISPR knockout in syngeneic ER+ SSM3 mouse mammary tumor cells
Authors: Insa Thale, Dixcy J. John Mary, Sarah Wang, Lora Rigatti, Jagmohan Hooda, Peter Lucas, George C. Tseng, Adrian V. Lee, Steffi Oesterreich
Journal: Cancer Research (2025)

Abstract Invasive lobular carcinoma (ILC) accounts for 10-15% of all breast cancers, making it the most common special histological subtype of breast cancer. Initially, ILC is associated with a better response to adjuvant hormonal therapy compared to invasive ductal breast cancer (IDC). However, patients with ILC often experience a worse long-term outcome. Over 90% of ILCs are estrogen receptor positive (ER+) and do not express functional E-cadherin (CDH1). There are limited studies aimed at improved understanding of the tumor microenvironment (TME) in ILC. Therefore, we set out to generate and characterize a syngeneic mouse cell line model that mimics the genetic loss of CDH1 seen in ILC. We created an ER+ ILC-like mammary cancer model using the syngeneic SSM3 cell line, derived from an ER+ mouse mammary tumor in STAT1-deficient mice. To mimic the hallmark feature of ILC, we used CRISPR-Cas9 to knock out Cdh1. In vitro assays were performed to evaluate the effects of Cdh1 knockout (KO) in both 2D and 3D environments, focusing on cell proliferation and estrogen sensitivity. These experiments demonstrated increased growth of Cdh1 KO SSM3 cells in both 2D and 3D environments, together with altered cell morphology and increased sensitivity to estrogen.For in vivo characterization, we focused on tumor growth and metastasis. SSM3 Scr and Cdh1 KO cells were injected into the mammary fat pad of mice. Initial findings revealed increased tumor growth in mice injected with SSM3 Cdh1 KO cells, while metastasis studies are ongoing. RNA-seq analysis of both SSM3 cells grown in vitro, and in vivo tumor tissues is ongoing and will help to identify distinctive gene expression changes in the Cdh1 KO model. We will also analyze changes in the TME, such as immune cells, ECM and fibroblasts. In summary, we have successfully generated an ER+ syngeneic ILC model, and we expect that growing the cells in vitro and in vivo represents a valuable tool for studying ILC and holds promise for advancing the development of targeted immunotherapies and endocrine therapies for this breast cancer subtype. Citation Format: Insa Thale, Dixcy J. John Mary, Sarah Wang, Lora Rigatti, Jagmohan Hooda, Peter Lucas, George C. Tseng, Adrian V. Lee, Steffi Oesterreich. In vitro and in vivo characterization of Cdh1 CRISPR knockout in syngeneic ER+ SSM3 mouse mammary tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3925.
Abstract 6395: Synthetic pathway activators enhance CAR-T functional persistence and prevent T cell exhaustion
Authors: Lan Chen, Thomas Gardner, Beatriz Millare, Anzhi Yao, Josephine Giles, Ashley Cass, Suchismita Mohanty, Jeremy Chen, Alma Gomez, David DeTomaso, Aaron Cooper, Levi Gray-Rupp, John Wherry, Nicholas Haining
Journal: Cancer Research (2025)

Abstract The emergence of T cell exhaustion in CAR-T cells used to treat solid tumors remains a barrier to clinical efficacy. T cell engineering approaches are increasingly used to enhance CAR-T cell function, but to date few approaches directly modulate the development of T cell exhaustion. We have used large scale screening of synthetic transmembrane signaling molecules to identify a class of SPA (Synthetic Pathway Activators) that result in constitutive STAT1/STAT3 activity with marked gains of CAR-T cell anti-tumor potency, expansion, and persistence both in-vitro and in-vivo. In vitro, CAR-T cells expressing SPA displayed higher proliferation in response to both TCR and tumor antigen stimulation, and secreted more Granzyme B and IL-10 cytokines, but did not show cytokine-independent proliferation. SPA-expressing CAR-T cells also retained superior function relative to control CAR-T cells in a repetitive stimulation assay that recapitulates T cell exhaustion. In vivo, SPA-expressing CAR-T cells showed greatly enhanced potency in both 786-O and A498 xenograft models of Renal Cell Carcinoma, and demonstrated increased T cell expansion followed by rapid contraction after tumor clearance. Mechanistic studies utilizing temporal RNAseq data and pseudotime analysis of SPA expressing cells throughout the 14-day RSA assay revealed a divergent trajectory of T cell differentiation in comparison to control CAR-T cells, with greater maintenance of memory marker expression. Importantly, SPA-expressing CAR-T failed to induce TOX - a canonical transcriptional regulator of exhausted T cells - compared to control CAR-T cells. ATAC-Seq analysis further confirmed that the TOX locus remains inactive in SPA cells following chronic antigen stimulation, while unmodified CAR-T cells develop characteristic open chromatin regions surrounding the TOX locus. Thus the SPA module is a T cell intrinsic enhancement that boosts CAR-T potency and persistence by limiting the development of exhaustion. Moreover, it suggests that persistent STAT3/STAT1 activation may provide a general approach to modulate the emergence of T cell exhaustion. Citation Format: Lan Chen, Thomas Gardner, Beatriz Millare, Anzhi Yao, Josephine Giles, Ashley Cass, Suchismita Mohanty, Jeremy Chen, Alma Gomez, David DeTomaso, Aaron Cooper, Levi Gray-Rupp, John Wherry, Nicholas Haining. Synthetic pathway activators enhance CAR-T functional persistence and prevent T cell exhaustion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6395.