tbuckley/cabot-search huggingface dataset:
Abstract 888: Uncovering clinically relevant omics signatures from pan-cancer imaging and multi-omics data integration
Authors: Joshua Wang, Runyu Hong, Jimin Tan, Wenke Liu, David Fenyȯ
Journal: Cancer Research (2024)

Abstract Despite advancements in deep learning for histopathology, integrating these insights with multi-omics data to uncover clinically relevant omics pathway-level signatures remains a challenge. Our study addresses this gap by applying unsupervised learning techniques on pan-cancer multi-omics data, leveraging 3,080 Hematoxylin and Eosin (H&amp;E) images from 1,010 patients in Clinical Proteomic Tumor Analysis Consortium (CPTAC) to uncover omics pathway-level signatures that drive discernable morphology phenotypes at the tissue level. First, imaging models were trained to predict clinical and mutation outcomes, and thereafter, integrated with transcriptomic and proteomic expression data using sparse canonical correlation analysis. Our findings reveal that images of TP53 mutated samples exhibited increased nuclear size and dense lymphoplasmacytic infiltration. These morphological changes correlated with neutrophil and macrophage signaling at the proteomic level, and IL-1 mediated signaling at the transcriptomic level, highlighting the complementary perspectives different omics can provide. To further elucidate immune interactions, we applied multi-omics deconvolution to identify 7 immune subtypes, characterizing each with gene set enrichment, germline DNA variations, and kinase activations. We show that imaging models trained to predict these subtypes differentiate tissue morphologies corresponding to immune enrichment (AUROC: 0.84). To further confirm the robustness of our approach, we trained models to predict co-regulated proteomic modules clustered by independent component analysis. We demonstrate a signature in pan-squamous tumors, consisting of T cell markers and interferon-gamma response proteins like CD4, CD48, and GBP5, which imaging models can successfully predict from histopathology. Manual review from pathologists confirmed lymphocytic T-cell density as a differentiator in samples with the highest and lowest T-cell signaling. Together, these approaches demonstrate that genomic characteristics discovered via unbiased mining of pan-cancer multi-omics data manifest as quantitative imaging phenotypes. These results underscore the potential of multi-omics and digital pathology to integratively uncover and confirm new cancer biology. Our ongoing work will explore predicting drug response and survival from morphology patterns related to multi-omics signatures. Citation Format: Joshua Wang, Runyu Hong, Jimin Tan, Wenke Liu, David Fenyȯ. Uncovering clinically relevant omics signatures from pan-cancer imaging and multi-omics data integration [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 888.
Abstract 88: Novel cell-based bioassays enable preclinical animal studies during immuno-oncology drug development
Authors: Jun Wang, Denise Garvin, Aileen Paguio, Elizabeth Perrin, Jim Hartnett, Mei Cong, Jamison Grailer
Journal: Cancer Research (2024)

Abstract Translation of immuno-oncology research into novel therapies relies on animal models to advise target selection and portray mechanism of action (MoA) and pharmacokinetics of lead candidates. Mouse, monkey, and more recently, canine models of human cancers are being utilized to this end. However, one major challenge in developing and utilizing these models is the lack of technology to characterize non-human analogs of therapeutic antibodies. Herein, we report the development of novel cell-based bioassays for mouse, monkey, and canine targets to enable immuno-oncology preclinical studies. Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) are important MoAs for antibody-based cancer immunotherapies. We have developed a suite of cell-based bioassays, each expressing a corresponding animal Fcγ receptor (FcγR) and a luciferase reporter that responds to FcγR activation. These assays exhibit sensitive and quantitative luciferase readouts of FcγR activation. Animal models are further used to provide insight into the potential efficacy of immune checkpoint (IC) inhibitors. Programmed cell death protein 1 (PD-1) is an IC receptor that negatively regulates T cell function. Blockade of PD-1 has demonstrated clinical efficacy, but there remains a significant fraction of patients unresponsive to this therapy. Combination of PD-1 inhibitors with other interventions has been a significant focus for many programs. However, tools for functional validation of non-human PD-1 inhibitors are lacking. We report here the development of two new bioassays for functional characterization of PD-1/PD-L1 inhibitors for mouse and canine targets. Each of these assays consists of two engineered cell lines: a T effector cell line that express a luciferase reporter driven by specific promoter/response elements responding to the intracellular signals mediated by the T cell receptor (TCR), with modulation from PD-1, and an artificial antigen presenting cell line (aAPC). The bioassays are sensitive, quantitative, and have demonstrated characteristics required for potency assays for validation of antibodies in preclinical combination studies. Citation Format: Jun Wang, Denise Garvin, Aileen Paguio, Elizabeth Perrin, Jim Hartnett, Mei Cong, Jamison Grailer. Novel cell-based bioassays enable preclinical animal studies during immuno-oncology drug 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 88.
Abstract 264: Differentiation therapy: Esculetin as a potent agent to alter cellular plasticity of leukemic &amp; solid tumor stem cells
Authors: Ankit Mathur, Daman Saluja
Journal: Cancer Research (2024)

Abstract Background The “Differentiation therapy” has been emerging as a promising and more effective strategy against acute leukemia relapses. Objective In extension to the revolutionising therapeutic outcomes of All Trans Retinoic Acid (ATRA) to induce terminal differentiation of Acute Promyelocytic Leukemic (APL) blast cells, we decipher the potential effect of a natural compound “Esculetin” to serve as a differentiating agent in Acute Myeloid Leukemia (AML) as well as solid tumour cells. Underlaying role of Wnt signaling pathways in esculetin mediated blast cell differentiation was also evaluated. Methods Human acute myeloid leukemic cells (Kasumi-1) with t(8;21/AML-ETO) translocation were used as a model system. Growth inhibitory and cytotoxic activity of esculetin were analysed using growth kinetics and MTT assay. Morphological alterations, cell scatter characteristics, NBT reduction assay and cell surface marker expression pat- terns were analysed to detect terminally differentiated phenotypes. We employed RT2profiler PCR array system for the analysis of transcriptome profile of Wnt signaling components. Calcium inhibitors (TMB8 and Amlodipine) and Transforming growth factor beta (TGF-β) were used to modulate the Wnt signaling axes. To investigate whether esculetin exerts the similar effects on the invasive solid tumour cancer stem cells subset, we used a cellular model system of colon carcinoma HCT116 cells reflecting EMT phenotype. Results We illustrate cytotoxic as well as blast cell differentiation potential of esculetin on Kasumi-1 cells. Morphological alterations akin to neutrophilic differentiation as well as the corresponding acquisition of myeloid lineage markers indicate terminal differentiation potential of esculetin in leukemic blast cells. Exposure to esculetin also resulted in downregulation of canonical Wnt axis while upto ~ 21 fold upregulation of non-canonical axis associated genes. Esculetin also showed potential to revert the CSC marker expressions and concurrent EMT consistent with reduced functional aggressiveness in colon cancer cells. Conclusions Our study highlights the importance of selective use of calcium pools as well as “axis shift” of the canonical to non-canonical Wnt signaling upon esculetin treatment which might abrogate the inherent proliferation to release maturation arrest and induce the differentiation in leukemic blast cells as well as CSC stem cells. The current findings provide further therapeutic interventions to consider esculetin as a potent differentiating agent to counteract relapses. Citation Format: Ankit Mathur, Daman Saluja. Differentiation therapy: Esculetin as a potent agent to alter cellular plasticity of leukemic &amp; solid tumor stem 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 264.
Abstract 2291: Bravo automation of Agilent Avida targeted enrichment for high-throughput detection of genomic alteration and DNA methylation
Authors: Ashraf Wahba, Tony Ho, Sarah Johns, Aswati Aravind, Heng Wang, Neelima V. Mehendale, Gilbert P. Amparo, Khine Win, Manuel Gomez, Grace Zhao, Douglas N. Roberts
Journal: Cancer Research (2024)

Abstract Background: Current genomic and epigenomic profiling of cancer tissue DNA or cfDNA (cell-free DNA) in liquid biopsy relies upon separate, time- and sample-consuming technologies for somatic variant detection or methylation analysis. Here we describe workflow and performance of the Agilent Bravo automated liquid handling platform with the Agilent Avida targeted enrichment solution for next generation sequencing of somatic variants and methylation profiling. This solution can effectively analyze low-input tumor DNA or cfDNA samples. The Avida Duo workflow enables highly sensitive detection of single nucleotide variant (SNV), insertions and deletions (INDEL), copy number variation (CNV) and DNA methylation profiles from a single sample, without any sample splitting. Methods and Results: Panels, reagents, and automated workflows for Avida DNA, Avida Methyl, and Avida Duo Methyl (combined DNA &amp; methylation) kits were developed to accommodate up to 96 samples on the Bravo NGS workstation. The automated solution supports independent single-day workflows for somatic variants or methylation sample preparation. The Avida Duo analysis combines both workflows without sample splitting, streamlining the process and reducing sample consumption. Leveraging a focused cancer hotspot panel, we demonstrate excellent reproducibility and low allele frequency (SNV at sub 1%) variant detection in cfDNA samples and reference standards with as little as 10ng DNA input. We exhibit similar performance with a larger ~300 kb target region tumor profiling panel. Finally, we demonstrate DNA methylation detection in the standalone or combined (“Duo”) workflows across differentially methylated regions (DMRs) with a panel of ~3400 targets. Conclusions: Automation of the Avida targeted enrichment solution with the Bravo NGS workstation enables a sensitive, high-throughput, end-to-end analysis for detection of genomic alterations and DNA methylation changes from a single low-input cfDNA or tumor DNA sample. Citation Format: Ashraf Wahba, Tony Ho, Sarah Johns, Aswati Aravind, Heng Wang, Neelima V. Mehendale, Gilbert P. Amparo, Khine Win, Manuel Gomez, Grace Zhao, Douglas N. Roberts. Bravo automation of Agilent Avida targeted enrichment for high-throughput detection of genomic alteration and DNA methylation [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 2291.
Abstract 2285: Mass spectrometry-based proteomics profiling reveals differential proteome composition in tumor and normal tissues, with implications for normalization
Authors: Ying Zheng, Lindsay Olita, McIver Nivens, Abby Chiang, Shreya Ahuja, Matthew Glover, John Bullen, Elaine Hurt, Wenyan Zhong
Journal: Cancer Research (2024)

Abstract The composition of the proteome varies significantly across different tissues and disease states creating a challenge of how best to compare expression levels of each protein across these tissue types. Traditionally, a median approach to normalization has been used, but this could obscure meaningful biological differences between tissues. Here, we present a quantitative proteomic study analyzing proteome composition across tumor and normal tissues in order to assess normalization methods. Human proteomes covering 7 cancer indications (244 samples) and 12 normal tissue organs (370 samples) were analyzed by data-independent acquisition mass spectrometry. On average, over 8,000 proteins were quantified across the study cohorts. Comparison of proteomes revealed an average of 11.4% higher protein identification in tumors compared to matched normal tissues (6 tumor types all p&amp;lt;0.003). Tissue origin strongly influenced proteome composition, most notably in bone marrow, while cancer tissues displayed less proteomic composition variation than normal tissues. Compared to global median normalization, riBAQ and tissue-specific quantile normalization reduced technical variances while maintaining biological differences between tissue types. By revealing tissue-specific proteome signatures as well as systemic proteomic alterations in tumors, this study lays the groundwork for appropriate comparative approaches accounting for tissue origins, and establishes a framework for discovery of tissue-specific biomarkers, which may facilitate the development of novel diagnostic and prognostic tests, and guide therapeutic interventions for cancer. Citation Format: Ying Zheng, Lindsay Olita, McIver Nivens, Abby Chiang, Shreya Ahuja, Matthew Glover, John Bullen, Elaine Hurt, Wenyan Zhong. Mass spectrometry-based proteomics profiling reveals differential proteome composition in tumor and normal tissues, with implications for normalization [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 2285.
Abstract 2618: BCG017, a bispecific ADC targeting PTK7 and EGFR exhibits anti-tumor efficacy in PDX models
Authors: Sufei Yao, Chengzhang Shang, Zhuolin Li, Gao An, Chaoshe Guo, W. Frank An, Yi Yang
Journal: Cancer Research (2024)

Abstract EGFR is a favored target in various cancer therapies. However, EGFR-based treatments have been challenged by drug resistance and cytotoxicity. Targeting EGFR with an antibody-drug conjugate (ADC) is a promising new therapeutic strategy to address the drug resistance, due to the potent killing effects of the payload. Furthermore, we hypothesized that development of a bispecific ADC (bsADC) targeting EGFR and another tumor-associated antigen (TAA) might improve the tumor selectivity, thereby limiting the on-target off-tumor toxicity. One such TAA candidate is PTK7, which belongs to the same receptor tyrosine kinase family as EGFR, and is co-expressed with EGFR in multiple types of solid tumors, including lung, esophageal, head and neck, and colon cancers. Herein, we developed a fully human anti-human PTK7 EGFR bsAb using our proprietary common light chain RenLite® mouse platform and knobs-into-holes technology. The anti-PTK7 EGFR bsAb demonstrates good purity by SEC-HPLC, and can cross-react with human and cynomolgus monkey antigens with favorable affinity. The PTK7 x EGFR bsAb demonstrated higher binding to various types of cancer cell lines, as well as enhanced internalization in vitro compared with PTK7 parental antibody. Next, the bsAb was conjugated with monomethyl auristatin E (MMAE) to generate an anti-PTK7 x EGFR bsADC, BCG017, with a drug-to-antibody ratio of approximately 4. BCG017 demonstrated superior anti-tumor activity compared to benchmarks and its PTK7 parental ADC in cell-derived non-small-cell lung cancer (NSCLC) xenografts, and showed enhanced anti-tumoractivity when compared to benchmark ADCs and parental ADCs in patient-derived breast and pancreatic ductal adenocarcinoma xenograft models. These results suggest that BCG017 have the potential to be a novel therapeutic alternative for PTK7 and EGFR co-expressing tumors. Citation Format: Sufei Yao, Chengzhang Shang, Zhuolin Li, Gao An, Chaoshe Guo, W. Frank An, Yi Yang. BCG017, a bispecific ADC targeting PTK7 and EGFR exhibits anti-tumor efficacy in PDX 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 2618.
Abstract 5360: Relief of chromosomal instability-induced cGAS-STING signaling sensitizes <i>STK11</i>-mutant non-small cell lung cancer to immune checkpoint blockade
Authors: Lindsay A. Caprio, Christy Hong, Amit D. Amin, Somnath Tagore, Mercedes Duran, Meri Rogava, Luke Cai, Leon Ebel, Johannes Melms, Hanina Hibshoosh, Samuel Bakhoum, Benjamin Izar
Journal: Cancer Research (2024)

Abstract Non-small cell lung cancers (NSCLCs) harboring deletions or inactivating mutations in STK11 (encoding LKB1) are associated with poor prognosis and immune evasion, but the underlying mechanisms are poorly understood. Through integrative analyses of &amp;gt;10,000 molecular profiles from public data sources and an additional ~15,000 new patient data profiles, we find identify STK11-deficient NSCLC as an archetypical chromosomally unstable tumor. Using high-content imaging, we show that both human and murine STK11-mutant models have a higher rate of micronuclei and chromosome mis-segregation events, confirming their high degree of chromosomal instability (CIN). We show that CIN-induced tonic activation of the cGAS-STING pathway results in impaired type I interferon expression, thus, turning the physiological function of this pathway on its head. We show that temporary relief of tonic CIN-induced signaling reprogrammed cancer cells towards production of type I interferons. We achieved this through orthogonal routes, including genetic suppression of CIN by overexpression of mitotic centromere-associated kinesin (MCAK), rescue of wild-type STK11 (but not its kinase-dead) allele, genetic deletion or pharmacological inhibition of cGAS. Relief through any of these approaches re-sensitized cells to acute STING agonism with its endogenous ligand (cGAMP) or pharmacological stimulation. Using otherwise isogenic, syngeneic KRAS-mutant Stk11/Lkb1-/- (KL) and KRAS-mutant p53 mutant (KP) murine models, we show that cGAS KO sensitized otherwise highly resistant KL models to immune checkpoint blockade (ICB), while an increase in CIN (through overexpression of dominant-negative MCAK) in KP conferred resistance in this otherwise ICB-sensitive model. In summary, we define STK11-mutant as archetypical chromosomally unstable form of NSCLC, provide mechanistic basis that correlates with poor clinical outcomes, and demonstrate how relief of tonic CIN-induced changes may be therapeutically leveraged. Citation Format: Lindsay A. Caprio, Christy Hong, Amit D. Amin, Somnath Tagore, Mercedes Duran, Meri Rogava, Luke Cai, Leon Ebel, Johannes Melms, Hanina Hibshoosh, Samuel Bakhoum, Benjamin Izar. Relief of chromosomal instability-induced cGAS-STING signaling sensitizes STK11-mutant non-small cell lung cancer to immune checkpoint blockade [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 5360.
Abstract 2965: <i>GADD45B</i> as a mechanism for enhanced treatment response with the combination of copanlisib and romidepsin in colorectal cancer
Authors: Kennedy Maduscha, Alexa Schmitz, Rebecca DeStefanis, Cheri Pasch, Dustin Deming
Journal: Cancer Research (2024)

Abstract Background: Treatment options for molecular subtypes of colorectal cancer (CRC) are urgently needed, including for PIK3CA mutant CRC. Previous work in our lab demonstrated enhanced activity of copanlisib in combination with romidepsin in PIK3CA mutant CRC models. Here we investigate the induction of GADD45B as a mechanism of the enhanced induction of apoptosis seen with this treatment strategy. Methods: RNA sequencing was done on the CRC 2D cell line, SW48PK (Horizon Discovery, SW48 PIK3CAH1047R/+ mutation) as well as PIK3CA mutant and wild-type patient derived cancer organoids (PDCOs) through the UW Biotechnology Center. All lines were treated with copanlisib, romidepsin, or combination and were compared with untreated controls. GADD45B gene expression was also confirmed on SW48PK, PIK3CA mutant, wild type, and PIK3CA and KRAS mutant PDCOs using RT-qPCR. Results: RNA sequencing determined that there was an increase of GADD45B expression in the SW48PK 2D cell line as well as in PIK3CA mutant and wild-type PDCOs treated with the combination compared to untreated controls (average log2 fold change= 1.83). A significant increase in GADD45B expression was seen in the SW48PK combination treatment group compared to the control group at 6 hours (combination median fold change= 2.7, p= 0.045) and 24 hours (4.1, p&amp;lt; 0.001). For PIK3CA mutant PDCOs treated with the combination, there was significant increase in GADD45B expression at 6 hours (9.45, p= 0.005) and 24 hours (14.7, p= 0.002) compared to untreated control. In wild type PDCOs, there was a significant increase in GADD45B expression in the combination compared to untreated control at 6 hours (32.95, p=0.004) but not after 24 hours (2.6, p= 0.42). For KRAS mutant PDCOs, there was a significant increase in GADD45B expression in combination treated cells at 6 (9.9, p= 0.001) and 24 hours (3.3, p= 0.047), however, this increase was less than PIK3CA mutant PDCOs at 24 hours (3.3 vs 14.7). Conclusions: Copanlisib in combination with romidepsin increases GADD45B expression in PDCOs and SW48PK. Further studies will determine if GADD45B is required for this treatment response. Citation Format: Kennedy Maduscha, Alexa Schmitz, Rebecca DeStefanis, Cheri Pasch, Dustin Deming. GADD45B as a mechanism for enhanced treatment response with the combination of copanlisib and romidepsin in colorectal 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 2965.