bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 6057: Evaluation of a highly potent and selective STAT3 degrader as a new class of immunotherapy
Authors: Bai Longchuan , Zhou Haibin , Zhou Jiajia , Wu Dimin , Acharyya Ranjan Kumar , Metwally Hoda , McEachern Donna , Wen Bo , Sun Duxin , Zou Weiping , Wang Shaomeng
Published: March 2024

STAT3 (signal transducer and activator of transcription 3) is a transcription factor and a promising therapeutic target for cancer and other human diseases. In addition to its role in regulation of tumor cells, STAT3 also plays a key role in regulation of immunity and is a promising therapeutic target for the development of new immuno-oncology drugs. Our laboratory has previously reported the development of potent and highly selective STAT3 degraders, including SD-36 and SD-91. Extensive optimization of SD-36 and SD-91 yielded new, highly potent, selective and efficacious STAT3 degraders. In direct comparison, our most potent, new STAT3 degrader (compound 1) is >50-times more potent than SD-36 in inducing STAT3 degradation in cells and demonstrates >500-fold degradation selectivity over other STAT members. A single intravenous administration of compound 1 in mice is highly effective in inducing complete depletion of STAT3 protein in tissues for 48-96 h without reducing the levels of other STAT proteins. Compound 1 is very effective in inhibition of tumor growth not only in tumor models responsive to immune checkpoint blockade (ICB) but also in tumor models resistant to ICB. Furthermore, combination of compound 1 with PD-1/PD-L1 antibodies greatly enhances the antitumor activity as compared to SD-1218 or ICB. Of significance, compound 1 is well tolerated in mice without any signs of toxicity in mice at highly efficacious doses. Our mechanistic studies show that STAT3 depletion has a major effect in modulation of the immune cells in mice. Collectively, our data suggest that selective STAT3 degradation hold great promise for new cancer immunotherapy.

Citation Format: Longchuan Bai, Haibin Zhou, Jiajia Zhou, Dimin Wu, Ranjan Kumar Acharyya, Hoda Metwally, Donna McEachern, Bo Wen, Duxin Sun, Weiping Zou, Shaomeng Wang. Evaluation of a highly potent and selective STAT3 degrader as a new class of immunotherapy [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 6057.
Abstract 6078: Circulating tumor cell-based early detection of breast cancer
Authors: Drake Justin M. , Kamalanathan Kaylee J. , Galeano-Garces Catalina , Bristow Nathaniel , Heller Nicholas , Ahmadi Mahdi , Hedeen Olivia , Hesch Alexa , Schaap Grant , Hapke Joel , Miller Jeff , Babris Ivo , Le Tuan , Clacko Tony , Hong Jiarong , Konety Badri , Parthasarathy Jayant
Published: March 2024

Although mammograms have been a useful tool since the first half of the 20th century and have an acceptable sensitivity (87%) in the general population, that drops to <50% in women with dense breasts making it an ineffective screening tool in this population. Cell free DNA (cfDNA) has proven to be an inadequate alternative in this population, and while MRI is acceptable, it is expensive. Astrin Biosciences has developed a blood-based assay that detects circulating tumor cells (CTCs) at a high sensitivity to serve as an alternative screening method to mammography in breast cancer early detection, specifically in women with high-density breasts.

Astrin’s technology integrates holographic imaging, machine learning, and microfluidics to identify CTCs in the blood stream. Omics analysis can then be performed on the collected cells to further differentiate patients with cancer from matched healthy controls. Astrin has initiated a small cohort study to investigate the sensitivity and specificity of CTC detection in women with early-stage breast cancer. Astrin’s small cohort study, including patients with ductal carcinoma in situ, stage 1, and stage 2 breast cancer patients, demonstrated > 85% sensitivity and specificity. A large cohort study is being conducted to validate these preliminary results.

The small cohort study demonstrates the ability of Astrin Bioscience’s platform to detect cancer cells at an early stage, particularly in breast cancer. This technology will drastically increase the effectiveness of breast cancer screening modalities available to patients. Additionally, since it is a blood-based assay, it can be performed at shorter intervals in high-risk populations than mammograms which require a full patient appointment.

Citation Format: Justin M. Drake, Kaylee J. Kamalanathan, Catalina Galeano-Garces, Nathaniel Bristow, Nicholas Heller, Mahdi Ahmadi, Olivia Hedeen, Alexa Hesch, Grant Schaap, Joel Hapke, Jeff Miller, Ivo Babris, Tuan Le, Tony Clacko, Jiarong Hong, Badri Konety, Jayant Parthasarathy. Circulating tumor cell-based early detection of breast 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 6078.
Abstract 6085: Leveraging targeted epigenetic and genetic detection for cost-effective cancer classification
Authors: Crawford Robert , Krajacich Ben , Lleshi Ermira , Negrea Aurel , Andreasen Lisabet , Fullgrabe Jens , Monahan Jack , Morley David , Puddu Fabio , Walker Donna McDade , Kruglyak Semyon , Creed Páidí
Published: March 2024

The combinatorial power of genetics and epigenetics is vital to understanding biology in healthy and cancerous states. Utilizing a recent novel approach, we enable the simultaneous identification of modified cytosine and the canonical bases A, C, T & G in an enzymatic single-workflow solution. Generating this information across the whole genome provides a much-improved understanding of genetic and epigenetic changes, but can require a large amount of sequencing, particularly when exploring at depth. Enrichment protocols such as target enrichment enable deep interrogation of target areas whilst maintaining cost effectiveness.

Target enrichment panels enable the selective isolation of sequences of interest through target hybridization. Using commercially available panels combined with the novel enzymatic single-workflow solution we show uniform performance across a range of input amounts with reduced sequencing requirements. Samples used were cell free DNA (cfDNA) from patient samples with either Stage I or IV Colorectal Cancer and reportedly healthy controls and were targeted using pan-cancer and methylome panels. Widespread differences such as hypermethylation are clearly observed in late-stage cancer vs early-stage or healthy controls demonstrating utility of the approach for applications such as liquid biopsy.

Refining genetic and epigenetic investigations to a narrower region of interest can improve detection of low prevalence disease associated biomarkers at significant sequencing depth and lower sequencing costs.

Citation Format: Robert Crawford, Ben Krajacich, Ermira Lleshi, Aurel Negrea, Lisabet Andreasen, Jens Fullgrabe, Jack Monahan, David Morley, Fabio Puddu, Donna McDade Walker, Semyon Kruglyak, Páidí Creed. Leveraging targeted epigenetic and genetic detection for cost-effective cancer classification [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 6085.
Abstract 6131: Increasing self efficacy, self confidence, and genetic knowledge via the Community Genetic Navigation Engagement Specialist Train-the-Trainer program
Authors: Rodriguez Janet , Mendez Joel Sanchez , Rodriguez Yaneth L. , Baezconde-Garbanati Lourdes , Ricker Charité , Barahona Rosa , Rosales Bianca , Hernandez Daisy , Gutierrez Natalia , Culver Julie , Stern Mariana
Published: March 2024

Background: Colorectal cancer (CRC) is the second and third leading cause of cancer deaths in US Hispanic/Latino (H/L) men and women, respectively. The Community Genetic Navigation Specialists (CoGENES) train-the-trainer program created a workforce of community health workers (CHWs) to educate H/L individuals about genetic testing, counseling, and research.

Methods: The CoGENES three-week program, consisted of six in-person sessions, with a curriculum in both Spanish/English developed and delivered by experts, in Spanish, using presentations and hands-on activities. Acculturation, Latino values, self-efficacy, genetics and tumor testing knowledge, and self-confidence were assessed via pre- and post-training. Differences in scores were analyzed via Wilcoxon matched-pairs signed-rank tests with exact p-values.

Results: Median age of the 12 participants was 50 (IQR = 12), 9 were female, 92% were Mexican-born, half completed 1-2 years of college, and 67% were very hispanic oriented. Self-efficacy increased after training, with pre- training median-score = 38.5 (IQR = 3) and post-training score = 39.5 (IQR =2.5) (p = 0.0547). Certainty about understanding tumor testing increased after training (p = 0.0039). The median number of correct answers on the 16-item genetic knowledge scale increased from 6.5 to 9.5 and the median number of “don’t know” responses decreased from 5 to 0 after training. Finally, self-confidence to train future CoGENES was significantly higher (p = 0.0098) at post-test.

Conclusion: The CoGENES culturally tailored program led to improved self-efficacy, increased genetic knowledge, and self-confidence in a cohort of Hispanic community health educators. Findings will be shared within COPECC, and other NCI funded programs.

Citation Format: Janet Rodriguez, Joel Sanchez Mendez, Yaneth L. Rodriguez, Lourdes Baezconde-Garbanati, Charité Ricker, Rosa Barahona, Bianca Rosales, Daisy Hernandez, Natalia Gutierrez, Julie Culver, Mariana Stern. Increasing self efficacy, self confidence, and genetic knowledge via the Community Genetic Navigation Engagement Specialist Train-the-Trainer program [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 6131.
Abstract 6168: Sex-distinct patterns of molecular pathways associated with brain tumor edema
Authors: Jackson Pamela R. , Curtin Lee , Ranjbar Sara , Singleton Kyle W. , Mrugala Maciej M. , Zimmerman Richard S. , Bendok Bernard R. , Canoll Peter , Swanson Kristin R.
Published: March 2024

Magnetic resonance imaging (MRI) is a centerpiece of clinical management of brain tumor patients, yet the biology underlying even commonly interpreted imaging changes is unclear. The purpose of this project was to understand what biology is associated with brain tumor edema abundance and if that association was sex distinct. We have developed a two-compartment model of MRI signal intensity to quantitatively estimate relative edema abundance from T2-weighted MRIs. Multiparametric MRIs were preprocessed with bias field correction and intensity normalization. The images were co-registered and segmented for abnormal regions and normal tissue. The segmentations and preprocessed images were utilized in the edema mathematical model to estimate the fraction of extracellular space (Fecs) and fraction of intracellular space (Fics). Through an ongoing image-localized biopsy collection protocol, we analyzed 179 samples (Female: 75; Male: 104) from 55 patients (Female: 21; Male: 34) for bulk RNA-Seq. Samples were characterized by their edema Fecs scores and underwent differential expression, gene set enrichment analysis using MSigDB hallmarks and cellular deconvolution using CIBERSORTx. Through differential expression and gene set enrichment analyses of these spatial biopsies, we have identified sex-distinct gene expression and pathways corresponding to regions of high vs low edema. Within highly edematous regions, male samples were amplified for respiratory pathways, while female samples were suppressed. Connecting changes on MRIs with molecular markers from image-localized biopsies provides an opportunity to identify the biological drivers of brain tumor associated imageable edema. Specifically, elucidating the sex-distinct patterns connecting changes on MRI with cellular populations and molecular pathways could be used to better interpret imaging of patients and interpreting treatment response.

Citation Format: Pamela R. Jackson, Lee Curtin, Sara Ranjbar, Kyle W. Singleton, Maciej M. Mrugala, Richard S. Zimmerman, Bernard R. Bendok, Peter Canoll, Kristin R. Swanson. Sex-distinct patterns of molecular pathways associated with brain tumor edema [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 6168.
Abstract 625: Remodeling of the tumor microenvironment in esophageal squamous cell carcinoma by neoadjuvant immunochemotherapy and its impact on therapeutic efficacy
Authors: Aizemaiti Rusidanmu , Zhang Huifang , Zhu Changbin , Zhou Kun , Hu Tao , Lin Shuang , Teng Xiao , Wang Jin , Li Xing , Ye Peng
Published: March 2024

Background: Patients with local advanced esophageal squamous cell carcinoma (ESCC) benefited from neoadjuvant immunochemotherapy (NAI) with 22%-55% of complete pathological responses (pCR). While unpredicted therapeutic resistance hampered prognosis of these patients. Thus, this study aimed to investigate tumor microenvironment (TME) remodeling pre- and post-NAI identifying predictive biomarkers and potential targets for patients with resistance to NAI.

Methods: 65 patients with locally advanced ESCC, who were treated with neoadjuvant anti-PD-1 antibody and platinum-based chemotherapy at the First Affiliated Hospital of Zhejiang University School of Medicine between November 2019 and June 2020, were included in this study. Genomic DNA and RNA from paired pre-and post-treatment FFPE samples were harvested and subjected to targeted DNA and RNA sequencing. Pre- and post- therapeutic microenvironment and immune cell infiltration were dynamically assessed based on RNA sequencing data.

Results: 37 of 65 patients responded to NAI(TRG0-1), while 28 of 65 patients displayed unfavored response (TRG2-3). Comparative analysis of TME characteristics before and after NAI revealed that, in the TRG2-3 group, LRRC15+ CAFs, and fibroblasts were significantly upregulated, while CD4 T cells and endothelium cells exhibited downregulation. Especially, TIGIT tended to be upregulated after NAI in the TRG 2-3 group. In the TRG0-1 group, significant upregulation of activated B cells, T-cells, myeloid dendritic cells, together with notable downregulations of immune suppressive features like Type 2 T helper cells, Tregs and LRRC15+ CAFs were observed in post-treatment samples.

Conclusions: Our study indicates the dynamic remodeling of TME during-NAI treatment might influence therapeutic efficacy and disclose potentially targetable resistant mechanisms. These preliminary findings pave the way for further validation through prospective clinical studies.

Citation Format: Rusidanmu Aizemaiti, Huifang Zhang, Changbin Zhu, Kun Zhou, Tao Hu, Shuang Lin, Xiao Teng, Jin Wang, Xing Li, Peng Ye. Remodeling of the tumor microenvironment in esophageal squamous cell carcinoma by neoadjuvant immunochemotherapy and its impact on therapeutic efficacy [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 625.
Abstract 6250: The RNA editing landscape of lung cancer in never smokers
Authors: Sang Jian , Zhao Wei , Zhang Tongwu , Landi Maria Teresa
Published: March 2024

Adenosine-to-Inosine (A-to-I) editing represents a crucial RNA modification mechanism, holding the potential to drive carcinogenesis. This sophisticated post-transcriptional process is catalyzed by a series of ADAR (adenosine deaminase acting on RNA) family members, which can profoundly reshape the cellular epitranscriptomic landscape. While previous explorations have illuminated the important role of A-to-I editing in lung cancer tumorigenesis and prognosis, most studies have focused on lung cancer from smokers. To investigate the contribution on RNA-editing in lung cancers in never smokers (LCINS) , we embarked on a rigorous dissection of A-to-I RNA editing events in 603 LCINS. Harnessing transcriptome and whole-genome sequencing technologies, we identified 15,880 A-to-I sites, of which 75% were positively linked to the enzymatic activity of ADAR1. 92.80% of detected editing sites were located at Alu repetitive regions, with the remainder in non_Alu repeat (4.1%) and non-repeat regions (3.1%). The global RNA editing levels, measured as Alu Editing Index (AEI), were found to be significantly associated with ADAR1 expression, Tumor Mutational Burden, and Neoantigens Burden. A subtle correlation between global RNA editing levels and tumor stage was also noted. Delving into cancer-associated editing events, we identified 5,539 differentially edited sites in tumors compared with normal tissues, which were located at 823 genes, including several key tumor suppressors and oncogenes, like MDM2, BRAF, TP53, BRCA2, ATM, and VHL. Subsequent pathway analysis identified TGF-beta, Notch Signaling, and DNA Damage Response as the key pathways for cancer progression. Using the characterized A-to-I editing profiles, we built a prognostic risk stratification model, with high risk scores significantly linked to poor survival outcomes, even after adjusting for other clinical factors. Our study provides a comprehensive A-to-I editing landscape of lung cancer in never smokers, highlighting the potential roles of RNA modifications in the pathogenesis of this lethal disease.

Citation Format: Jian Sang, Wei Zhao, Tongwu Zhang, Maria Teresa Landi. The RNA editing landscape of lung cancer in never smokers [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 6250.
Abstract 626: EGFL6 induced HER2-HER3 signaling controls accurate centrosome deposition of activated ERK and mitotic spindle formation in ovarian cancer cells
Authors: Bai Shoumei , Gupta Navneet , Jiang Qi , Buckanovich Ronald J.
Published: March 2024

Epidermal growth factor EGF-like domain multiple-6 (EGFL6) is highly expressed in high grade serous ovarian cancer (HGSOC) cells and ovarian tumor vasculature. EGFL6 acts on tumor cells to drive tumor cell proliferation and migration. To better understand EGFL6 signaling and develop therapeutic strategies to target EGFL6 signaling in HGSOC, we evaluated phosphorylation of putative EGFL6 receptors and their downstream signaling. We demonstrated that EGFL6 induced phosphorylation and activation of ERBB/HER family of receptors; EGFL6 treatment of ovarian cancer cells led to rapid and transient phosphorylation of EGFR while inducing prolonged activation of both HER2 and HER3, with subsequent phosphorylation of ERK. Interestingly, we found that in EGFL6 stimulated ovarian cancer cells undergoing mitosis, pERK localized to the centrosome and the contractile ring. EGFL6 neutralizing antibodies reduce ERK phosphorylation and resulted in pERK being aberrantly localized. This resulted in altered mitotic spindle alignment and an increased number of cells undergoing mitotic catastrophe. Furthermore, combination anti-EGFL6 therapy with the pan-EGFR receptor inhibitor neratinib, compared to either therapy alone, led to an increase in aberrant pERK localization and cancer cell death in vitro. Consistent with these findings, dual anti-EGFL6 and neratinib therapy significantly restricted tumor growth in vivo, resulting in increased tumor cell death and a reduction in angiogenesis. Combined our data identify an unexplored role for pERK at the centrosome and suggest that dual targeting of the EGFL6/HER signaling axis maybe an effective therapeutic strategy in ovarian cancer.

Citation Format: Shoumei Bai, Navneet Gupta, Qi Jiang, Ronald J. Buckanovich. EGFL6 induced HER2-HER3 signaling controls accurate centrosome deposition of activated ERK and mitotic spindle formation in ovarian 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 626.
Abstract 6266: Neurotensin receptor 1 regulates dimerization of HER2-HER4 and proliferation of non-small cell lung cancer cells
Authors: Moody Terry W. , Ramos-Alvarez Irene , Jensen Robert T.
Published: March 2024

The neurotensin receptor 1 (NTSR1) is a 418 amino acid type A G protein-coupled receptor which causes phosphatidylinositol turnover and proliferation of non-small cell lung cancer (NSCLC) cells (Moody et al., Peptides 2021; 137: 710480). Adding the agonist NTS to NSCLC cells increases transactivation of the receptor tyrosine kinases (RTK) EGFR, HER2 and HER3 (Moody et al., Biology 2023 12: 957). The RTK tyrosine phosphorylation and growth caused by NTS is impaired by SR48692, a small molecule NTSR1 antagonist. The effects of NTS were investigated on HER4 using NSCLC cells. By Western blot, cell lines NCI-H522 and H661 had high levels of NTSR1, HER 4 and neuregulin 1 (NRG1), a ligand for HER4 but not NTSR2, HER3 or NRG2. By RT-PCT, high levels of HER4 and its isoforms JM-a, CYT1 and CYT2 were present in NCI-H522 and H661 cells. Adding NTS (0.1 μM) or NRG1 (0.01 μg/ml) to NCI-H522 or H661 cells increased P-Tyr1284-HER4 and P-ERK 3-fold. Using immunoprecipitation techniques, adding NTS to NSCLC cells increased formation of HER4-HER2 heterodimers which leads to cancer proliferation (Lucas et al., Pharmacol Rev 2022; 74:18). The increase in PY1284-HER4 caused by NTS was impaired by SR48692, HER4 siRNA, NRG1 siRNA or ibrutinib (TKI). The NTSR1 regulation of HER4 transactivation is impaired by GM6001 (MMP inhibitor]), PP2 (Src inhibitor) or N-acetylcysteine (antioxidant). The clonal growth of NSCLC cells is increased by NTS or NRG1 but decreased by SR48692 or ibrutinib. The results indicate that NTS increases the formation of HER2/HER4 heterodimers leading to the proliferation of NSCLC cells.

Citation Format: Terry W. Moody, Irene Ramos-Alvarez, Robert T. Jensen. Neurotensin receptor 1 regulates dimerization of HER2-HER4 and proliferation of non-small cell lung 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 6266.
Abstract 6267: Evaluating estrogen receptor signaling modifications at bone marrow related stiffnesses in metastatic breast cancer
Authors: Northcutt Logan Alexander , Rafat Marjan , Rhoades Julie
Published: March 2024

Bone metastasis is highly prevalent in breast cancer (BC) patients with metastatic disease and can increase the risk of hypercalcemia and pathological fractures. Several studies have evaluated the mechanisms of metastasized BC cells’ involvement in bone destruction, but how the bone marrow (BM) microenvironment contributes to this process remains ambiguous. Recent studies have shown that as BC cells experience increased stiffnesses outside of the primary microenvironment, there is higher expression of epithelial-to-mesenchymal transition (EMT) markers, increased expression of osteolytic proteins, and decreased drug responses. However, these changes have not been evaluated at stiffnesses relative to the BM. Estrogen receptor (ER) status also plays a pivotal role in BC patient survival. Clinical studies have indicated that the majority of ER+ patients with metastatic disease have more incidences of bone metastases compared to ER- patients. There is some evidence that suggests that the physical properties can also affect estrogen receptor signaling at the primary site, however, there is minimal work to establish how the physical factors of the BM can affect ER sensitivity after metastasis. We hypothesize that higher stiffness ranges of the BM can alter the estrogen receptor sensitivity of metastasized tumor cells and increase osteolysis. To analyze this question, we seeded ER+ BC cell lines (MCF7s and T47Ds) on CytoSoft® Rigidity Plates that mimicked the stiffness of the BM (0.5 - 32 kPa). After 2 days in culture, we probed the expression of downstream estrogen signaling factors, GREB1, PGR, and TIFF1, to evaluate estrogen activity using western blot. Our results show an increase in downstream estrogen signaling at higher stiffnesses (32 kPa) compared to lower stiffnesses (0.5 kPa) at the protein level but not at the transcriptional level. In the future, we will analyze factors associated with osteolysis (ITGB3, TGFB-RII, and PTHLH). Additionally, we plan to conduct RNA sequencing to analyze any larger transcriptional changes at different stiffnesses. Overall, this work gives insight into how estrogen signaling changes in the BM compared to the primary site. It will also give us insight into potential therapeutic targets for ER+ BC after metastasis to the bone.

Citation Format: Logan Alexander Northcutt, Marjan Rafat, Julie Rhoades. Evaluating estrogen receptor signaling modifications at bone marrow related stiffnesses in metastatic breast 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 6267.
Abstract 6270: Anti-metastatic effects of estrogen receptor β in inflammatory breast cancer
Authors: Nagandla Harika , Tastsoglou Spyros , Cap Kim Cuong , Phillips Aireana , Qian Wei , Zhou Jianying , Chang Jenny , Krishnamurthy Savitri , Ueno Naoto , Hatzigeorgiou Artemis , Thomas Christoforos
Published: March 2024

Inflammatory breast cancer (IBC) is a rare but highly aggressive form of breast cancer with a 5-year survival rate of less than 50%. Although 20-30% of women with IBC have distant metastasis at the time of diagnosis, the biology underlying the aggressive behavior of the disease is poorly understood and molecular markers that distinguish IBC from non-IBC have not yet been identified. In response to the urgent need of discovering new targeted therapies in IBC, we have studied the second estrogen receptor (ERβ) since prior work from our lab correlated higher tumor expression of ERβ in samples from IBC patients with longer metastasis free survival. We showed that ERβ exerted anti-metastatic activity in IBC by inhibiting actin-based cell migration through the suppression of RhoC GTPase signaling. However, since estrogen receptors elicit their effects by inducing global cellular alterations, we have now adopted an integrated genomic approach to fully understand the anti-metastatic effects of ERβ in IBC and delineate the underlying transcriptional regulatory circuits. We found ERβ binding sites in IBC cells and combined this information with gene expression data to identify downstream direct target genes and associated pathways. Our findings suggest the regulation of tumor micro-environment and metabolism as the primary targets of ERβ and we are currently working to pinpoint the crucial regulatory components in these functions. Our findings thus offer an opportunity to better understand the mechanism of ERβ action in aggressive breast cancer, serving as a critical step in validating its tumor repressive role.

Citation Format: Harika Nagandla, Spyros Tastsoglou, Kim Cuong Cap, Aireana Phillips, Wei Qian, Jianying Zhou, Jenny Chang, Savitri Krishnamurthy, Naoto Ueno, Artemis Hatzigeorgiou, Christoforos Thomas. Anti-metastatic effects of estrogen receptor β in inflammatory breast 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 6270.
Abstract 6291: Changes in physical activity and ischemic stroke risk after cancer diagnosis: A nationwide cohort study
Authors: Shin Dong Wook , Jung Wonyoung , Cho In Young , Jung Jinhyung , Cho Mihee , Koo Hye Yeon , Cho Be-Long , Park Jin Ho , Kwon Hyuk Tae , Han Kyungdo , Park Yong-Moon Mark
Published: March 2024

Background: Physical inactivity is prevalent after cancer treatment, which may pose a greater risk of ischemic stroke in cancer survivors.

Objective: To investigate the association between physical activity change from pre- to post-diagnosis and ischemic stroke risk among cancer survivors.

Methods: Cancer survivors without prior history of cardiovascular disease were identified. Pre- and Post-adherence to physical activity was determined within two years from cancer diagnosis. The primary outcome was incident ischemic stroke. Using the Fine-Gray model, sub-distribution hazard ratios (sHRs) and 95% confidence intervals (CIs) for ischemic stroke risk were calculated, considering death as a competing risk.

Results: Among 269,943 cancer survivors (mean [SD] age 56.3 [12.1] years, 45.7% male), 10.1% remained active, 11.4% became inactive, and 16.6% became active post-diagnosis. During 1,109,566.68 person-years[YMP1] , remaining active both pre- and post-diagnosis was associated with 15% decreased risk of ischemic stroke (sHR 0.85, 95% CI 0.75-0.96), compared to those who remained inactive. Cancer survivors who became active, and inactive post-diagnosis showed a 16%, and 11% lower risk of ischemic stroke (sHR 0.84, 95% CI 0.75-0.93; sHR 0.89, 95% CI 0.79-0.99) than those who remained inactive.

Conclusions: Our findings suggest that staying physically active is associated with a reduced risk of ischemic stroke among cancer survivors. Notably, these advantages are not limited to individuals who were physically active before their diagnosis, and it is not too late to start post-diagnosis. Preventive strategies against ischemic stroke in cancer survivors should emphasize the incorporation of regular physical activity at any stage of their cancer journey.

Citation Format: Dong Wook Shin, Wonyoung Jung, In Young Cho, Jinhyung Jung, Mihee Cho, Hye Yeon Koo, Be-Long Cho, Jin Ho Park, Hyuk Tae Kwon, Kyungdo Han, Yong-Moon Mark Park. Changes in physical activity and ischemic stroke risk after cancer diagnosis: A nationwide cohort study [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 6291.
Abstract 6295: Role of MAPK11 in the protective mechanisms against toxicity of tyrosine kinase inhibitors
Authors: Hnatiuk Anna Pavlovna , Staudt David , Mercola Mark
Published: March 2024

Introduction and purpose of the study: Targeted therapies with Tyrosine Kinase Inhibitors (TKIs) have drastically improved the survival of cancer patients. However, long term exposure to TKIs has been associated with severe adverse events such as heart failure, impairing patient survival and life quality, and limiting treatment options. Cardioprotective effect of MAPK11 has been described against cardiac ischemic disease. In addition, MAPK11 has also been reported as an important mediator in cancer development and progression. Therefore the aim of this study is to evaluate the potential therapeutic and dual anti-cancer and cardio-protective effect of MAPK11 inhibition during TKI treatment.

Experimental procedures: For this study we used the TKI ponatinib as a paradigm of cardiac toxicity. Ponatinib has been used as a gold standard therapy for the drug resistant type of Chronic Myeloid Leukemia (CML) due to T315I-ABL1 mutation, and has been associated with high risk of cardiac toxicity. We performed in vitro functional assays to evaluate the cardiotoxicity and cardiac protection using human iPSC-cardiomyocytes (hiPSC-CMs), and anti-cancer effect in T315I mutated KCL-22 CML cells. The cardiotoxicity was evaluated by impairment of cardiomyocytes contractile function during TKI (ponatinib) treatment, the cardiac-protection was evaluated by restoration of contractile function post-inhibition of MAPK11 with RNA silencing (siRNA) technique. The anti-cancer effect was evaluated using a cell viability and proliferation assay during inhibition of MAPK11 by siRNA and ABL1 inhibition as a positive control.

Summary of unpublished data: Pretreatment with siRNA MAPK11 inhibition significantly improved the contractile function of the cardiomyocytes during treatment with ponatinib when compared to those that did not receive MAPK11 inhibition. Moreover, when compared to the positive control of siRNA ABL1 inhibition, the MAPK11 inhibition showed similar anti-cancer effect in the T315I mutated KCL-22 CML cells proliferation and survival assay.

Conclusions: Our study suggests that the inhibition of MAPK11 is a potential druggable therapeutic target with dual action of anti-cancer effect for the mutant form of CML, as well as a substantial protective effect against the cardiac toxicity associated with the TKI ponatinib that could bring insights in the development of safer oncological drugs.

Citation Format: Anna Pavlovna Hnatiuk, David Staudt, Mark Mercola. Role of MAPK11 in the protective mechanisms against toxicity of tyrosine kinase inhibitors [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 6295.
Abstract 6311: From bench to bedside: GMP manufacturing and testing of an LGR5-targeting CAR-T against colorectal cancer
Authors: Bandara Veronika , Gundsambuu Batjargal , Napoli Silvana , Foeng Jade , McPeake Dylan , Tylis Timona , Thompson Emma , Mills Stuart , Cowin Allison , Bonder Claudine , Sadlon Timothy , McColl Shaun , Barry Simon
Published: March 2024

Colorectal cancer is the third most diagnosed cancer worldwide, and is responsible for the second largest number of cancer related deaths, warranting the need for new treatments. The successful use of chimeric antigen receptor T (CAR-T) cells against B-cell malignancies has inspired the search for CAR-T cell therapies against solid tumours such as colorectal cancer. Cancer stem cells (CSC) are a small population of cells within a tumour with the capacity to self-renew, differentiate, and initiate new tumours. CSC are resistant to chemotherapy and radiotherapy and are enriched in residual disease. Targeting CSC is a strategy to reduce the tumours’ ability to generate new cells. Leucine-rich G protein-coupled receptor 5 (LGR5) is a marker of CSC and LGR5+ cancer cells are implicated in tumour progression and metastasis in colorectal cancer. We designed and tested a chimeric antigen receptor (CAR) targeting the extracellular domain of LGR5. LGR5-targeting CAR-T cells showed significant antigen-specific cytotoxicity and IFNγ release against colorectal cancer (CRC) cell lines in vitro, and in vivo efficacy in a CRC xenograft mouse model. We confirmed the specificity and safety of the LGR5 targeting CAR-T cells by testing against normal human tissues. A GMP ready protocol for clinical scale manufacture of LGR5-targeting CAR-T cells have been developed using CD3+ T-cells from healthy donors. We have successfully tested this protocol using CRC patient-derived CD3+ T-cells and were able to generate clinically relevant cell numbers (80-fold expansion) with high CAR expression. Cells manufactured using this GMP protocol expressed markers of self-renewing naïve-like and central memory phenotype and showed very low percentage of cells that were triple-positive for PD1, TIM3 and LAG3. This protocol has been successfully tested and validated in a GMP manufacturing facility for the production of LGR5 targeting CAR-T cells, in preparation for an FDA approved first in man clinical trial against metastatic colorectal cancer, starting in 2023 (NCT05759728).

Citation Format: Veronika Bandara, Batjargal Gundsambuu, Silvana Napoli, Jade Foeng, Dylan McPeake, Timona Tylis, Emma Thompson, Stuart Mills, Allison Cowin, Claudine Bonder, Timothy Sadlon, Shaun McColl, Simon Barry. From bench to bedside: GMP manufacturing and testing of an LGR5-targeting CAR-T against 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 6311.
Abstract 6430: Gene expression signature quantifies the cellular contribution of the tumor vs. the microenvironment in determining colorectal cancer prognosis and therapeutic outcome
Authors: Yang Mingli , Yeatman Timothy J. , Nebozhyn Michael V. , Schell Michael J. , Pflieger Lance , Loboda Andrey , Pledger Warren J. , Soundararajan Ramani , Maurin Michelle , Wang Heiman , Silva Jetsen Rodriguez , Alden Ashley
Published: March 2024

Accumulating evidence has suggested that cancer progression and therapeutic response may depend on not only tumor cells but also their tumor microenvironment (TME). However, their contributory roles are complex and not well understood. Here we report an analysis of 2373 human colorectal cancer (CRC) tumors representing all stages, leading to identification of a 20-gene signature capable of quantifying the cellular contribution of the tumor vs. the TME in determining colorectal cancer prognosis and therapeutic outcome. We classified these tumors into the consensus molecular subtypes (CMS1-4) with distinct, variable TME cellular features defined by CIBERSORT deconvolution analysis of bulk gene expression data. Surprisingly, all the 10 positive signature genes (portending worse survival) were strongly correlated with the TME-rich CMS1 and CMS4 tumors. By contrast, all the 10 negative signature genes (portending better survival) were highly related to the TME-poor CMS2 and CMS3 tumors. A single cell expression analysis from an independent database further revealed that strikingly, all the 10 positive genes were principally expressed by the immune/stromal TME whereas all the 10 negative genes were predominantly expressed in epithelial tumor cells. These data suggest that the TME has an equally important role as do tumor cells in determining CRC prognosis and support targeting the TME to improve survival. Moreover, distinct gene expression from tumor cells versus the TME also showed a differential impact on therapeutic outcome. Retrospective analyses on two independent clinical trial datasets show that the 20-gene signature score significantly predicted progression free survival in metastatic CRC patients treated with cetuximab, an FDA-approved EGFR inhibitor therapy. These data suggest a potential for the 20-gene signature as a predictive biomarker to identify “sensitive” versus “resistant” subpopulations of CRC patients to improve outcome of EGFR-targeted therapy.

Citation Format: Mingli Yang, Timothy J. Yeatman, Michael V. Nebozhyn, Michael J. Schell, Lance Pflieger, Andrey Loboda, Warren J. Pledger, Ramani Soundararajan, Michelle Maurin, Heiman Wang, Jetsen Rodriguez Silva, Ashley Alden. Gene expression signature quantifies the cellular contribution of the tumor vs. the microenvironment in determining colorectal cancer prognosis and therapeutic outcome [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 6430.
Abstract 6436: Tumor-educated platelets for therapy stratification of metastasized castration resistant prostate cancer (CRPC)
Authors: Nilsson Jonas A. , Lundholm Marie , Tjon-Kon-Fat Lee-Ann , Köhn Linda , Thellenberg-Karlsson Camilla , Josefsson Andreas , Wikström Pernilla
Published: March 2024

One in ten men diagnosed with prostate cancer will have metastases. At some point the metastases becomes castration therapy resistant, contributing leading to the high mortality of prostate cancer. Novel androgen directed treatments, like abiraterone and enzalutamide, have made substantial difference to therapy response, yet only within subgroups of CRPC patients. Correct therapy stratification may prolong the life of the patients, possibly turning a deadly disease into a more chronic disease. For this to happen we need predictive biomarkers that can be used to longitudinally follow the disease in order to identify vulnerabilities and to monitor acquired resistance, e.g. we need to develop personalized liquid biopsy platforms. Using the platelet enriched fraction of a blood sample we here show that we can use the platelets ability to sequester material during circulation to provide information derived from the tumor, a.k.a. tumor-educated platelets. This information could be used as a companion diagnostic to identify patients that will respond to therapy, and to longitudinally monitor tumor progression. In this study, a previously published three gene profile, plt3G profile, was validated in a larger cohort (n=97) and showed that combined analysis of the three genes transcripts (KLK3, FOLH1, NPY) could be used to identify long-term responders regarding progression-free survival after enzalutamide (n=47; PFS; LR p<0,001, HR 0,32, p<0,001) or abiraterone (n=50; PFS; LR p=0.007, HR 0.45, p=0,009) -treatment. Furthermore, progression and resistance development could be accurately longitudinal followed. The plt3G profile showed a significant overlap with circulating tumor DNA (ctDNA) biomarkers, but in addition also provided predictive information around treatment response. Tumor-educated platelets provide therapy-predictive biomarkers as well as biomarkers for longitudinal monitoring of disease progression and resistance development, which ultimately could provide information for therapy switching. Their easy accessibility makes tumor-educated platelets an attractive biosource to be used alone or in combination others, to enable a fluid biomarker platform with the aim to turn a lethal cancer disease into a more chronic disease.

Citation Format: Jonas A. Nilsson, Marie Lundholm, Lee-Ann Tjon-Kon-Fat, Linda Köhn, Camilla Thellenberg-Karlsson, Andreas Josefsson, Pernilla Wikström. Tumor-educated platelets for therapy stratification of metastasized castration resistant prostate cancer (CRPC) [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 6436.
Abstract 6445: Exploring the relationship between PSCA and PD-L1 by a comprehensive tumor immunohistochemical analysis
Authors: Guo Yichen , Gonzalez Rachel , Yom Jina , Gilmore Bailey , Qu Tianli , Hu Xiaomin , Han Andy (Xi) , Guo Zhaoying , Zewdu Eden , Liu Xuan , Fu Wei
Published: March 2024

Prostate Stem Cell Antigen (PSCA) is a well-established diagnostic marker in various cancers and a promising target for immunotherapy. Programmed Death-Ligand 1 (PD-L1) plays a crucial role in cancer immune regulation and is known to influence patient response to checkpoint inhibitors. The objective of this study is to elucidate the relationship between PSCA and PD-L1 in diverse cancer types and to provide valuable insights for the development of an effective immunotherapy strategy.

To accomplish this, immunohistochemical (IHC) analysis was conducted on paraffin-embedded Cytosections obtained from 20 lung cancers, 20 prostate cancers, 32 bladder cancers, and 20 normal tissues for each respective cancer type. Antibodies generated by Origene were utilized to detect the expression of PSCA and PD-L1 on the cell surface. The IHC results of tumor tissue were standardized against corresponding normal samples, and the correlation between these two genes was statistically analyzed using analysis of variance (ANOVA). The findings reveal a significant positive correlation between the expression of PSCA and PD-L1 (r=+0.78, P=0.016), suggesting an underlying mechanism driving their co-expression in the studied cancers.

Understanding PSCA and PD-L1 coexpression in bladder, lung, and prostate cancers has great potential for informing tailored immunotherapies. Future research should explore functional consequences within the tumor microenvironment, advancing precision immunotherapy for improved outcomes in these challenging malignancies.

Citation Format: Yichen Guo, Rachel Gonzalez, Jina Yom, Bailey Gilmore, Tianli Qu, Xiaomin Hu, Andy (Xi) Han, Zhaoying Guo, Eden Zewdu, Xuan Liu, Wei Fu. Exploring the relationship between PSCA and PD-L1 by a comprehensive tumor immunohistochemical analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6445.
Abstract 6499: The landscape of MET exon 14 skipping mutations in non-small cell lung cancer patients identified by next-generation sequencing
Authors: Shi Chen , Ning Gao , Qinglan Zong
Published: March 2024

Background: MET exon 14 skipping mutations (METex14) account for approximately 0.9%-4% in patients with non-small cell lung cancer (NSCLC). The primary detection methods are DNA and RNA-based next-generation sequencing (NGS). However, the effect of amplicon-based library construction (ALC) and capture-based library construction (CLC) on the detection characteristics of METex14 during the NGS process is not yet fully understood. Here we described the landscape of METex14 in NSCLC patients, as identified by NGS using two different library construction methods.

Methods: A total of 6811 samples with NSCLC were enrolled in this study, including 3839 samples performed by DNA-based NGS with CLC, 64 samples performed by RNA-based NGS with CLC and 2908 samples performed by the synchronous DNA-based and RNA-based NGS with ALC. Only the pathogenic mutations and likely pathogenic mutations in clinical significance were rolled into our analysis.

Results: The ranking of different methods, as determined by the positive rates for METex14, was RNA-based NGS with ALC (71/2908, 2.44%), RNA-based NGS with CLC (1/64, 1.56%), DNA-based NGS with CLC (54/3839, 1.41%) and DNA-based NGS with ALC (14/2908, 0.48%). Out of 2908 samples performed by the synchronous DNA-based and RNA-based NGS with ALC, 73 samples (2.51%) had METex14 detected at either the DNA or RNA level. METex14 were only detected at the RNA level in 59 patients, while they were only detected at the DNA level in 2 patients. This might be due to the limited probe design at DNA level and the Y1003 site which could not be detected at RNA level. As revealed by DNA-based NGS, the mutation forms causing METex14 include point mutations, indels, and large segment duplications. And the highest mutation rate is in the splice donor site (30.9%), the lowest is observed at position Y1003 (2.9%). Additionally, METex14 is more prevalent in patients over 60 years of age in Chinese NSCLC, with a statistically significant difference (P=0.0043).

Conclusion: RNA-based detection of MET 14 skipping yielded a higher detection rate compared to DNA-based NGS, regardless of ALC or CLC. Combining DNA and RNA analysis is more suitable for detecting MET exon 14 skipping and increases the positive rate.

Citation Format: Chen Shi, Gao Ning, Zong Qinglan. The landscape of MET exon 14 skipping mutations in non-small cell lung cancer patients identified by next-generation sequencing [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 6499.