Tumor Types Research Articles

Abstract IA019: Regulation of EMT tumor states by stromal cells

Abstract Epithelial-to-mesenchymal transition (EMT) is a reversible process during which epithelial cells lose their epithelial characteristics and acquire mesenchymal features, that are important for tumor initiation, progression, stemness, metastasis, and therapy resistance. Different EMT states, each with distinct functional properties, have been identified across various tumor models. These EMT states reside within specific physical niches, characterized by unique stromal cell populations. Understanding the cellular interactions within the tumor microenvironment (TME) and their influence on EMT could lead to novel therapeutic strategies. To understand how the TME regulates the distinct tumor states, we performed single-cell RNA sequencing of the tumor cells and their TME in mouse cancer models presenting EMT. We identified distinct subsets of cancer-associated fibroblasts (CAFs), macrophages, neutrophils, endothelial cells, pericytes, adipocytes, dendritic cells, mast cells, Schwann cells, and T cells in different tumor types. To unravel how TME-tumor cell interactions regulates EMT, we used different bioinformatic approaches to identify ligand-receptor pairs that are likely to organize the tumor niche and to regulate tumor transition states. In vitro treatment of tumor cells with some of these ligands demonstrated their EMT-promoting effects. These findings provide novel mechanistic insights on the crosstalk between tumor cells and the surrounding TME, that may have important implications for anti-cancer therapy. Citation Format: Cédric Blanpain. Regulation of EMT tumor states by stromal cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr IA019.

Abstract B029: Mapping the vascular walls of colorectal cancer

Abstract Introduction: Properties of tumor angiogenesis impact on tumor growth and composition of the tumor microenvironment. Tumor vessels are composed of pericytes and other mural cells. Detailed characterization of the cellular composition of the microvasculature can suggest functional vessel and case properties relevant for outcome, response to treatment and immune surveillance. Results: Based on single cell RNA-seq from three human stage II/III colon cancers and pilot in-situ multi-antibody staining of six tumors two main clusters of perivascular cells were identified; B1 (MCAM+, MYH11-) and B2 (MCAM+, MYH11+) cells. B1 cells displayed pericyte features including expression of RGS5, whereas B2 cells showed high expression of smooth muscle cell markers like ACTG2 and Desmin. Desmin-high B2 cells were predominantly located in muscular layers, whereas Desmin-low/MYH11-high B2 cells showed perivascular enrichment. An extended novel analyses workflow of digital image analysis was used to profile peri-endothelial composition in 19 intervals; 11 1-µm intervals from 0 to 10 µm and 8 5-µm intervals from 10 to 50 µm from endothelial areas. Each of these expansion areas was quantitated regarding density of PDGFRB+/- cells including B1/B2 cells, and a MYH11+/MCAM- cells. Density of macrophage subsets (CD68-positive subsets defined by CD163 and CD11c) were also quantitated. In general, B1 cells showed stronger spatial association with endothelial cells than B2 cells, and this spatial association was stronger for the PDGFRB+ B1 subset. Survival analysis indicated that prognostic relevance was strongest when PDGFRB+ (favorable prognosis) cells were closest to endothelial cells. Regarding perivascular macrophage density, M0 and transit M1/M2 macrophages were predominantly enriched in the peri-endothelial regions, whereas density of M1 and M2 increased gradually as distance from vessels increased. M2 density was overall associated with poor prognosis, whereas high density of other macrophage subsets overall was associated with good prognosis. Ongoing studies are using a clustering-based approach to identify vessel subsets, and prognosis associations are being consolidated in additional cohorts. Summary: This study provides a novel approach for high resolution profiling of perivascular status in CRC, and possibly other tumor types, that could be of specific importance to identify tumor features associated with response to angiogenesis-directed therapies. Citation Format: Linglong( 凌 龙 ) Huang( 黄 ), Mercedes Herrera, Jonas Sjölund, Vladimir Chocoloff, Simon Joost, Rasul M. Tabiev, Lina Wik Leiss, Carina Strell, Luis Nunes, Artur Mezheyeuski, David Edler, Anna Martling, Fredrik Pontén, Bengt Glimelius, Tobias Sjöblom, Maria Kasper, Kristian Pietras, Arne Östman. Mapping the vascular walls of colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B029.

Abstract B038: Establishing a screening platform to identify key signaling molecules regulating cold tumor formation through immune evasion and exclusion

Abstract Many trial data have shown that cancer immunotherapy can successfully induce long lasting anti-cancer immune responses and increased the survival rate of cancer patients. One of the key challenges facing cancer immunotherapy is the low response rate of cancer patients to immunotherapy, suggesting that these cancer patients may have acquired resistance toward immunotherapy before treatments. Therefore, there is an unmet need for identifying the underlying mechanisms that promote resistance. One important hypothesis is that immune-excluded tumors (so called cold tumors) that lack of functional T cells have been often found in cancer patients who cannot respond well to cancer immunotherapy. To address this, we have successfully established a preclinical model for cold lung tumors, conducted RNA-seq, performed hallmark gene set enrichment analysis (GSEA) on cold tumor cells sorted in vivo, and identified several candidates associated with epithelial-mesenchymal transition, Wnt signaling, type I and II interferon (IFN) signaling, and p53 signaling. We hypothesize that their roles may either promote or inhibit the formation of cold tumors. One of the molecular candidates we identified, a molecule designated as IRC001, represents a crucial proof of concept for our experimental tumor model. We have unveiled a novel role for IRC001 in enhancing anti-tumor immunity, leading to the transformation of cold tumors into hot tumors and facilitating swift tumor regression through pathways reliant on T cells and type I IFN signaling. Our mechanistic studies have shown that IRC001 can trigger type I IFN signaling by engaging STING/TBK-1/IRF3-dependent pathways. To delve deeper into the spatial and molecular distinctions in mouse tumors (± IRC001), we initiated a preliminary study utilizing 10x Genomics/Visium to examine the spatial variations between these tumor types. Significantly, our spatial transcriptomic analysis revealed consistent immune-excluded and immune-enriched characteristics compared to traditional RNA sequencing methods. We conducted an analysis of TCGA datasets (The Cancer Genome Atlas) and observed that elevated IRC001 expression is associated with improved prognosis in SKCM (Skin Cutaneous Melanoma). Furthermore, our bioinformatics analysis revealed that melanoma patients exhibiting heightened IRC001 expression displayed positive responses to immune checkpoint blockade therapies. Therefore, we believe that our experimental tumor model can provide vital insights into the cold tumor microenvironment, shaping future therapeutic strategies, and pinpointing molecular candidates that can assist in selecting patients for successful immunotherapy. Citation Format: Yi-Ting Liao, Li-Mei Chen, Wen-Jye Lin. Establishing a screening platform to identify key signaling molecules regulating cold tumor formation through immune evasion and exclusion [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B038.

Towards precision medicine: design considerations for nanozymes in tumor treatment.

Since the discovery of Fe3O4 nanoparticles with enzyme-like activity in 2007, nanozymes have emerged as a promising class of catalysts, offering advantages such as high catalytic efficiency, low cost, mild reaction conditions, and excellent stability. These properties make nanozymes highly suitable for large-scale production. In recent years, the convergence of nanomedicine and nanocatalysis has highlighted the potential of nanozymes in diagnostic and therapeutic applications, particularly in tumor therapy. Despite these advancements, the clinical translation of nanozymes remains hindered by the lack of designs tailored to specific tumor characteristics, limiting their effectiveness in targeted therapy. This review addresses the mechanisms by which nanozymes induce cell death in various tumor types and emphasizes the key design considerations needed to enhance their therapeutic potential. By identifying the challenges and opportunities in the field, this study aims to provide a foundation for future nanozyme development, ultimately contributing to more precise and effective cancer treatments.

The prognostic implications and oncogenic role of NSUN5 in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC), a predominant form of urinary malignancy, requires the identification of reliable biomarkers to enhance both prognostic outcomes and therapeutic developments specific to ccRCC. NSUN5, a member of the NOL1/NOP2/SUN domain (NSUN) family, plays a critical role in RNA stabilization and exhibits widespread expression across various tumor types. However, the exact function of NSUN5 in ccRCC remains insufficiently understood. Data were collated from cohorts of ccRCC patients who underwent nephrectomy, including those from the Cancer Genome Atlas (TCGA) and the Sun Yat-sen University Cancer Center (SYSUCC), to evaluate the clinical relevance of NSUN5. Integrative models based on NSUN5 expression were subsequently developed to predict the prognosis of ccRCC within the TCGA and SYSUCC cohorts. Furthermore, the impact of NSUN5 on RCC cells and its association with cellular senescence were corroborated through in vitro experimental analyses. NSUN5 exhibited elevated expression in both ccRCC patients and renal cancer cell lines, whose upregulation significantly correlated with age, tumor size, TNM stage, WHO/International Society of Urological Pathology (ISUP) grade, presence of necrosis, and a poor prognosis. An accessible nomogram, incorporating NSUN5 along with various clinicopathological parameters, was adept at predicting outcomes for ccRCC patients. Additionally, in vitro findings indicated that reduced expression of NSUN5 enhanced tumor cell senescence and simultaneously inhibiting cell proliferation and migration. These observations suggest that elevated NSUN5 expression is linked to poorer overall survival (OS) and progression-free survival (PFS), positioning NSUN5 as a viable diagnostic and prognostic biomarker in ccRCC.

UK guidelines for the management of bone sarcomas.

This document is an update of the British Sarcoma Group guidelines (2016) and provides a reference standard for the clinical care of UK patients with primary malignant bone tumours (PMBT) and giant cell tumours (GCTB) of bone. The guidelines recommend treatments that are effective and should be available in the UK, and support decisions about management and service delivery. The document represents a consensus amongst British Sarcoma Group members in 2024. Key recommendations are that bone pain, or a palpable mass should always lead to further investigation and that patients with clinical or radiological findings suggestive of a primary bone tumour at any anatomic site should be referred to a specialist centre and managed by an accredited bone sarcoma multidisciplinary team. Treatment recommendations are provided for the major tumour types and for localised, metastatic and recurrent disease. Follow-up schedules are suggested.

The role and mechanism of “eight famous herbals in Zhejiang” in cancer via network pharmacology and experimental validation

In recent years, some components and active ingredients from the herbal formula “eight famous herbals in Zhejiang” (Zhe-Ba-Wei) have been reported to possess antitumor properties. However, there is still no systemic study on the role and mechanism of Zhe-Ba-Wei in cancer. To systematically investigate the anticancer efficacy of Zhe-Ba-Wei, we first identified 16 reported active ingredients with gene targets associated with various types of tumors. Second, we screened these active ingredients and their responding multiple shared targets by analyzing the convergence of diverse and tumor-specific target sites and identified four crucial active ingredients (ferulic acid, quercetin, rutin, luteolin), which were characterized by 27 overlapping gene targets. Third, these 27 gene targets were subsequently mapped onto the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology term, and among the 27 total potential targets, 12 were involved in plasma membrane function. Fourth, we investigated the binding affinities between the four crucial active ingredients and their potential targets such as EGFR and MET, both of which are well-known oncogenes in various cancers. Subsequently, an investigation of the computational ADMET properties showed that most of these four ingredients exhibited good ADMET properties. Finally, we found that three active ingredients (ferulic acid, luteolin, and quercetin) could inhibit the proliferation of NSCLC cells and decrease the protein expression of EGFR in a concentration-dependent manner. All these results shed light on the bioactive components, pharmacological effects, and drug development and utilization of Zhe-Ba-Wei, aiming to provide useful support for its further research and clinical application.

The Role of Small-Bowel Endoscopy in the Diagnosis and Management of Small-Bowel Neuroendocrine Tumours

Neuroendocrine tumours (NETs) are relatively rare neoplasms but represent one of the most frequent types of primary small-bowel tumours. Their incidence is rising, and this is most likely because of their more frequent early-stage detection, physician awareness, and increasing availability and use of imaging and small-bowel endoscopic techniques, such as video capsule endoscopy and device-assisted enteroscopy, which enable the detection, localisation, and histological sampling of previously inaccessible and underdiagnosed small-bowel lesions. This review summarises the role of small-bowel endoscopy in the diagnosis and management of small-bowel NETs to assist clinicians in their practice. Small-bowel endoscopy may play a complementary role in the diagnosis of these tumours alongside other diagnostic tests, such as biomarkers, conventional radiology, and functional imaging. In addition, small-bowel enteroscopy may play a role in the preoperative setting for the identification and marking of these tumours for surgical resection and the management of rare complications, such as small-bowel variceal bleeding, in cases of portal hypertension due to the encasement of mesenteric vessels in fibrotic small-bowel NETs.

The impact of 9-azaglycophymine and phenylguanidine derivatives on the proliferation of various breast cancer cell lines in vitro and in vivo.

Quinazolinones, particularly 9-azaglycophymines, and closely related derivatives and precursors were tested in vitro against various breast cancer cell lines representing the major types of breast tumors. Among the 49 compounds tested, azaglycophymine derivative 19 with an electron-withdrawing substituentdemonstrated the most significant anti-proliferative effects, with IC50 values of around 4µM. Extensive cell-based investigations revealed that compound 19 induced caspase-dependent apoptosis in HCC1937 (human TNBC), BT-474 (human HER2+/HR+), and 4T1 (mouse TNBC) cells. In contrast, in MDA-MB-468 (human TNBC) and MCF-7 (human HR+) cells, the cell death was induced via a non-apoptotic pathway. The in vivo efficacy of compound 19 was validated using a syngeneic orthotopic 4T1 model in BALB/c mice, resulting in significant reduction of 4T1 breast tumor growth upon intraperitoneal (i.p.) application of doses of 5 or 20mg/kg. These findings highlight the potential of compound 19 as a promising scaffold for the development of new therapeutic agents for various types of breast cancerand a first structure-activity insight.

Radiotherapy in patients with brain metastases with and without concomitant immunotherapy: comparison of patient outcome and neurotoxicity.

Recently, immune checkpoint inhibitors (ICI) have been added to the treatment of brain metastases. While combining radiotherapy and ICI can enhance therapeutic effects, it might also increase the risk of severe autoimmune adverse events. This retrospective study aims to compare treatment responses and neurotoxicity in patients treated with radiotherapy alone versus those receiving a combination of radiotherapy and ICI. All patients with brain metastases who received radiotherapy at Hannover Medical School from 2017 to 2019 were included. The medical reports of all study participants were evaluated. Patients who received radiotherapy alone and those who received a combination of radiation and ICI were compared. A total of 248 patients were analyzed, with the most common tumor types being non-small cell lung cancer (NSCLC) and malignant melanoma. Half of the patients received whole-brain radiotherapy (WBRT) and the other half stereotactic radiotherapy (SRT). Of these, 29 patients received concurrent immunotherapy and radiotherapy, 30 completed immunotherapy before radiotherapy, and 29 started ICI after completing radiotherapy. Two cases lacked information on the duration of immunotherapy. Overall survival post-initial tumor diagnosis within the total cohort was 52months, with significantly worse survival for patients with multiple brain metastases (p = 0.020). No significant differences in survival or incidence of neurological adverse events were observed between patients with or without ICI. Combining radiotherapy and ICI did not significantly increase neurotoxicity or improve survival in this cohort, though the heterogeneity of the subgroups limits the generalizability of these findings.

Next step of molecular pathology: next-generation sequencing in cytology

The evolving landscape of precision oncology underscores the pivotal shift from morphological diagnosis to treatment decisions driven by molecular profiling. Recent guidelines from the European Society for Medical Oncology recomend the use of next-generation sequencing (NGS) across a broader range of cancers, reflecting its superior efficiency and clinical value. NGS not only updates oncology testing by offering quicker, sample-friendly, and sensitive analysis but also reduces the need for multiple individual tests. Cytology samples, often obtained through less invasive methods, can yield high-quality genetic material suitable for molecular analysis. This article focuses on optimizing the use of cytology samples in NGS, and outlines their potential benefits in identifying actionable molecular alterations for targeted therapies across various solid tumors. It also addresses the need for validation studies and the strategies to incorporate or combine different types of samples into routine clinical practice. Integrating cytological and liquid biopsies into routine clinical practice, alongside conventional tissue biopsies, offers a comprehensive approach to tumor genotyping, early disease detection, and monitoring of therapeutic responses across various solid tumor types. For comprehensive biomarker characterization, all patient specimens, although limited, is always valuable.

Chondroblastic Osteosarcoma of the Mandible: An Uncommon Site for Osteosarcoma

Osteosarcoma is one of the most common types of malignant bone tumors, typically involving long bones such as the femur, tibia, and humerus. However, osteosarcomas occurring in the jaws are exceptionally rare, accounting for approximately 7% of all osteosarcoma cases and just 1% of malignancies in the head and neck region. This type of tumor usually affects individuals in their second and third decades of life. The subtypes of osteosarcoma include osteoblastic, chondroblastic, fibroblastic, small cell, and epithelioid. Chondroblastic osteosarcoma is associated with a poor prognosis, marked by a high recurrence rate, metastatic potential, and poor long-term survival outcomes. Here, we present the case of a 65-year-old woman with a painless swelling over the left cheek for 1 year, which significantly increased in size over the past 3 months, accompanied by trismus, reduced oral intake, and weight loss. Examination revealed a non-tender, hard swelling on the left cheek measuring 20x20cm, with prominent dilated veins. The left external auditory canal was collapsed due to the mass effect. Histopathological examination resulted as chondroblastic osteosarcoma of the left mandible. Computer tomography showed a large lobulated enhancing mass occupying the left cheek, associated with bone erosion and an aggressive periosteal reaction resembling a 'sunburst' pattern involving the ramus extending to the angle of the left mandible. The patient undergone open tracheostomy, left temporary tarsorrhaphy, wide local excision of tumor, left hemimandibulectomy, left partial maxillectomy and anterolateral thigh free flap reconstruction as patient unable to tolerate neoadjuvant chemotherapy.

Malignancy risk in diabetes; A population study based on electronic health records

Objective: To document the risk of the most common types of malignancies in people with diabetes compared to the people without diabetes. Methods: The data source of this study is the national electronic health records system of Turkey (e-Nabız). We analysed only the data of people over 14 years old in 2019. All the people with ICD-O-3 codes recorded for the first time in 2019 were accepted as new tumour cases. Tumours with /3 behaviour codes were accepted as malignant. Results: We detected 6,775,054 (10.6%) people with diabetes and 57,167,598 people without diabetes in our database. There were 63,696 new malignant cases in the group with diabetes and 123,662 new malignant cases in the group without diabetes. The total number of malignant tumours was 187,358. All types of major tumours seem to have increased risk. Pancreas cancer has the highest OR (odds ratio), 4.02 (3.71-4.36, 95% confidence interval), and larynx cancer has the lowest OR, 1.29 (1.19-1.41). OR for the presence of any malignancy in a person with diabetes is 1.87 (1.85-1.89). Conclusion: All major types of malignant tumours have an increased incidence in people with diabetes. The results confirm the presence of a relationship between diabetes and malignancy.

Single-cell transcriptomic landscape deciphers olfactory neuroblastoma subtypes and intra-tumoral heterogeneity.

Olfactory neuroblastoma (ONB) is a rare malignancy known to originate from the olfactory epithelium. The complex tumor ecosystem of this pathology remains unclear. Here, we explored the cellular components within ten ONB tumors and one olfactory mucosa sample based on single-cell RNA profiles. We showed the intra-tumoral heterogeneity by identifying five unique expression programs among malignant epithelial cells. A distinct three-classification system (neural, basal, mesenchymal) for ONB was established according to the distinguished gene expression patterns. Biomarkers for categorizing bulk tumors into uncharacterized subtypes were elucidated. Different responses towards certain chemotherapy regimens could be cautiously inferred according to the molecular features representing the three tumor types, thus helping with precision chemotherapy. We also analyzed subclusters of the tumor microenvironment (TME) and the interactions among different cell types within the TME. The relative abundance of immunosuppressive tumor-associated macrophages suggests potential benefits of immunotherapies targeting macrophages.

Abstract I004: Systematic Discovery and Annotation of Cancer Emergent Orphan non-coding RNAs in human Cancers

Abstract We recently described orphan non-coding RNAs (oncRNAs) as a class of cancer-specific small RNAs with the potential to play functional roles in breast cancer progression1. Here, we report a systematic search to annotate and characterize cancer-emergent oncRNAs across 32 tumor types. We also leverage large-scale in vivo genetic screens in xenografted mice to functionally identify driver oncRNAs in multiple tumor types. We have not only discovered a large repertoire of oncRNAs, but also found that their presence and absence represent a digital molecular barcode that faithfully captures the types and subtypes of cancer. Importantly, we discovered that this molecular barcode is partially accessible from the cell-free space as some oncRNAs are secreted by cancer cells. In a large retrospective study across 192 breast cancer patients, we showed that oncRNAs can be reliably detected in the blood and that changes in the cell-free oncRNA burden captures both short-term and long-term clinical outcomes upon completion of a neoadjuvant chemotherapy regimen. Citation Format: Hani Goodarzi. Systematic Discovery and Annotation of Cancer Emergent Orphan non-coding RNAs in human Cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr I004.

Partial adrenalectomy by the posterior retroperitoneoscopic approach: A single institution series of 766 consecutive procedures.

Partial adrenalectomy (PA), as an alternative to total adrenalectomy in selected cases, allows for the preservation of adrenocortical function, especially in hereditary and/or bilateral diseases. In this study, we analyze our experience in posterior retroperitoneoscopic PA (PRPA) and its impact on adrenocortical function. From January 2010 to December 2023, 709 PRPAs were performed on 766 adrenal glands in a total of 697 patients (421F; 276M; and mean age 49.3±15.3). Patients suffered from all types of adrenal tumors (239 pheochromocytoma, 225 Conn's syndrome, 102 Cushing's syndrome (CS), 66 nonfunctioning adenomas, 38 adrenal metastases, and 27 others). Mean tumor size was 2.7±1.5cm. Bilateral disease occurred in 135 patients (60 pheochromocytoma, 19 Conn's syndrome, 32 CS, 2 nonfunctioning adenomas, 17 adrenal metastases, and 5 combined diseases). Mean operating time for unilateral operation was 39.2±17.2min. Minor postoperative complications were observed in 1.5% and major complications in 0.1%. The median hospital stay was 2days. In bilateral cases, 18 of 33 (54%) Cushing patients and nine of 102 (9%) non-Cushing patients received corticosteroid replacement therapy (CRT) early postoperatively. Long-term follow-up data were collected for 242 patients (35%). After unilateral surgery, only patients with CS required CRT (8/24). Eleven (24.4%) out of 45 patients with bilateral non-Cushing disease needed CRT. Eight patients (3%) developed ipsilateral recurrent disease. PRPA is a safe procedure with a low complication and recurrence rate. This makes it the preferred operation in cases of bilateral disease and for selected patients with benign pathologies.

Identification of Non-Coding RNA Biomarkers in Non-Small Cell Lung Cancer to Address Racial Disparities.

Lung cancer significantly impacts mortality, with African Americans (AAs) showing higher rates than White Americans (WAs). Noncoding RNAs (ncRNAs) play a crucial role in lung tumorigenesis. To identify ncRNA biomarkers associated with racial disparities in lung cancer, we used droplet digital PCR to examine 93 lung cancer-associated ncRNAs in plasma and sputum samples from participants with AA and WA, including 118 patients and 92 cancer-free smokers. In the AA population, plasma showed differential expression of ten ncRNAs, while sputum revealed four ncRNAs when comparing lung cancer patients to the control group. In the WA population, the plasma displayed 11 ncRNAs, and the sputum had five ncRNAs showing differential expression between lung cancer patients and the control group. For AAs, we identified a three-ncRNA panel (plasma miRs-147b, 324-3p, 422a) for diagnosing lung cancer in AAs with 86% sensitivity and 89% specificity. For WAs, a four-ncRNA panel comprising sputum miR-34a-5p and plasma miRs-103-3p, 126-3p, and 205-5p was developed, achieving 88% sensitivity and 87% specificity. These panels remained effective across various stages and types of lung tumors, and were validated in an independent cohort of 56 patients and 72 controls. Ethnicity-related ncRNA signatures hold promise as biomarkers for tackling racial disparities in patients with lung cancer.

Therapeutic potential of β-hydroxybutyrate in the management of pancreatic neoplasms: exploring novel diagnostic and treatment strategies.

Pancreatic neoplasm, a highly aggressive and often fatal cancer, poses challenges due to late detection and nonspecific symptoms. Therefore, both early diagnosis and appropriate therapeutic approaches are necessary to augment the condition of these patients. Cancer cells undergo metabolic deregulation, which enables their proliferation, survival, and invasion. As a result, it is crucial to focus on the metabolic pathways in prevalent cancers and explore treatment strategies that target these pathways to control tumor growth effectively. This is particularly relevant in cancers like pancreatic cancer, which undergo numerous metabolic alterations. The ketogenic regimen, characterized by low carbohydrate and protein contents and high-fat sources, does not involve caloric restriction. This allows for the induction of ketogenesis and an increase in ketone bodies, while insulin and glucose levels remain low even after meals. This unique metabolic state may influence the tumor microenvironment. Given the lack of unanimous agreement on the precise role and mechanism of the ketogenic diet, this review aims to clarify the diagnostic value and accuracy of ketone bodies in various types of pancreatic tumors and explore the potential anti-cancer effects of the ketogenic diet when used alone or in conjunction with chemotherapy, also to determine the potential of the ketogenic diet to be used as adjuvant therapy. The outcomes of this study are instrumental in enhancing our understanding of the benefits and drawbacks associated with employing this diet for the management and diagnosis of pancreatic cancer.

Abstract A005: APC mutations dysregulate alternative polyadenylation in cancer

Abstract Alternative polyadenylation (APA) affects most human genes and is recurrently dysregulated in cancers. However, the mechanistic origins of this dysregulation are incompletely understood. We completed an unbiased computational analysis of molecular regulators of poly(A) site selection across The Cancer Genome Atlas and identified that colorectal adenocarcinoma is distinct from all other cancer subtypes. We linked this distinction to the frequent presence of loss-of-function APC mutations in colorectal adenocarcinoma, which were strongly associated with expression of long 3′ UTRs relative to tumors lacking APC mutations. APC knockout similarly dysregulated APA in human colon organoids, and reduced APC expression was associated with APA dysregulation in tumor types lacking APC mutations. Building on previous work that identified APC as an RNA-binding protein that preferentially binds 3′ UTRs during mouse neurogenesis, we found that APC binding is most significantly enriched just upstream of proximal poly(A) sites within 3′ UTRs. Our results suggest that APC promotes proximal poly(A) site use and that APC loss contributes to pervasive APA dysregulation in human cancers. Citation Format: Austin M Gabel, Andrea E Belliville, James D Thomas, Jose Mario B Pineda, Robert K Bradley. APC mutations dysregulate alternative polyadenylation in cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A005.

Pan-cancer analysis of STAT3 indicates its potential prognostic value and correlation with immune cell infiltration in prostate cancer.

Targeting the STAT3 signaling pathway is a promising therapeutic approach for cancer patients. However, the association between STAT3 expression, the tumor immune microenvironment, and genetic variation remains unclear across human cancers, especially prostate cancer. We used R software and other tools to analyze pan-cancer and mutation data from publicly available databases statistically. A comprehensive investigation was performed to assess the genetic heterogeneity and clinical relevance of STAT3 in various malignancies, with a specific focus on its role in the immune landscape and prognostic significance in prostate cancer. The findings were validated through immunohistochemistry (IHC) and multiplex immunofluorescence (mIF). STAT3 expression is abnormal in the majority of cancer tissues, which is strongly correlated with these patients' prognosis. Eight measures of tumor heterogeneity and six measures of tumor stemness of multiple tumor types showed a strong correlation with STAT3 expression. Furthermore, in individuals with prostate cancer, STAT3 expression indicated the degree of immune cell infiltration and the advancement of the disease. IHC analysis revealed that STAT3 was down-regulated in prostate tumor tissues, while mIF analysis demonstrated that STAT3 signaling (p-STAT3) was extensively active in tumor tissues and positive lymph node tissues. STAT3 may serve as a valuable prognostic biomarker and therapeutic target across various cancers, with particular relevance to prostate cancer.