Key Oncogenic Pathways Research Articles

In Silico Analysis of Non-Conventional Oxidative Stress-Related Enzymes and Their Potential Relationship with Carcinogenesis

Carcinogenesis is driven by complex molecular events, often involving key enzymes that regulate oxidative stress (OS). While classical enzymes such as SOD, catalase, and GPx have been extensively studied, other, non-classical oxidative stress-related enzymes (OSRE) may play critical roles in cancer progression. We aimed to explore the role of OSRE involved in an OS scenario and to assess their potential contribution to carcinogenesis in some of the most prevalent cancer types. Through data mining and bioinformatic analysis of gene and protein expression and mutation data, we identified OSRE with altered expression and mutations across cancer types. Functional pathways involving EGFR, MT-ND, GST, PLCG2, PRDX6, SRC, and JAK2 were investigated. Our findings reveal that enzymes traditionally considered peripheral to OS play significant roles in tumor progression. Those OSRE may contribute to cancer initiation and progression, as well as be involved with cancer hallmarks, such as EMT and invasion, proliferation, and ROS production. In addition, enzymes like SRC and JAK2 were found to have dual roles in both promoting ROS generation and being modulated by OS. OSRE also interact with key oncogenic signaling pathways, including Wnt/β-catenin and JAK2/STAT3, linking them to cancer aggressiveness and therapeutic resistance. Future research should focus on translating these findings into clinical applications, including the development of novel inhibitors or drugs targeting these non-classical enzymes.

Advances in microRNAs as Emerging Biomarkers for Colorectal Cancer Early Detection and Diagnosis.

Colorectal cancer (CRC) remains the second most common cause of cancer-related mortality worldwide, necessitating advancements in early detection and innovative treatment strategies. MicroRNAs (miRNAs), small non-coding RNAs involved in gene regulation, have emerged as crucial players in the pathogenesis of CRC. This review synthesizes the latest findings on miRNA deregulated in precancerous lesions and in CRC. By examining the deregulation patterns of miRNAs across different stages of CRC development, this review highlights their potential as diagnostic tools. We specifically analyse the roles and diagnostic relevance of four miRNAs-miR-15b, miR-21, miR-31, and miR-146a-that consistently exhibit altered expression in CRC. The current knowledge of their role in key oncogenic pathways, drug resistance, and clinical relevance is discussed. Despite challenges posed by the heterogeneity of the research findings on miRNA deregulation and their role in CRC, integrating miRNA diagnostics into current screening methods holds promise for enhancing personalized medicine approaches. This review emphasizes the transformative potential of miRNAs in CRC diagnosis, paving the way for improved patient outcomes and novel therapeutic paradigms.

Penfluridol inhibits melanoma growth and metastasis through enhancing von Hippel‒Lindau tumor suppressor-mediated cancerous inhibitor of protein phosphatase 2A (CIP2A) degradation.

Melanoma's high metastatic potential, especially to the brain, poses significant challenges to patient survival. The blood‒brain barrier (BBB) is a major obstacle to the effective treatment of melanoma brain metastases. We screened antipsychotic drugs capable of crossing the BBB and identified penfluridol (PF) as the most active candidate. PF reduced melanoma cell viability and induced apoptosis. In animal models, PF effectively inhibited melanoma growth and metastasis to the lung and brain. Using immunoprecipitation combined with high-resolution mass spectrometry, and other techniques such as drug affinity responsive target stability, we identified CIP2A as a direct binding protein of PF. CIP2A is highly expressed in melanoma and its metastases, and is linked to poor prognosis. PF can restore Protein Phosphatase 2A activity by promoting CIP2A degradation, thereby inhibiting several key oncogenic pathways, including AKT and c-Myc. Additionally, von Hippel‒Lindau (VHL) is the endogenous E3 ligase for CIP2A, and PF enhances the interaction between VHL and CIP2A, promoting the ubiquitin‒proteasome degradation of CIP2A, thereby inhibiting melanoma growth and metastasis. Overall, this study not only suggests PF's potential in treating melanoma and its brain metastases but also highlights CIP2A degradation as a therapeutic strategy for melanoma.

Non-Coding RNA as a Biomarker in Lung Cancer.

Lung cancer remains one of the most prevalent and deadly cancers globally, with high mortality rates largely due to late-stage diagnosis, aggressive progression, and frequent recurrence. Despite advancements in diagnostic techniques and therapeutic interventions, the overall prognosis for lung cancer patients continues to be dismal. Emerging research has identified non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, and circular RNAs, as critical regulators of gene expression, significantly influencing cancer biology. These ncRNAs play pivotal roles in various aspects of lung cancer pathogenesis, including tumor initiation, progression, metastasis, and resistance to therapy. We provide a comprehensive analysis of the current understanding of ncRNAs in lung cancer, emphasizing their potential as biomarkers for early diagnosis, prognostication, and the prediction of the therapeutic response. We explore the biological functions of ncRNAs, their involvement in key oncogenic pathways, and the molecular mechanisms by which they modulate gene expression and cellular processes in lung cancer. Furthermore, this review highlights recent advances in ncRNA-based diagnostic tools and therapeutic strategies, such as miRNA mimics and inhibitors, lncRNA-targeted therapies, and circRNA-modulating approaches, offering promising avenues for personalized medicine. Finally, we discuss the challenges and future directions in ncRNA research, including the need for large-scale validation studies and the development of efficient delivery systems for ncRNA-based therapies. This review underscores the potential of ncRNAs to revolutionize lung cancer management by providing novel diagnostic and therapeutic options that could improve patient outcomes.

Interlinking Human-Derived Leukemia Cells with Clinicopathological Therapeutics: Exploring Capsaicin's Anti-Cancer Mechanisms/potential for Leukemia Patients

Capsaicin, a bioactive compound isolated from chilli peppers, comes out as a potential agent for its anti-proliferation role in leukemia patients’ therapy. Objectives: This systematic review describes the Clinicopathological therapeutic potential of capsaicin against leukemia emphasizing the mechanism by which it inhibits growth through apoptosis, the cell cycle, and regulation of oncogenic signalling pathways in human-derived leukemia cell lines. Methods: According to PRISMA guidelines, the 75 studies were obtained from the various databases January 2013 and April 2024; Semantic Scholar, Google Scholar, PubMed as well as Frontiers and Link Springer. 50% (38) of the articles were taken from Semantic Scholar, 30% (22) from Google Scholar and 20% (15) from other search engines including PubMed and Link Springer. The papers included the inclusion criteria of PRISMA based on demographics, key outcomes and Anti-Cancer mechanisms majorly. Results: Capsaicin research published in America, Europe, Asia and Africa proves that it regulates vital processes at the cellular level including production of ROS, inhibition of NF-κB, STAT3, MAPK and cellular apoptosis. As human-derived cell lines are playing a pivotal role in cancer therapy, silicon methodologies along with in-vitro and in-vivo verification also shed more light on the improvement by capsaicin of the effectiveness of standard chemotherapeutic agents in combination with preferential killing of leukemic cells. Conclusions: Significantly, there were low levels of cytotoxicity of capsaicin to normal peripheral blood hematopoietic cells indicating that the compound is safe to use inhibiting the key oncogenic pathways and enhancing the efficacy of existing chemotherapeutic agents makes it a promising candidate for future therapeutic development.

Xanthine negatively regulates c-MYC through the PI3K/AKT signaling pathway and inhibits the proliferation, invasion, and migration of breast cancer cells.

Breast cancer is a prevalent and aggressive malignancy associated with elevated mortality rates worldwide. Dysregulation of the c-MYC oncogene and aberrant activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway are common features in breast cancer progression, rendering them attractive therapeutic targets. Here, we assessed the effects of the plant derivative, xanthine, on breast cancer cells and explored the molecular mechanisms underlying its activity. Breast cancer cell lines were treated with xanthine, followed by assessment of c-MYC expression levels. Cell proliferation, invasion, and migration were analyzed to assess the effects of xanthine treatment on breast cancer cell behavior. Xanthine treatment induced a decrease in c-MYC expression, resulting in significant inhibition of breast cancer cell proliferation, invasion, and migration. Mechanistic investigations revealed that these effects were mediated by suppression of the PI3K/AKT signaling pathway. Xanthine shows great potential for breast cancer treatment by targeting c-MYC via the PI3K/AKT signaling pathway. Our findings indicate that development of xanthine as a novel treatment option for breast cancer, which acts by influencing key oncogenic pathways involved in tumor progression, may be warranted.

Development and Characterization of Syngeneic Orthotopic Transplant Models of Obesity-Responsive Triple-Negative Breast Cancer in C57BL/6J Mice.

Obesity is an established risk and progression factor for triple-negative breast cancer (TNBC), but preclinical studies to delineate the mechanisms underlying the obesity-TNBC link as well as strategies to break that link are constrained by the lack of tumor models syngeneic to obesity-prone mouse strains. C3(1)/SV40 T-antigen (C3-TAg) transgenic mice on an FVB genetic background develop tumors with molecular and pathologic features that closely resemble human TNBC, but FVB mice are resistant to diet-induced obesity (DIO). Herein, we sought to develop transplantable C3-TAg cell lines syngeneic to C57BL/6 mice, an inbred mouse strain that is sensitive to DIO. We backcrossed FVB-Tg(C3-1-TAg)cJeg/JegJ to C57BL/6 mice for ten generations, and spontaneous tumors from those mice were excised and used to generate four clonal cell lines (B6TAg1.02, B6TAg2.03, B6TAg2.10, and B6TAg2.51). We characterized the growth of the four cell lines in both lean and DIO C57BL/6J female mice and performed transcriptomic profiling. Each cell line was readily tumorigenic and had transcriptional profiles that clustered as claudin-low, yet markedly differed from each other in their rate of tumor progression and transcriptomic signatures for key metabolic, immune, and oncogenic signaling pathways. DIO accelerated tumor growth of orthotopically transplanted B6TAg1.02, B6TAg2.03, and B6TAg2.51 cells. Thus, the B6TAg cell lines described herein offer promising and diverse new models to augment the study of DIO-associated TNBC.

Somatic Mutation Profile as a Predictor of Treatment Response and Survival in Unresectable Pancreatic Ductal Adenocarcinoma Treated with FOLFIRINOX and Gemcitabine Nab-Paclitaxel.

(1) Background: Pancreatic ductal adenocarcinoma (PDAC) has low survival rates despite treatment advancements. Aim: This study aims to show how molecular profiling could possibly guide personalized treatment strategies, which may help improve survival outcomes in patients with PDAC. (2) Materials and Methods: A retrospective analysis of 142 PDAC patients from a single academic center was conducted. Patients underwent chemotherapy and next-generation sequencing for molecular profiling. Key oncogenic pathways were identified using the Reactome pathway database. Survival analysis was performed using Kaplan-Meier curves and Cox Proportional Hazards Regression. (3) Results: Patients mainly received FOLFIRINOX (n = 62) or gemcitabine nab-paclitaxel (n = 62) as initial chemotherapy. The median OS was 13.6 months. Longer median OS was noted in patients with NOTCH (15 vs. 12.3 months, p = 0.007) and KIT pathway mutations (21.3 vs. 12.12 months, p = 0.04). Combinatorial pathway analysis indicated potential synergistic effects on survival. In the PFS, PI3K pathway (6.6 vs. 5.7 months, p = 0.03) and KIT pathway (10.3 vs. 6.2 months, p = 0.03) mutations correlated with improved PFS within the gemcitabine nab-paclitaxel subgroup. (4) Conclusions: Molecular profiling could play a role in PDAC for predicting outcomes and responses to therapies like FOLFIRINOX and gemcitabine nab-paclitaxel. Integrating genomic data into clinical decision-making can benefit PDAC treatment, though further validation is needed to fully utilize precision oncology in PDAC management.

The Prognostic and Therapeutic Potential of Fragile X Mental Retardation 1 (FMR1) Gene Expression in Prostate Adenocarcinoma: Insights into Survival Outcomes and Oncogenic Pathway Modulation.

Prostate adenocarcinoma (PRAD) is the second most common tumor associated with death. The role and mechanisms of the fragile X mental retardation 1 (FMR1) gene in PRAD remain unknown. We conducted an analysis of FMR1 expression in PRAD to determine its prognostic importance and connection to carcinogenic pathways such as PI3K_AKT_mTOR. Survival analyses were utilized to establish a correlation between FMR1 expression and patient outcomes. We used the integration of genomic data with bioinformatic predictions to predict the regulatory factors of the FMR1 gene in PRAD. Our data revealed that individuals with higher levels of FMR1 expression experience worse survival outcomes compared to those with lower expression (hazard ratio [HR] = 5.08, 95% confidence interval [CI] = 1.07 - 24, p = 0.0412). FMR1 expression was significantly higher in patients with advanced pathological tumor stages, particularly in the pT3 and pT4 combined stages and the pN1 nodal stage. Furthermore, patients with high Gleason scores (GSs) (combined GSs 8 and 9) exhibited increased levels of FMR1 expression. Our results further identify a possible regulatory link between FMR1 and key oncogenic pathways, including PI3K_AKT_mTOR, and predict the possible mechanism by which FMR1 is regulated in PRAD. Our data suggest that the FMR1 gene could serve as a biomarker for PRAD progression. However, in-depth investigations, including those with large patient samples and in vitro studies, are needed to validate this finding and understand the mechanisms involved.

MLIP and Its Potential Influence on Key Oncogenic Pathways.

Muscle-enriched A-type lamin-interacting protein (MLIP) is an emerging protein involved in cellular homeostasis and stress adaptation. Eukaryotic cells regulate various cellular processes, including metabolism, DNA repair, and cell cycle progression, to maintain cellular homeostasis. Disruptions in this homeostasis can lead to diseases such as cancer, characterized by uncontrolled cell growth and division. This review aims to explore for the first time the unique role MLIP may play in cancer development and progression, given its interactions with the PI3K/Akt/mTOR pathway, p53, MAPK9, and FOXO transcription factors, all critical regulators of cellular homeostasis and tumor suppression. We discuss the current understanding of MLIP's involvement in pro-survival pathways and its potential implications in cancer cells' metabolic remodeling and dysregulated homeostasis. Additionally, we examine the potential of MLIP as a novel therapeutic target for cancer treatment. This review aims to shed light on MLIP's potential impact on cancer biology and contribute to developing innovative therapeutic strategies.

Population Pharmacokinetics, Pharmacodynamics and Safety Properties of Trametinib in Dogs With Cancer: A Phase I Dose Escalating Clinical Trial.

MAPK has been reported as a key oncogenic pathway for canine histiocytic sarcoma, which can be pharmacologically targeted with trametinib, a small inhibitor of MEK1/2. Preliminary data showed promising antitumor activity in in vitro and in vivo models and represented a proof of concept to translate the findings from bench to bedside. In this phase I, dose escalating study using a 3 + 3 cohort design, trametinib was evaluated in 18 dogs with cancer. Adverse events were graded according to VCOG-CTCAE v2. Blood samples and tumour biopsies were collected for pharmacokinetic and pharmacodynamic assessment. Trametinib was well tolerated with a maximum tolerated dose of 0.5 mg/m2/day, PO. Dose-limiting toxicities included systemic hypertension, proteinuria, lethargy and elevated ALP, and were all Grade 3. The drug exposures increased more than linearly with dose since the elimination of trametinib was saturable. At a dose of 500 μg Q24h (0.5 mg/m2/day in a 30 kg dog), approximately 70% of dogs had an average steady-state concentration of 10 ng/mL, achieved after approximately 2 weeks. This threshold was associated with clinical efficacy in humans. Target engagement was not observed in biospecimens collected on Days 0 and 7. In conclusion, trametinib was considered safe in dogs with cancer, and the dose of 0.5 mg/m2/day was the recommended dose for phase II studies.

The Protective Role of miR-125b in Hepatocellular Carcinoma: Unraveling Tumor-Suppressive Mechanisms

Abstract: MicroRNAs (miRNAs) have emerged as crucial regulators of gene expression, playing pivotal roles in various biological processes, including cancer development and progression. Among them, miR-125b has garnered significant attention due to its multifaceted functional roles in human hepatocellular carcinoma (HCC). Extensive research has revealed that miR-125b plays a dual role in HCC, acting as both a tumor suppressor and an oncogene, depending on the context. As a tumor suppressor, miR-125b inhibits HCC by targeting key oncogenic pathways and genes involved in cell proliferation, migration, invasion, and angiogenesis. Its downregulation in HCC is frequently observed and correlates with aggressive tumor characteristics and poor prognosis. Conversely, miR-125b can also function as an oncogene in specific HCC subtypes or under certain conditions. It has been shown to promote HCC growth, metastasis, and therapeutic resistance by targeting tumor suppressor genes, modulating the epithelial-mesenchymal transition (EMT) process, and enhancing cancer stem cell-like properties. The upregulation of miR-125b in HCC has been associated with advanced disease stages and unfavorable clinical outcomes. Furthermore, a complex network of regulatory mechanisms influences the dysregulation of miR-125b expression in HCC. Understanding these regulatory mechanisms is crucial for deciphering the precise functional roles of miR-125b in HCC and exploring its potential as a diagnostic biomarker or therapeutic target. In the current review study, we comprehensively elucidated the diverse functional roles of miR-125b in HCC, providing a comprehensive overview of its regulatory mechanisms and impact on key cellular processes involved in HCC progression.

Drug Repurposing: Exploring Potential Anti-Cancer Strategies by Targeting Cancer Signalling Pathways.

The repurposing of previously clinically approved drugs as an alternative therapeutic approach to treating disease has gained significant attention in recent years. A multitude of studies have demonstrated various and successful therapeutic interventions with these drugs in a wide range of neoplastic diseases, including multiple myeloma, leukaemia, glioblastoma, and colon cancer. Drug repurposing has been widely encouraged due to the known efficacy, safety, and convenience of already established drugs, allowing the bypass of the long and difficult road of lead optimization and drug development. Repurposing drugs in cancer therapy is an exciting prospect due to the ability of these drugs to successfully target cancer-associated genes, often dysregulated in oncogenic signalling pathways, amongst which are the classical cancer signalling pathways; WNT (wingless-related integration type) and Hippo signalling. These pathways play a fundamental role in controlling organ size, tissue homeostasis, cell proliferation, and apoptosis, all hallmarks of cancer initiation and progression. Prolonged dysregulation of these pathways has been found to promote uncontrolled cellular growth and malignant transformation, contributing to carcinogenesis and ultimately leading to malignancy. However, the translation of cancer signalling pathways and potential targeted therapies in cancer treatment faces ongoing challenges due to the pleiotropic nature of cancer cells, contributing to resistance and an increased rate of incomplete remission in patients. This review provides analyses of a range of potential anti-cancer compounds in drug repurposing. It unravels the current understanding of the molecular rationale for repurposing these drugs and their potential for targeting key oncogenic signalling pathways.

The impact of ribosome biogenesis in cancer: from proliferation to metastasis.

The dysregulation of ribosome biogenesis is a hallmark of cancer, facilitating the adaptation to altered translational demands essential for various aspects of tumor progression. This review explores the intricate interplay between ribosome biogenesis and cancer development, highlighting dynamic regulation orchestrated by key oncogenic signaling pathways. Recent studies reveal the multifaceted roles of ribosomes, extending beyond protein factories to include regulatory functions in mRNA translation. Dysregulated ribosome biogenesis not only hampers precise control of global protein production and proliferation but also influences processes such as the maintenance of stem cell-like properties and epithelial-mesenchymal transition, contributing to cancer progression. Interference with ribosome biogenesis, notably through RNA Pol I inhibition, elicits a stress response marked by nucleolar integrity loss, and subsequent G1-cell cycle arrest or cell death. These findings suggest that cancer cells may rely on heightened RNA Pol I transcription, rendering ribosomal RNA synthesis a potential therapeutic vulnerability. The review further explores targeting ribosome biogenesis vulnerabilities as a promising strategy to disrupt global ribosome production, presenting therapeutic opportunities for cancer treatment.

Abstract CT040: First-in-human dose-expansion study of NBF-006, a novel investigational siRNA targeting GSTP, in patients with KRAS-mutated non-small cell lung cancer

Abstract Background Glutathione S-transferase Pi (GSTP) has a role in detoxification and anti-oxidative damage response. Additionally, GSTP has a chaperone function which regulates key oncogenic pathways such as the KRAS and JNK. Since redundant pathways could compensate for the inhibition of a single kinase, targeting multiple pathways may lead to more effective therapy. NBF-006 is a novel drug product comprised of GSTP siRNA encapsulated within a proprietary lipid nanoparticle. It is designed to deliver siRNA to localized and metastatic lung tumors. As GSTP downregulation leads to inhibition of KRAS signaling through modulation of both MAPK and PI3K pathways, NBF-006 is being developed to treat KRAS mutant tumors. NBF-006-001 is a first-in-human dose escalation and expansion study evaluating safety, tolerability, PK, and preliminary efficacy of NBF-006 administered intravenously. The dose escalation phase enrolled 21 patients with advanced non-small cell lung cancer (NSCLC), pancreatic, or colorectal cancer. No DLTs or treatment-related SAEs were observed. NSCLC disease control rate of 55% (6/11) was observed in heavily pre-treated patient population, warranting further investigations. Final results from the dose escalation and expansion of NBF-006-001 are reported here. Results Thirty-eight NSCLC patients, with or without KRAS mutation, received treatment at 0.3 mg/kg [n=1], 0.6 mg/kg [n=12], 1.2 mg/kg [n=14], or 1.6 mg/kg [n=11]. NBF-006 was well tolerated with no treatment-related grade 4-5 AEs, SAEs, or DLTs. Two grade 3 events were assessed as possibly related to study treatment, anemia and bilateral pleural effusions (both at 0.6 mg/kg). The most common NBF-006-related AEs were Grade 1 or 2 infusion related reactions (IRRs) (18 %) and nausea (11 %). IRRs (n=8 in seven patients), occurred in the first cycle and were well-managed. One patient discontinued due to recurring IRR. Cytokine elevation was only noted in this patient. No clinically meaningful complement activation nor ADA response has been observed. Linear PK (t1/2 ~41 hrs) was observed with dose proportional increases up to 1.6 mg/kg without exposure accumulation or reduction after repeat doses. GSTP mRNA knock-down in PBMCs was statistically significant at 1.2 and 1.6 mg/kg dose levels. Patients had received 1-7 prior lines of therapy (1 line [n=10], 2 lines [n=10], and ≥ 3 lines [n=16] respectively). Two patients (1.2 and 1.6 mg/kg) experienced a durable PR, 17 patients experienced SD. The disease control rate is 19/38 (59%). Patient enrichment strategies were evaluated with interesting trends observed. Conclusion NBF-006 is well tolerated up to 1.6 mg/kg dose level for over a year with early signs of efficacy in heavily pre-treated pan-KRAS mutant NSCLC patients. The results suggest that further clinical development of NBF-006, alone or in combination with standard therapy, is warranted. Citation Format: Lyudmila Bazhenova, Hirva Mamdani, Alberto Chiappori, Alexander Spira, Wade Iams, Anthony Tolcher, Minal Barve, Afshin Gabayan, Andrae Vandross, Cima Cina, Yael Cohen-Arazi, Zachary Albaugh, Annie Huynh, Joachim Gullbo, Sonya Zabludoff. First-in-human dose-expansion study of NBF-006, a novel investigational siRNA targeting GSTP, in patients with KRAS-mutated non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT040.

Investigating diagnostic, Prognostic, and therapeutic role of Long Non-Coding RNA MALAT1 in Breast Carcinoma:<i> in silico</i> study

Background: Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) is a nuclear-enriched long non-coding RNA, implicated in the tumorigenesis of various cancers, including breast carcinoma (BC). It is associated with cancer proliferation, invasion, migration, and metastasis, and plays a role in immune system modulation. Aims and Objectives: This in silico study investigates MALAT1's diagnostic, prognostic, and therapeutic potential in BC. It examines MALAT1's differential expression in Breast Cancer (BC) versus normal tissues, its impact on patient survival, and its interaction with miR-561 affecting TOP2A mRNA degradation. Methodology: Using publicly available datasets from GEO and TCGA, we conducted differential expression, survival, and prognostic analyses, along with network and pathway studies and drug repurposing analyzes and Tools like Graph Pad Prism and GEPIA data set was used for demographics. Results: Our analyzes indicate overexpression of MALAT1 in BC tissues, its correlation with poorer survival rates, and involvement in key oncogenic pathways. Additionally, drug repurposing analyzes have identified potential MALAT1-targeted therapeutic strategies. Conclusion: MALAT1 serves as a significant biomarker for BC diagnosis and prognosis and is identified as a potential therapeutic target. This study lays the groundwork for future research into MALAT1-targeted therapies in BC

Abstract 4931: The Cancer Proteome Atlas: Expanded datasets and empowered with an AI-driven chatbot

Abstract Reverse-phase protein arrays (RPPAs) represent a powerful functional proteomic approach to elucidate cancer-related molecular mechanisms and develop novel cancer therapies. To facilitate community-based investigation of the large-scale protein expression data generated by this platform, we have developed a user-friendly, open-access bioinformatic resource, The Cancer Proteome Atlas (TCPA, http://tcpaportal.org), which contains several applications. The first one focuses on RPPA data of patient tumors, which contains >8,000 samples of 32 cancer types from The Cancer Genome Atlas (TCGA) and other independent patient cohorts. The second application focuses on the RPPA data of >1,500 cancer cell lines with publicly available, high-quality DNA, RNA and drug screening data. The third one focuses on perturbed RPPA profiles of >14,000 samples given drug treatments. We recently expanded our RPPA protein set from 200 to 500 proteins Importantly, this highly selected set is enriched in therapeutic targets and biomarkers and covers key oncogenic pathways such as PI3K/AKT, RAS/MAPK, Src/FAK, TGFβ/SMAD, JAK/STAT, epithelial-mesenchymal transition, DNA damage repair, Hippo, Notch, cell cycle, apoptosis, and immune-oncology. Using this upgraded RPPA platform, we generated an harmonized, expanded RPPA dataset of 8000 TCGA patient samples and 1000 CCLE cell line samples. To further address the informatic challenges of analyzing such large, diverse datasets, in addition to the GUI interfaces, we recently developed a chatbot through which users can analyze the RPPA data through human nature languages and obtain the results and related analytic reports without a learning curve. Such a chatbot empowers a broad research community to explore high-quality RPPA datasets and generate testable hypotheses in an effective and intuitive manner, representing the direction of next-generation data analytics. Citation Format: Han Liang, Wei Liu, Jun Li, Yitao Tang. The Cancer Proteome Atlas: Expanded datasets and empowered with an AI-driven chatbot [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 4931.

Key oncogenic signaling pathways affecting tumor-infiltrating lymphocytes infiltration in hepatocellular carcinoma: basic principles and recent advances.

The incidence of hepatocellular carcinoma (HCC) ranks first among primary liver cancers, and its mortality rate exhibits a consistent annual increase. The treatment of HCC has witnessed a significant surge in recent years, with the emergence of targeted immune therapy as an adjunct to early surgical resection. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has shown promising results in other types of solid tumors. This article aims to provide a comprehensive overview of the intricate interactions between different types of TILs and their impact on HCC, elucidate strategies for targeting neoantigens through TILs, and address the challenges encountered in TIL therapies along with potential solutions. Furthermore, this article specifically examines the impact of oncogenic signaling pathways activation within the HCC tumor microenvironment on the infiltration dynamics of TILs. Additionally, a concise overview is provided regarding TIL preparation techniques and an update on clinical trials investigating TIL-based immunotherapy in solid tumors.

Hyperthermia in Combination with Emerging Targeted and Immunotherapies as a New Approach in Cancer Treatment

Despite significant advancements in the development of novel therapies, cancer continues to stand as a prominent global cause of death. In many cases, the cornerstone of standard-of-care therapy consists of chemotherapy (CT), radiotherapy (RT), or a combination of both. Notably, hyperthermia (HT), which has been in clinical use in the last four decades, has proven to enhance the effectiveness of CT and RT, owing to its recognized potency as a sensitizer. Furthermore, HT exerts effects on all steps of the cancer–immunity cycle and exerts a significant impact on key oncogenic pathways. Most recently, there has been a noticeable expansion of cancer research related to treatment options involving immunotherapy (IT) and targeted therapy (TT), a trend also visible in the research and development pipelines of pharmaceutical companies. However, the potential results arising from the combination of these innovative therapeutic approaches with HT remain largely unexplored. Therefore, this review aims to explore the oncology pipelines of major pharmaceutical companies, with the primary objective of identifying the principal targets of forthcoming therapies that have the potential to be advantageous for patients by specifically targeting molecular pathways involved in HT. The ultimate goal of this review is to pave the way for future research initiatives and clinical trials that harness the synergy between emerging IT and TT medications when used in conjunction with HT.

Therapeutic Opportunities in Breast Cancer by Targeting Macrophage Migration Inhibitory Factor as a Pleiotropic Cytokine.

As a heterogeneous disease, breast cancer (BC) has been characterized by the uncontrolled proliferation of mammary epithelial cells. The tumor microenvironment (TME) also contains inflammatory cells, fibroblasts, the extracellular matrix (ECM), and soluble factors that all promote BC progression. In this sense, the macrophage migration inhibitory factor (MIF), a pleiotropic pro-inflammatory cytokine and an upstream regulator of the immune response, enhances breast tumorigenesis through escalating cancer cell proliferation, survival, angiogenesis, invasion, metastasis, and stemness, which then brings tumorigenic effects by activating key oncogenic signaling pathways and inducing immunosuppression. Against this background, this review was to summarize the current understanding of the MIF pathogenic mechanisms in cancer, particularly BC, and address the central role of this immunoregulatory cytokine in signaling pathways and breast tumorigenesis. Furthermore, different inhibitors, such as small molecules as well as antibodies (Abs) or small interfering RNA (siRNA) and their anti-tumor effects in BC studies were examined. Small molecules and other therapy target MIF. Considering MIF as a promising therapeutic target, further clinical evaluation of MIF-targeted agents in patients with BC was warranted.