Drugs For Treatment Of Cancer Research Articles

Exploring Anticancer Potential: Synthesis and Assessment of the Biological Activity of Novel Synthesized Pyrazinoic Acid Derivatives

AbstractOne of the most effective approaches to discovering novel drugs for cancer treatment involves the exploration of new synthetic compounds. The pyrazinoic acid or pyrazine‐2‐carboxylic acid (PA)‐derivative compounds can be explored as a new anticancer agent due to their nitrogenous heteroaromatic ring. In this study, ten novels PA derivatives were synthesized by Ugi multicomponent reaction and characterized using IR, NMR, and mass spectroscopy. The cytotoxic activity was assayed in three different cancer cell lines, including colon (HT‐29), lung (A549), and breast (MCF‐7). The U10 was the most potent compound, exhibiting moderate cytotoxicity with IC50 of 8.26 μM, 8.23 μM, and 22.58 μM against HT‐29, A549, and MCF‐7 cell lines, respectively. In addition, the effect of U10 exposure in the MRC‐5 cell line as a non‐tumoral lung cell line showed a selectivity index of 3.76. The apoptotic activity and intracellular ROS level induction of U10 were assayed in MCF‐7 cells. The results demonstrated that apoptosis increases from 23.94 % at 10 μM to 36.8 % at 25 μM. Intracellular ROS level assay showed that U10 was able to significantly increase intracellular ROS by increasing the concentration. Molecular docking was utilized to predict the binding sites and interactions between the synthesized compound and DNA, as well as the Bcl‐2 apoptosis regulator.

Beneficial Effects of Oral Carbon Monoxide on Doxorubicin-Induced Cardiotoxicity.

Doxorubicin and other anthracyclines are crucial cancer treatment drugs. However, they are associated with significant cardiotoxicity, severely affecting patient care and limiting dosage and usage. Previous studies have shown that low carbon monoxide (CO) concentrations protect against doxorubicin toxicity. However, traditional methods of CO delivery pose complex challenges for daily administration, such as dosing and toxicity. To address these challenges, we developed a novel oral liquid drug product containing CO (HBI-002) that can be easily self-administered by patients with cancer undergoing doxorubicin treatment, resulting in CO being delivered through the upper gastrointestinal tract. HBI-002 was tested in a murine model of doxorubicin cardiotoxicity in the presence and absence of lung or breast cancer. The mice received HBI-002 twice daily before doxorubicin administration and experienced increased carboxyhemoglobin levels from a baseline of ≈1% to 7%. Heart tissue from mice treated with HBI-002 had a 6.3-fold increase in CO concentrations and higher expression of the cytoprotective enzyme heme oxygenase-1 compared with placebo control. In both acute and chronic doxorubicin toxicity scenarios, HBI-002 protected the heart from cardiotoxic effects, including limiting tissue damage and cardiac dysfunction and improving survival. In addition, HBI-002 did not compromise the efficacy of doxorubicin in reducing tumor volume, but rather enhanced the sensitivity of breast 4T1 cancer cells to doxorubicin while simultaneously protecting cardiac function. These findings strongly support using HBI-002 as a cardioprotective agent that maintains the therapeutic benefits of doxorubicin cancer treatment while mitigating cardiac damage.

Abstract PO3-10-09: The allocation of US $2.6 billion in global funding for breast cancer research between 2016 – 2020: are we investing wisely for breast cancer patients?

Abstract Background: Breast cancer is a global health challenge and the highest incident cancer globally, with over 2 million new cases and 685,000 deaths in 2020, making it the highest incident cancer globally. Furthermore, it is the most prevalent cancer, resulting in the loss of more disability-adjusted life years than any other malignancy. Research is thus crucial to improving outcomes and reducing suffering for breast cancer patients worldwide. This study aimed to analyse global patterns of funding for breast cancer research. Methods: We have previously created a comprehensive database of awards for human cancer research in this period using publicly available data on research funding awards. From this database we extracted all awards relating to breast cancer research, and categorised these by cancer type, cross-cutting research theme and phase of research. Findings: We identified 7051 awards with a total investment of $2.6 billion in 2016-2020, representing 11.2% of all global public and philanthropic cancer research funding during this period. Breast cancer research funding fell year on year, from $773.4 million in 2016 to $243.8 million in 2020. The majority of the investment was in pre-clinical research ($1.9 billion, 73.9%), with clinical trials ($276 million, 10.7%) and public health ($269.2 million, 10.5%) receiving roughly equivalent amounts of funding. The USA accounted for 66.9% of all global breast cancer research investment, with China ($110.4 million, 4.3%) and the UK ($96.6 million, 3.8%) the next largest funders. By research theme, cancer biology research received most funding ($926.2 million, 37.5% of investment), with drug treatment the next best funded research area ($600.5 million, 23.4%), and diagnosis, screening and monitoring third ($396 million, 15.4%). Surgery ($65.2 million, 2.5%) and radiotherapy ($35.3 million, 1.4%) accounted for only a small proportion of research investment. There was minimal investment into breast cancer as a global health issue ($8.1 million, 0.3%). Research into metastatic disease received a greater proportion of investment in breast cancer than in the overall cancer portfolio (23.2% in breast cancer, $597.4 million, compared with 11.7% across all cancers). Conclusions: Breast cancer public and philanthropic research funding is largely invested in pre-clinical research in high-income countries, with the main areas of investment being cancer biology research and drug treatment. The direct benefit to patients from such research is likely to be low and only apparent after a substantial time lag (if at all). Despite their pivotal role in the treatment of the majority of breast cancer patients, surgery and radiotherapy research received a tiny proportion of the overall research investment. Furthermore, relatively little investment is directed towards cancer prevention and early detection, despite their acknowledged key role in cancer control globally. Finally, more equitable research funding is required to align with the global burden of breast cancer, with increased funding for low- and middle-income countries, which account for an increasing proportion of this burden. These data should be considered by funders and policymakers in the allocation of finite resources, which must be invested wisely. Citation Format: Stuart McIntosh, Ellen Copson, Ramsey Cutress, Michael Head. The allocation of US $2.6 billion in global funding for breast cancer research between 2016 – 2020: are we investing wisely for breast cancer patients? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-10-09.

A novel microfluidic chip integrated with Pt micro-thermometer for temperature measurement at the single-cell level

Noninvasive and sensitive thermometry of a single cell during the normal physiological process is crucial for analyzing fundamental cellular metabolism and applications to cancer treatment. However, current thermometers generally sense the average temperature variation for many cells, thereby failing to obtain real-time and continuous data of an individual cell. In this study, we employed platinum (Pt) electrodes to construct an integrated microfluidic chip as a single-cell thermometer. The single-cell isolation unit in the microchip consisted of a main channel, which was connected to the inlet and outlet of a single-cell capture funnel. A single cell can be trapped in the funnel and the remaining cells can bypass and flow along the main channel to the outlet. The best capture ratio of a single MCF7 cell at a single-cell isolation unit was 90 % under optimal condition. The thermometer in the micro-chip had a temperature resolution of 0.007 °C and showed a good linear relationship in the range of 20–40 °C (R2 = 0.9999). Slight temperature increment of different single tumor cell (MCF7 cell, H1975 cell, and HepG2 cell) cultured on the chip was continuously recorded under normal physiological condition. In addition, the temperature variation of single MCF7 cell in-situ after exposure to a stimulus (4 % paraformaldehyde treatment) was also monitored, showing an amplitude of temperature fluctuations gradually decreased over time. Taken together, this integrated microchip is a practical tool for detecting the change in the temperature of a single cell in real-time, thereby offering valuable information for the drug screening, diagnosis, and treatment of cancer.

Transcriptomic analysis revealed potential regulatory biomarkers and repurposable drugs for breast cancer treatment.

Breast cancer (BC) is the most widespread cancer worldwide. Over 2 million new cases of BC were identified in 2020 alone. Despite previous studies, the lack of specific biomarkers and signaling pathways implicated in BC impedes the development of potential therapeutic strategies. We employed several RNAseq datasets to extract differentially expressed genes (DEGs) based on the intersection of all datasets, followed by protein-protein interaction network construction. Using the shared DEGs, we also identified significant gene ontology (GO) and KEGG pathways to understand the signaling pathways involved in BC development. A molecular docking simulation was performed to explore potential interactions between proteins and drugs. The intersection of the four datasets resulted in 146 DEGs common, including AURKB, PLK1, TTK, UBE2C, CDCA8, KIF15, and CDC45 that are significant hub-proteins associated with breastcancer development. These genes are crucial in complement activation, mitotic cytokinesis, aging, and cancer development. We identified key microRNAs (i.e., hsa-miR-16-5p, hsa-miR-1-3p, hsa-miR-147a, hsa-miR-195-5p, and hsa-miR-155-5p) that are associated with aggressive tumor behavior and poor clinical outcomes in BC. Notable transcription factors (TFs) were FOXC1, GATA2, FOXL1, ZNF24 and NR2F6. These biomarkers are involved in regulating cancer cell proliferation, invasion, and migration. Finally, molecular docking suggested Hesperidin, 2-amino-isoxazolopyridines, and NMS-P715 as potential lead compounds against BC progression. We believe that these findings will provide important insight into the BC progression as well as potential biomarkers and drug candidates for therapeutic development.

Cytotoxic steroidal compounds, enriched fraction and extract of Trillium govanianum against HCT‐116 cell line

AbstractTrillium govanianum is a source of steroidal compounds and is used for the treatment of sexual disorders, dysentery, cancer, and inflammation. In the current investigation, steroidal compounds 1–5 (20‐hydroxyecdysone [1], pennogenin‐3‐O‐β‐chacotrioside [2], dioscin [3], trillin [4], diosgenin [5]) were isolated, including dioscin and trillin, as a new report from this species. Further, extract (TGE), steroids enriched fraction (TGEF) and 1–5 were evaluated for cytotoxicity against the HCT‐116 cell line. Cytotoxicity activity was found to be significant in samples and might be due to the generation of intracellular reactive oxygen species production. TGE and TGEF showed maximum inhibition (>92%) at 25 and 5 µg/mL in 72 h, while 2 and 3 showed better activity (>95%) at 5.65 and 11.51 µM in 72 h than the vinblastine drug (20 µM). Furthermore, the ultra‐performance liquid chromatography‐photo diode array method was validated for a determination of 1–5. Compounds 1–3, and 5 were quantified in TGE and TGEF while 4 was only identified. The findings revealed that activity of TGE and TGEF, might be due to compounds 2 (49.04 ± 2.22 and 77.40 ± 0.72 mg/g) and 3 (230.88 ± 7.07 and 584.67 ± 5.34 mg/g), respectively. The study also suggested that 2 and 3 can be a drug molecule as vinblastine while TGEF may be developed as a phytopharmaceutical drug for colon cancer treatment.

Evaluation of 1,10-phenanthroline-based hydroxamate derivative as dual histone deacetylases/ribonucleotide reductase inhibitor with antitumor activities.

Aberrant expression of histone deacetylases (HDACs) and ribonucleotide reductase (RR) enzymes are commonly observed in various cancers. Researchers are focusing on these enzymes in cancer studies with the aim of developing effective chemotherapeutic drugs for cancer treatment. Targeting both HDAC and RR simultaneously with a dual HDAC/RR inhibitor has exhibited enhanced effectiveness compared to monotherapy in cancer treatment, making it a promising strategy. The objective of the study is to synthesize and assess the anti-cancer properties of a 1,10-phenanthroline-based hydroxamate derivative, characterizing it as a novel dual HDAC/RR inhibitor. The N1-hydroxy-N8-(1,10-phenanthrolin-5-yl)octanediamide (PA), a 1,10-phenanthroline-based hydroxamate derivative, was synthesized and structurally characterized. The compound was subjected to in vitro assessments of its anti-cancer, HDAC, and RR inhibitory activities. In silico docking and molecular dynamics simulations were further studied to explore its interactions with HDACs and RRM2. The structurally confirmed PA exhibited antiproliferative activity in SiHa cells with an IC50 of 16.43μM. It displayed potent inhibitory activity against HDAC and RR with IC50 values of 10.80μM and 9.34μM, respectively. Co-inhibition of HDAC and RR resulted in apoptosis-induced cell death in SiHa cells, mediated by the accumulation of reactive oxygen species (ROS). In silico docking studies demonstrated that PA can effectively bind to the active sites of HDAC isoforms and RRM2. Furthermore, PA demonstrated a more favorable interaction with HDAC7, displaying a docking score of -9.633kcal/mol, as compared to the standard HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), which exhibited a docking score of -8.244kcal/mol against HDAC7. The present study emphasizes the prospect of designing a potential 1,10-phenanthroline hydroxamic acid derivative as a novel dual HDAC and RR-inhibiting anti-cancer molecule.

Potential JAK2 Inhibitors from Selected Natural Compounds: A Promising Approach for Complementary Therapy in Cancer Patients.

Janus-activated kinase 2 (JAK2) plays a pivotal role in numerous essential biological processes, including proliferation, apoptosis, and metastasis in human cells. Prior studies have indicated that inhibiting JAK2 could be a promising strategy to mitigate cell proliferation and induce apoptosis in tumor cells. This study aimed to estimate the binding affinity of 79 herbal compounds, comprising 46 flavonoids, 21 anthraquinones, and 12 cinnamic acids, to the ATP-binding cleft of JAK2 to identify potential herbal inhibitors of JAK2. The binding affinities between ligands and JAK2 were calculated utilizing AutoDock 4.0 software in conjunction with the Cygwin environment. Cross-validation was conducted using the Schrödinger tool. Molecular dynamics simulations were employed to evaluate the stability of docked poses for the most significant JAK2 inhibitors. Furthermore, the Discovery Studio Visualizer tool was utilized to elucidate interactions between the top-ranked JAK2 inhibitors and residues within the JAK2 ATP-binding site. Twelve flavonoids, two anthraquinones, and three cinnamic acids demonstrated substantial binding affinities to the protein kinase domain of the receptor, with a criterion of ΔGbinding < -10 kcal/mol. Among the studied flavonoids, anthraquinones, and cinnamic acid derivatives, orientin, chlorogenic acid, and pulmatin emerged as the most potent JAK2 inhibitors, exhibiting ΔGbinding scores of -14.49, -11.87, and -10.76 kcal/mol, respectively. Furthermore, the docked poses of orientin, pulmatin, and chlorogenic acid remained stable throughout 60 ns computer simulations. The average root mean square deviation values calculated for JAK2 when complexed with orientin, chlorogenic acid, and pulmatin were 2.04 Å, 2.06 Å, and 1.95 Å, respectively. This study underscores the robust inhibitory potential of orientin, pulmatin, and chlorogenic acid against JAK2. The findings hold promise for the development of novel and effective drugs for cancer treatment.

Development of a biophotonic fiber sensor using direct-taper and anti-taper techniques with seven-core and four-core fiber for the detection of doxorubicin in cancer treatment

Doxorubicin (DOX) is an important drug for cancer treatment, but its clinical application is limited due to its toxicity and side effects. Therefore, detecting the concentration of DOX during treatment is crucial for enhancing efficacy and reducing side effects. In this study, the authors developed a biophotonic fiber sensor based on localized surface plasmon resonance (LSPR) with the multimode fiber (MMF)-four core fiber (FCF)-seven core fiber (SCF)-MMF-based direct-taper and anti-taper structures for the specific detection of DOX. Compared to other detection methods, it has the advantages of high sensitivity, low cost, and strong anti-interference ability. In this experiment, multi-walled carbon nanotubes (MWCNTs), cerium-oxide nanorods (CeO2-NRs), and gold nanoparticles (AuNPs) were immobilized on the probe surface to enhance the sensor's biocompatibility. MWCNTs and CeO2-NRs provided more binding sites for the fixation of AuNPs. By immobilizing AuNPs on the surface, the LSPR was stimulated by the evanescent field to detect DOX. The sensor surface was functionalized with DOX aptamers for specific detection, enhancing its specificity. The experiments demonstrated that within a linear detection range of 0-10 µM, the sensitivity of the sensor is 0.77 nm/µM, and the limit of detection (LoD) is 0.42 µM. Additionally, the probe's repeatability, reproducibility, stability, and selectivity were evaluated, indicating that the probe has high potential for detecting DOX during cancer treatment.

Comprehensive review of the repositioning of non-oncologic drugs for cancer immunotherapy.

Drug repositioning or repurposing has gained worldwide attention as a plausible way to search for novel molecules for the treatment of particular diseases or disorders. Drug repurposing essentially refers to uncovering approved or failed compounds for use in various diseases. Cancer is a deadly disease and leading cause of mortality. The search for approved non-oncologic drugs for cancer treatment involved in silico modeling, databases, and literature searches. In this review, we provide a concise account of the existing non-oncologic drug molecules and their therapeutic potential in chemotherapy. The mechanisms and modes of action of the repurposed drugs using computational techniques are also highlighted. Furthermore, we discuss potential targets, critical pathways, and highlight in detail the different challenges pertaining to drug repositioning for cancer immunotherapy.

Research progress on the role and mechanism of Sirtuin family in doxorubicin cardiotoxicity

BackgroundDoxorubicin (DOX) is a widely utilized anthracycline chemotherapy drug in cancer treatment, yet its efficacy is hindered by both short-term and long-term cardiotoxicity. Although oxidative stress, inflammation and mitochondrial dysfunction are established factors in DOX-induced cardiotoxicity, the precise molecular pathways remain elusive. Further exploration of the pathogenesis and identification of novel molecular targets are imperative. Recent studies have implicated the Sirtuins family in various physiological and pathological processes, suggesting their potential in ameliorating DOX-induced cardiotoxicity. Moreover, research on Sirtuins has discovered small-molecule compounds or medicinal plants with regulatory effects, representing a notable advancement in preventing and treating DOX-induced cardiac injury. PurposeIn this review, we delve into the pathogenesis of DOX-induced cardiotoxicity and explore the therapeutic effects of Sirtuins in mitigating this condition, along with the associated molecular mechanisms. Furthermore, we delineate the roles and mechanisms of small-molecule regulators of Sirtuins in the prevention and treatment of DOX-induced cardiotoxicity. Study-design/methodsData for this review were sourced from various scientific databases (such as Web of Science, PubMed and Science Direct) up to March 2024. Search terms included “Sirtuins,” “DOX-induced cardiotoxicity,” “DOX,” “Sirtuins regulators,” “histone deacetylation,” among others, as well as several combinations thereof. ResultsMembers of the Sirtuins family regulate both the onset and progression of DOX-induced cardiotoxicity through anti-inflammatory, antioxidative stress and anti-apoptotic mechanisms, as well as by maintaining mitochondrial stability. Moreover, natural plant-derived active compounds such as Resveratrol (RES), curcumin, berberine, along with synthetic small-molecule compounds like EX527, modulate the expression and activity of Sirtuins. ConclusionThe therapeutic role of the Sirtuins family in mitigating DOX-induced cardiotoxicity represents a potential molecular target. However, further research is urgently needed to elucidate the relevant molecular mechanisms and to assess the safety and biological activity of Sirtuins regulators. This review offers an in-depth understanding of the therapeutic role of the Sirtuins family in mitigating DOX-induced cardiotoxicity, providing a preliminary basis for the clinical application of Sirtuins regulators in this condition.

Arene-Arene Coupled Disulfamethazines (or Sulfadiazine)-Phenanthroline-Metal(II) Complexes were Synthesized by In Situ Reactions and Inhibited the Growth and Development of Triple-Negative Breast Cancer through the Synergistic Effect of Antiangiogenesis, Anti-Inflammation, Pro-Apoptosis, and Cuproptosis.

The novel metal(II)-based complexes HA-Cu, HA-Co, and HA-Ni with phenanthroline, sulfamethazine, and aromatic-aromatic coupled disulfamethazines as ligands were synthesized and characterized. HA-Cu, HA-Co, and HA-Ni all showed a broad spectrum of cytotoxicity and antiangiogenesis. HA-Cu was superior to HA-Co and HA-Ni, and even superior to DDP, showing significant inhibitory effect on the growth and development of tripe-negative breast cancer in vivo and in vitro. HA-Cu exhibited observable synergistic effects of antiproliferation, antiangiogenesis, anti-inflammatory, pro-apoptosis, and cuproptosis to effectively inhibited tumor survival and development. The molecular mechanism was confirmed that HA-Cu could downregulate the expression of key proteins in the VEGF/VEGFR2 signaling pathway and the expression of inflammatory cytokines, enhance the advantage of pro-apoptotic protein Bax, and enforce cuproptosis by weakening the expression of FDX1 and enhancing the expression of HSP70. Our research will provide a theoretical and practical reference for the development of metal-sulfamethazine and its derivatives as chemotherapy drugs for cancer treatment.

Potentials and future perspectives of multi-target drugs in cancer treatment: the next generation anti-cancer agents.

Cancer is a major public health problem worldwide with more than an estimated 19.3 million new cases in 2020. The occurrence rises dramatically with age, and the overall risk accumulation is combined with the tendency for cellular repair mechanisms to be less effective in older individuals. Conventional cancer treatments, such as radiotherapy, surgery, and chemotherapy, have been used for decades to combat cancer. However, the emergence of novel fields of cancer research has led to the exploration of innovative treatment approaches focused on immunotherapy, epigenetic therapy, targeted therapy, multi-omics, and also multi-target therapy. The hypothesis was based on that drugs designed to act against individual targets cannot usually battle multigenic diseases like cancer. Multi-target therapies, either in combination or sequential order, have been recommended to combat acquired and intrinsic resistance to anti-cancer treatments. Several studies focused on multi-targeting treatments due to their advantages include; overcoming clonal heterogeneity, lower risk of multi-drug resistance (MDR), decreased drug toxicity, and thereby lower side effects. In this study, we'll discuss about multi-target drugs, their benefits in improving cancer treatments, and recent advances in the field of multi-targeted drugs. Also, we will study the research that performed clinical trials using multi-target therapeutic agents for cancer treatment.

Efficacy and safety of tyrosine kinase inhibitors for advanced metastatic thyroid cancer: A systematic review and network meta-analysis of randomized controlled trials.

Tyrosine kinase inhibitors (TKIs) have been approved for treating patients with clinically advanced metastatic thyroid cancer. However among the many TKIs, it remains unknown which regimen is the best choice for these patients. We conducted a systematic review and network meta-analysis to compare the survival benefits and efficacy of the available first-line regimens. We conducted an active search for phase II, III, or IV randomized controlled trials (RCTs) in the PubMed, Embase, and Cochrane databases to compare the effects of at least 2 drugs in the systemic treatment of advanced or metastatic thyroid cancer up to May 2023. The network meta-analysis model was adjusted using Bayesian Network model. Twelve trials with 2535 patients were included in our meta-analysis. The overall survival (OS), progression-free survival (PFS), and serious adverse events (SAEs) were taken as reference indicators. We also performed subgroup analyses of OS and PFS in medullary thyroid cancer (MTC) and radioiodine-refractory differentiated thyroid cancer (RR-DTC) to explore the variations of TKIs in different groups. As a result, apatinib had the best effect on overall survival (OS) (hazards ratio [HR] = 0.42, 95% confidence interval [CI] = 0.18-0.98), lenvatinib 18 mg/d has the best effect on progression-free survival (PFS) (HR = 0.13, 95% CI = 0.064-0.27), and cabozantinib 60 mg/d has the best safety profile. Our network meta-analysis showed that we believe that cabozantinib has the potential to become a widely used drug in clinical practice.

Abstract SY31-03: Cancer takes a nerve: Challenges and opportunities in cancer neuroscience

Abstract Neuronal reprogramming in cancer represents a groundbreaking frontier that intricately links the nervous system's plasticity to tumor progression and response to treatment. This process involves the aberrant activation or suppression of neuronal signals that can significantly influence cancer cell behavior, including proliferation, migration, and resistance to therapies. The concept of repurposing drugs originally designed to target the nervous system for use in clinical oncology offers a promising therapeutic strategy, potentially revolutionizing cancer treatment. By intercepting neuronal pathways that cancer cells exploit for their growth and survival, these drugs could modulate the tumor microenvironment, enhance the efficacy of conventional therapies, and potentially reverse drug resistance mechanisms. Moreover, targeting neuronal signaling in cancer could lead to improvements in patients' functional outcomes, mitigating cancer-related neurological deficits and improving quality of life. Importantly, this approach may also have profound implications for survival outcomes, as modulating the neuro-cancer interface could slow tumor progression and reduce metastatic spread. The repurposing of neuroactive drugs for cancer treatment thus opens a new avenue for personalized medicine, where the intricacies of neuronal reprogramming are leveraged to tailor therapy, improve response rates, and ultimately, enhance patient survival and well-being. Citation Format: Moran Amit. Cancer takes a nerve: Challenges and opportunities in cancer neuroscience [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 SY31-03.

The Construction of a Multi-Gene Risk Model for Colon Cancer Prognosis and Drug Treatments Prediction.

In clinical practice, colon cancer is a prevalent malignant tumor of the digestive system, characterized by a complex and progressive process involving multiple genes and molecular pathways. Historically, research efforts have primarily focused on investigating individual genes; however, our current study aims to explore the collective impact of multiple genes on colon cancer and to identify potential therapeutic targets associated with these genes. For this research, we acquired the gene expression profiles and RNA sequencing data of colon cancer from TCGA. Subsequently, we conducted differential gene expression analysis using R, followed by GO and KEGG pathway enrichment analyses. To construct a protein-protein interaction (PPI) network, we selected survival-related genes using the log-rank test and single-factor Cox regression analysis. Additionally, we performed LASSO regression analysis, immune infiltration analysis, mutation analysis, and cMAP analysis, as well as an investigation into ferroptosis. Our differential expression and survival analyses identified 47 hub genes, and subsequent LASSO regression analysis refined the focus to 23 key genes. These genes are closely linked to cancer metastasis, proliferation, apoptosis, cell cycle regulation, signal transduction, cancer microenvironment, immunotherapy, and neurodevelopment. Overall, the hub genes discovered in our study are pivotal in colon cancer and are anticipated to serve as important biological markers for the diagnosis and treatment of the disease.

Exploring the role of histone deacetylase inhibitors in cancer development and therapeutic potential.

The process of acetylation and deacetylation of histones within the nucleus operates within a dynamic equilibrium. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) collaboratively and precisely regulate normal gene transcription and expression. Any disorder in the activity of HATs/HDACs can lead to uncontrolled gene expression, consequently resulting in tumorigenesis. Histone deacetylase inhibitors (HDACIs) have the capacity to block the cell cycle, thereby restraining tumor cell proliferation and tumor growth. Also, HDACIs exhibit a significant capability to diminish the expression of apoptosis protein inhibitors such as Bcl-2 and B-cell lymphoma-extra-large (Bcl-xL), while concurrently up-regulating pro-apoptotic proteins such as Bax, Bad, and Bim. Also, HDACIs demonstrate the ability to inhibit tumor cell angiogenesis. Representing a new category of targeted anti-cancer therapeutics, HDACIs possess the capability to restore the expression of tumor suppressor genes, induce apoptosis, and stimulate cell differentiation. Additionally, they exert anti-cancer effects through diverse pathways both in vivo and in vitro, thereby presenting promising prospects in tumor therapy. This review delves into the involvement of HDACs in cancer pathology and the therapeutic potential of HDACIs as emerging drugs in cancer treatment.

PGD2/PTGDR2 Signal Affects the Viability, Invasion, Apoptosis, and Stemness of Gastric Cancer Stem Cells and Prevents the Progression of Gastric Cancer.

Prostaglandin D2 (PGD2) has been shown to restrict the occurrence and development of multiple cancers; nevertheless, its underlying molecular mechanism has not been fully elucidated. The present study investigated the effect of PGD2 on the biological function of the enriched gastric cancer stem cells (GCSCs), as well as its underlying molecular mechanism, to provide a theoretical basis and potential therapeutic drugs for gastric cancer (GC) treatment. The plasma PGD2 levels were detected by Enzyme-linked immunosorbent assay (ELISA). Silencing of lipocalin prostaglandin D synthetases (L-PTGDS) and prostaglandin D2 receptor 2 (PTGDR2) was carried out in GCSCs from SGC-7901 and HGC-27 cell lines. Cell Counting Kit-8, transwell, flow cytometry, and western blotting assays were used to determine cell viability, invasion, apoptosis, and stemness of GCSCs. In vivo xenograft models were used to assess tumor growth. Clinically, it was found that the plasma PGD2 level decreased significantly in patients with GC. PGD2 suppressed viability, invasion, and stemness and increased the apoptosis of GCSCs. Downregulating L-PTGDS and PTGDR2 promoted viability, invasion, and stemness and reduced the apoptosis of GCSCs. Moreover, the inhibition of GCSCs induced by PGD2 was eliminated by downregulating the expression of PTGDR2. The results of in vivo experiments were consistent with those of in vitro experiments. Our data suggest that PGD2 may be an important marker and potential therapeutic target in the clinical management of GC. L-PTGDS/PTGDR2 may be one of the critical targets for GC therapy. The PGD2/PTGDR2 signal affects the viability, invasion, apoptosis, and stemness of GCSCs and prevents the progression of GC.

Application and Prospects of Artificial Intelligence in Breast Cancer Early Diagnosis, Screening, and Treatment

In modern society, as artificial intelligence technology becomes increasingly mature, AI can already be utilized to assess and treat breast carcinoma. By summarizing results and data of experiments that use AI to help breast carcinoma diagnosis and cure, this article states the positive impact of AI on breast cancer screening, detection of breast cancer-related genes, and prediction of efficacy of breast cancer treatment drugs. What is more, illustrating the moral, legal, and social challenges encountered by scientists when they use artificial intelligence. Also, this article makes some suggestions for the future development of AI technology. The author believes that AI technology have the ability to contribute significantly to the diagnosis and cure of breast cancer and can enhance the chances of patients surviving to a considerable extent. However, currently, artificial intelligence technology remains in a relatively nascent stage, necessitating ongoing attention and dedicated efforts for its advancement.

Abstract 3522: Application of large language models to nucleotide sequences for profiling signaling pathway disruptions in ovarian cancer patients

Abstract Ovarian cancer is a challenging disease, often exhibiting recurrence after initial treatment. The complexity arises from simultaneous disruptions in multiple signaling pathways within tumor cells, rendering targeted inhibitors ineffective in providing sustained therapeutic impact. While targeted sequencing panels can identify specific therapeutically relevant events, they often fail to capture the complete picture of targetable tumor driving aberrations, and provide biomarkers relevant to disease resistance and/or recurrence. A potential solution lies in comprehensively defining the landscape of signaling pathway alterations by identifying molecular triggers underlying their dysregulation. While individual DNA mutations sometimes may not lead to carcinogenesis or changes in tumor cell behavior, combination of deactivating mutations in suppressor genes, can influence tumor development and prognosis, warranting a comprehensive delineation of their effect on the broad signaling network level. To this end, we propose the Large Language Models (LLMs), which have been successful in natural language processing, particularly in understanding context. Such tools are essential for discerning the effect of mutation combinations, their physical proximity to other mutations, and functional gene regions. We obtained mutation annotation files for 177 ovarian cancer patients from the TCGA database, reconstructing consensus nucleotide sequences using a reference genome. To input this data into LLMs, we generated embeddings for these sequences using the Nucleotide Transformer algorithm, pre-trained on 500 million variants of the reference genome. Additionally, we extracted data on detected disruptions in 10 signaling pathways (Cell Cycle, HIPPO, MYC, NOTCH, NRF2, PI3K, RTK RAS, TP53, TGF-Beta, WNT) for these patients from TCGA. Each pathway was associated with the percentage of its alteration. We trained a deep learning algorithm on these data to predict a combination of 10 numerical values, each corresponding to the percentage of disruption for a given signaling pathway. Our findings revealed that nearly half of the patients exhibited disruptions in 5 or more signaling pathways. The algorithm developed enables the determination of the extent of disruption in each pathway based on whole exome sequencing results. This approach facilitates more informed treatment strategy planning and enhances the efficient development of new drugs for ovarian cancer treatment. Citation Format: Dmitrii K. Chebanov, Nadezhda S. Tatevosova. Application of large language models to nucleotide sequences for profiling signaling pathway disruptions in ovarian cancer patients [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 3522.