Target-based Therapy Research Articles

The Impact of Transcriptional Profiling Cadherin Family and Therapeutic Approaches of Gastric Cancer: A Translational Outlook on Multi-omics Data Analysis.

The classical cadherin gene has been linked to a variety of human malignancies, including gastric cancer. However, the link between cadherin genes and gastric cancer outcome is still unclear. This study used multi-omics data to examine the cadherin genes that were differentially regulated in gastric cancer. Differential expression of genes, epigenetic, molecular alterations, and protein expression analyses was conducted. Male SD rats were given N-methyl-N-nitrosourea (MNU) to induce stomach carcinoma in order to verify the activation of cadherin genes. CDH5, CDH6, CDH11, and CDH24 levels were found to be considerably higher in gastric cancer and may serve as useful indicators of stomach adenocarcinoma (STAD). Cadherin genes with variable expression had considerably more promoter methylation in cancers than in normal tissues. In individuals with gastric cancer, high expression of these cadherin genes was related to lower total mortality and disease-free survival rates. Furthermore, compared to normal rats, gastric cancer-induced rats had significantly higher expression and distribution of CDH5, CDH6, CDH11, and CDH24. This study sheds new light on the diagnosis and prognosis of gastric cancer by identifying potential prognostic markers such as CDH5, CDH6, CDH11, and CDH24. The multi-omics approach provided a potential tool for target-based therapy by accurately predicting the outcome of stomach cancer. Researchers may gain more knowledge about the role of cadherin genes in the development and dissemination of tumors to the activated rat model of gastric cancer.

Molecular Docking: An Emerging Tool for Target-Based Cancer Therapy

Molecular Docking: An Emerging Tool for Target-Based Cancer Therapy

Abstract 3161: Novel gene signature for predicting aggressive type of bladder cancer and the associated therapeutic strategies

Abstract We have previously developed a unique HD-MAC (high-dimensional analysis of molecular alterations in cancer) platform that enables us to define independent tumor biomarkers from a group of clinically-significant genes. Using this platform, 26 genes were identified as independent prognosis biomarkers whose overexpression determine shorter overall survivals in patients with bladder cancer. Through clinical association study (including tumor stage, lymph node invasion, angiogenesis, and metastasis), a gene signature containing 6 biomarkers was established which can be validated by two independent cohorts. Gene knock down effects on cancer cell survival further revealed PPT2 and PRPF19 as potential targets for target-based therapy. Correlation study between genetic dependencies and drug sensitivities across cell lines suggested several potent lead compounds which are likely to function through similar mechanisms of gene effect actions. Our study therefore provides newly defined prognostic biomarkers as well as the associated therapeutic strategies for possible clinical applications in patients with bladder cancer. Citation Format: Jim Jinn-Chyuan Sheu, Chung Chang, Bo-Chen Lin, Tritium Hwang. Novel gene signature for predicting aggressive type of bladder cancer and the associated therapeutic strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3161.

Abstract 3398: Clinical use of next-generation sequencing panel in pediatric oncology patients

Abstract Background: Next-generation sequencing (NGS) technology is gradually expanding in cancer diagnosis and therapeutic decision-making. However, reports on the clinical performance and utility of pan-cancer NGS panel in pediatric patients are still lacking. Methods: We analyzed the patients who underwent brain tumor or pan-cancer NGS panel sequencing at Seoul National University Children’s Hospital. DNA-based NGS panel testing was started in April 2018, and RNA panel was added from January 2022. Single nucleotide variants/small insertions and deletions (SNV/INDEL), fusion, copy number alteration (CNA), microsatellite instability (MSI) and tumor mutational burden (TMB) were evaluated. Results: A total of 140 patients were analyzed between August 2018 and March 2022. The median age at diagnosis was 8.5 (range 0.0-31.8) years. The diagnoses were CNS tumors in 56 (40.0%), sarcoma in 45 (32.1%), other solid tumors in 36 (25.7%) and histiocytosis in 3 (2.1%) patients. At the time of NGS testing, 115 patients (75.2%) were newly diagnosed and 38 patients (24.8%) were in relapsed or refractory status. In all patients, 85.7% had at least one pathogenic or likely pathogenic variant. Diagnosis was refined or changed in five patients (3.6%) after the NGS panel results were reported. Oncogenic gene fusions were discovered in 45 (32.1%) patients. EWSR1, BRAF, NTRK and RET-related fusions were the most common. Frequent SNV/INDEL included BRAF, CTNNB1 and TP53 mutations. Common CNA were CDKN2A and CDKN2B loss, MYCN amplification, CCND3 amplification and PTEN loss. Nine (6.4%) patients were identified with germline alteration, additionally. No patient had MSI, and two patients had high TMB. Fifteen patients (10.7%) were enrolled in clinical trials or compassionate use program according to molecular profiling (DAY101 [BRAF inhibitor] in 3, selpercatinib in 3, palbociclib in 2, olaparib in 2, alectinib in 1, repotrectinib in 1, larotrectinib in 1, atezolizumab in 1 and erdafitinib in 1). Two (1.4%), one (0.7%) and one (0.7%) patients received vemurafenib, larotrectinib, and pembrolizumab with non-reimbursement. Best responses included two complete response (1 high grade glioma [HGG] and 1 renal cell carcinoma), five partial responses (2 low grade glioma, 1 HGG, 1 Langerhans cell histiocytosis, and 1 papillary thyroid carcinoma), two stable disease and six progressive diseases. Four patients were not evaluable due to short duration of drug administration. One-year progression free survival and overall survival was 54.5% and 52.7%, respectively. Conclusions: Application of NGS panel in pediatric cancer aid in diagnosis, treatment decision, clinical trial enrollment and germline risk determination. Although there are not many cases linked with molecular target-based therapy, it is leading to clinical benefits in pediatric patients and more understanding genomic profiling of pediatric cancer. Citation Format: Jung Yoon Choi, Hyun Jin Park, Bo Kyung Kim, Kyung Taek Hong, Jaemoon Koh, Sung-Hye Park, Jeong Mo Bae, Hongseok Yun, Hyoung Jin Kang. Clinical use of next-generation sequencing panel in pediatric oncology patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3398.

808 Analysis of Medulloblastomas Subgroups in Pediatric Patients in Latin-America

INTRODUCTION: The 4 groups molecular-based classification of medulloblastomas is widely accepted. However, technology inaccessibility and low-quality formalin-fixed and paraffin-embedded (FFPE) samples, unable its application for most Latin-American cancer centers. METHODS: The goal of this study was to perform a feasibility analysis based on 18 mRNA expression by qPCR integrated with immunohistochemistry (IH) and fluorescent hybridization in situ (FISH) (c-MYC, n-MYC and monosomy 6) for molecular stratification to create an International Treatment Protocol at a low cost for low-income centers. RESULTS: Fifty-four FFPE samples were classified according to histologic and molecular aspects. Classic medulloblastoma was the commonest histology (53.7%), followed by desmoplastic/extensive nodularity (24.1%), NOS (16,7%) and anaplastic (5,6%). IH markers classified patients in three groups (WNT, SHH and non-WNT/non-SHH) in 98% of cases. PCR-based method confirmed results from IH in 81.5%. Additionally, it detected WNT activation in 2 more patients, previously classified as SHH. For both cases, the presence of monosomy 6 confirmed WNT subgroup. The integration of these three techniques resulted in the following frequencies: WNT (13.0%), SHH (38.9%), group 3 (9.3%), group 4 (20.3%) and non-WNT/non-SHH (18.5%). From 40 patients with clinical follow-up available, 3-year overall survival (n = 40) for low, intermediate and high-risk groups were 100%, 60% and 20%, respectively (p < 0.05), based only in molecular criteria, which confirmed the prognostic importance of this method at a low cost. CONCLUSIONS: The prognosis of the treatment of medulloblastomas has changed after novel studies on the molecular subgroups and the introduction of target-based therapy. The current protocol will enable different centers to implement treatment based on the knowledge of molecular subgroups.

Icariin ameliorates oxidative stress-induced inflammation, apoptosis, and heart failure in isoproterenol-challenged Wistar rats.

Cardiovascular diseases are widespread across the globe, and heart failure (HF) accounts for the majority of heart-associated deaths. Target-based drug therapy is much needed for the management of heart failure. We have designed this study to evaluate icariin for its cardioprotective activity in the isoproterenol (ISO) induced postinfarction model. We have randomly distributed Wistar rats into seven groups, i.e., vehicle control; isoproterenol-treated; icariin per se; sildenafil per se; ISO + icariin 5; ISO + icariin 10; and ISO + sildenafil groups. ISO (85 mg/kg, subcutaneous) was administered at 24 hr for two consecutive days to produce cardiac injury, followed by icariin administration at 5 mg/kg and 10 mg/kg orally for 56 days. Rats were subjected to hemodynamic measurements biweekly. After 24 hr of the completion of dosing, animals were sacrificed, and markers for oxidative stress, fibrosis, inflammation, and cell death were measured. Transmission electron microscopy (TEM), histopathology, and MT staining of cardiac tissue were also done to assess the pathological and fibrotic architectural damage. A significant decline in hemodynamics and an anti-oxidant collapse were found in ISO-intoxicated rats. Alterations in the levels of cyclic guanosine monophosphate (cGMP), interleukin-10 (IL-10), Tumor necrosis factor (TNF-α), and brain natriuretic peptide (BNP) were also observed in serum. Up-regulation of caspase-3, nuclear factor (NF-ĸB), and decline in expression of nuclear factor (NrF-2) contribute to cardiac damage. The treatment with icariin and sildenafil considerably reversed the toxic changes toward normal. Increased cGMP and Nrf2 expression and suppressed NF-ĸB-caspase-3 signaling play a pivotal role in icariin-mediated cardioprotection.

Melanoma Immunotherapy and Precision Medicine in the Era of Tumor Micro-Tissue Engineering: Where Are We Now and Where Are We Going?

Malignant melanoma still remains a cancer with very poor survival rates, although it is at the forefront of personalized medicine. Most patients show partial responses and disease progressed due to adaptative resistance mechanisms, preventing long-lasting clinical benefits to the current treatments. The response to therapies can be shaped by not only taking into account cancer cell heterogeneity and plasticity, but also by its structural context as well as the cellular component of the tumor microenvironment (TME). Here, we review the recent development in the field of immunotherapy and target-based therapy and how, in the era of tumor micro-tissue engineering, ex-vivo assays could help to enhance our melanoma biology knowledge in its complexity, translating it in the development of successful therapeutic strategies, as well as in the prediction of therapeutic benefits.

Autophagy in Endometriosis: Beta-Catenin Suppressive Role

Study ObjectiveTo evaluate the occurrence of the autophagic process in ovarian endometriomas (OE), rectocervical endometriosis (RE), adenomyosis (A), and peritoneal endometriosis (PE) compared with eutopic endometrium.DesignProspective cohort study, Level II-1.SettingNational Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Healthcare of the Russian Federation.Patients or ParticipantsWe recruited 120 patients with endometriosis and adenomyosis: 47 patients with (OE), 20 patients with (RE), 20 patients with (A), 33 patients with (PE).InterventionsAll patients had laparoscopic surgery performed in the proliferative non-menstrual phase of their menstrual cycle. Histological analysis was carried out according to a standard procedure. Immuno-histochemical analysis of ectopic and eutopic endometrium samples was carried out using the Tissue-Tek Quick-Ray kit, which allows for the preparation of paraffin blocks with a large number of tissue samples (tissue microarray). Antibodies to LAMP 1 (1:100), LC3 (1:50), bcl-2 (1:50), (Ventana, Roche) were used.Measurements and Main ResultsIn patients with EO, RE, A and PE, we noticed a significant down-regulation of autophagy (LAMP1 and LC3 expression) and up-regulation of beta-catenin expression in ectopic endometrium compared with the eutopic endometrium of affected women (p<0.05). Our study did not demonstrate the difference in expression of tested markers among endometriosis lesions of different localizations (p>0.05). This data is consistent with our previous observation made on smaller number of patents, possibly confirming the data.ConclusionWe hypothesized that there is a relationship between autophagy and wnt/signaling pathway regulation, demonstrating the inverse ratio between beta-catenin and autophagy-marker expression. Based on the results in this study, we can say with increased certainty that increased beta-catenin could suppress autophagy, supporting ectopic endometrium through anoikis and other types of apoptosis. So we can suppose that target-based therapy suppressing the wnt/beta-catenin pathway can activate autophagy in endometriosis and, pending clinical studies, become a part of target-based pre-surgical, intra-operative, an post-operative endometriosis therapy.

Design and Development of Small-Molecule Arylaldoxime/5-Nitroimidazole Hybrids as Potent Inhibitors of MARK4: A Promising Approach for Target-Based Cancer Therapy

Microtubule affinity-regulating kinase 4 (MARK4), a member of the serine/threonine kinase family, is an emerging therapeutic target in anticancer drug discovery paradigm due to its involvement in regulation of microtubule dynamics, cell cycle regulation, and cancer progression. Therefore, to identify the novel chemical architecture for the design and development of novel MARK4 inhibitors with concomitant radical scavenging property, a series of small-molecule arylaldoxime/5-nitroimidazole conjugates were designed and synthesized via multistep chemical reactions following the pharmacophoric hybridization approach. Compound 4h was identified as a promising MARK4 inhibitor with high selectivity toward MARK4 inhibition as compared to the panel of screened 30 kinases pertaining to the serine/threonine family, which was validated by molecular docking and fluorescence binding studies. The comprehensive cell-based examination divulged the promising apoptotic, antiproliferative, and antioxidant potential for the chemotype 4h. The compound 4h was endowed with the Ka value of 3.6 × 103 M–1 for human serum albumin, which reflects its remarkable transportation and delivery properties to the target site via blood. The present study impedes that in the future, such compounds may stand as optimized pharmacological lead candidates in drug discovery for targeting cancer via MARK4 inhibition with a remarkable anticancer profile.

Abstract 2508: Characteristics and clinical correlations of PI3K/AKT/mTOR pathway genetic variations in Chinese endometrial carcinoma

Abstract Background: Next-generation sequencing (NGS) and the resulting target-based precision therapy has shown promising efficacy in many tumors. The PI3K/AKT/mTOR pathway is the most common abnormal pathway in endometrial carcinoma. Here we report the genetic characteristics of the PI3K/AKT/mTOR pathway in Chinese endometrial cancer and explored their clinical application to support further precision therapy strategy studies. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor samples and matched peripheral blood samples of 76 Chinese endometrial adenocarcinoma patients were collected for YuansuTM NGS-panel assay (OrigiMed, Shanghai). Pathological diagnosis was confirmed by independent pathologists. Genomic alterations (GAs) included single base substitution, short and long insertions/deletion (Indel), copy number variation, gene fusion, and rearrangement. Tumor mutational burden (TMB) and microsatellite instability (MSI) were assessed. FIGO stage, age, gender, and differentiation degree were collected for clinical application analysis. Results: GAs in the PI3K/AKT/mTOR pathway were found in 93.4% (71/76) of patients and were mostly substitution/Indels (75.0%) and truncations (24.5%). The most common GAs were PTEN (72.4%), PIK3CA (51.3%), PIK3R1 (32.9%), FBXW7 (9.2%), and AKT1 (7.9%). Hotspot mutation sites were p.R130X (17.9%) of PTEN and p.H1047X (21.2%) and p.R88Q (15.4%) of PIK3CA. The median TMB was 7.55 Muts/Mb, but patients with PTEN, PIK3CA, and PIK3R1 mutations had a significantly higher TMB (PTEN: 20.9 vs 2.5 Muts/Mb, respectively, p &amp;lt; 0.001; PIK3CA: 23.2 vs 5 Muts/Mb, respectively, p = 0.003; PIK3R1: 25.5 vs 6.2 Muts/Mb, respectively, p = 0.037). MSI-high was found in 9.2% of patients. PIK3R1 mutation patients were younger compared to wild type patients (51 vs 56 years old, respectively, p = 0.024), whereas FBXW7 mutation patients were older (63 vs 54 years old, respectively, p = 0.040). The rates of PTEN mutations and truncation variations were lower in FIGO IV stage (33.3% and 41.7%, p = 0.023 and p = 0.002, respectively) and higher in highly differentiated tissues (92% and 92%, p = 0.009 and p = 0.035, respectively), indicating that these GAs were associated with low grade phenotypes. A 56-year-old female with metastatic endometrial cancer, who could not tolerate a needle biopsy and standard treatment protocols, had ctDNA testing. A PTEN deletion was found and she received mTOR inhibitor everolimus treatment and achieved a partial response which lasted for more than 12 months. Conclusions: Our study revealed gene variation characteristics of the PI3K/AKT/mTOR pathway in Chinese endometrial adenocarcinoma patients and the clinical correlations of these variations. PTEN mutations and truncation variations were associated with low grade phenotypes. This study was helpful for optimizing the usage of mTOR inhibitor everolimus. Citation Format: Fengxia Xue, Yingmei Wang, Haifang Wang, Jun Zhang, Li Meng, Honglin Guo, Junping Shi. Characteristics and clinical correlations of PI3K/AKT/mTOR pathway genetic variations in Chinese endometrial carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2508.

Multiple target-based combination therapy of galantamine, memantine and lycopene for the possible treatment of Alzheimer’s disease

Alzheimer’s disease is type of dementia in which cognitive functions get declined. More than 50 million people are affected by this disease across the world. Many clinical and preclinical studies have been conducted on the treatment of AD but very limited number of drugs have found a clinical application. Because regeneration of neuron is a complicated process due to the involvement of multiple pathways, a combination of drugs that can work through multiple pathways could prove to be effective in treating AD. Based on prior studies and different mechanisms involved in the treatment, a new hypothesis has been proposed that a combination of galantamine, memantine and lycopene is anticipated to produce better activity as compared to the current therapies available in market for the treatment of this disease.

Use of Small-molecule Inhibitory Compound of PERK-dependent Signaling Pathway as a Promising Target-based Therapy for Colorectal Cancer.

Colorectal cancer constitutes one of the most common cancer with a high mortality rate. The newest data has reported that activation of the pro-apoptotic PERK-dependent unfolded protein response signaling pathway by small-molecule inhibitors may constitute an innovative anti-cancer treatment strategy. In the presented study, we evaluated the effectiveness of the PERK-dependent unfolded protein response signaling pathway small-molecule inhibitor 42215 both on HT-29 human colon adenocarcinoma and CCD 841 CoN normal human colon epithelial cell lines. Cytotoxicity of the PERK inhibitor was evaluated by the resazurin-based and lactate dehydrogenase (LDH) tests. Apoptotic cell death was measured by flow cytometry using the FITCconjugated Annexin V to indicate apoptosis and propidium iodide to indicate necrosis as well as by colorimetric caspase-3 assay. The effect of tested PERK inhibitor on cell cycle progression was measured by flow cytometry using the propidium iodide staining. The level of the phosphorylated form of the eukaryotic initiation factor 2 alpha was detected by the Western blot technique. Obtained results showed that investigated PERK inhibitor is selective only toward cancer cells, since inhibited their viability in a dose- and time-dependent manner and induced their apoptosis and G2/M cell cycle arrest. Furthermore, 42215 PERK inhibitor evoked significant inhibition of eIF2α phosphorylation within HT-29 cancer cells. Highly-selective PERK inhibitors may provide a ground-breaking, anti-cancer treatment strategy via activation of the pro-apoptotic branch of the PERK-dependent unfolded protein response signaling pathway.

Abstract P4-07-03: Comprehensive genomic analysis of Chinese breast cancer and clinical application

Abstract Background: Next generation sequencing (NGS) and the according target-based precision therapy has shown promising efficacy in many tumors. Here we report the genomic characteristics of Chinese breast cancer to support the development of more precise treatment strategy. Methods: Formalin fixed, paraffin embedded (FFPE) tumor samples and matched peripheral blood samples of 220 Chinese cancer patients including 218 females and 2 males were collected for NGS-based 450-genes panel assay. Pathological subtypes included 104 HR+/HER2-, 30 HR-/HER2+, 44 HR+/HER2+ and 42 triple negative breast cancers (TNBC). Assessed genomic alterations included single base substitution, short and long insertions/deletion, copy number variation, gene fusion and rearrangement. MSK breast cancer data was obtained from cBioPortal for comparing the difference between Chinese and Western patients. Results: The top mutated genes were TP53 (88.1%), PIK3CA (26.2%) and PTEN (21.4%) in TNBC; ERBB2 (86.7%), TP53 (86.7%), CDK12 (80.0%) and PIK3CA (23.3%) in HR-/HER2+ patients; ERBB2 (75%), TP53 (61.4%), CDK12 (54.5%) and PIK3CA (45.5%) in HR+/HER2+ patients. In HR+/HER2- patients, the most frequently mutated genes was PIK3CA (49.0%), followed by TP53 (30.8%) and GATA3 (27.9%), whereas the frequency of PIK3CA and GATA3 mutation were lower (41.6% and 19%, respectively) in Western patients. Although Alpelisib was approved by FDA in PIK3CA mutated HR+/HER2- patients, we observed PIK3CA mutation frequency had no difference among four subtypes. In this cohort, patients with PIK3CA mutation were significantly elder than patient without PIK3CA mutation (50 vs 47 years old, p=0.006). The hotspot mutations of PIK3CA (E542X, E545X and H1047X) accounted for 79.8% of PIK3CA mutations (71/89). Gene fusion/rearrangement was observed in 26% patients, in which 4 patients had gene fusions. Gene variations in homologous recombination pathway were found in 27.7% of patients. Among the 11.4% of patients with BRCA1/2 mutations, 11 patients harbored germline mutations and 19 patients had somatic mutations. Rearrangement accounted for 35% in somatic BRCA1/2 mutations. In the patients with germline BRCA1/2 mutation, 6 were HR+/HER2- patients who have been approved to use Olaparib. Based on the usage of CDK4/6 inhibitor in HR+/HER2- patients, this 450-genes panel enabled us to find that 41.3% HR+/HER2- patients had genes variations are related to CDK4/6 inhibitor resistance (CCND1, 18.3%; FGFR1 17.3%; NF1, 7.7%; MDM2, 6.7%; ESR1, 6.7% and RB1, 1.9%). The median TMB was 4.3 Muts/Mb in the whole cohort and patients with KMT2C mutations had significantly higher TMB (5.5 vs 3.8 Muts/Mb, p=0.004). In addition, Chinese breast cancer patients had a significantly higher frequency of KMT2C mutations compared to western patients (11.4% vs 1.4%, p&amp;lt;0.001). Conclusions: Our study revealed the genomic variation characteristics in Chinese breast cancer patients and the value of NGS-based panel analysis in identifying potential benefit and resistance mechanisms of precision therapy. Integrating genomic features into the diagnosis and treatment of breast cancer patients is necessary to maximize the clinical benefits for each patient. Citation Format: Ning Liao, Guochun Zhang, Bo Chen, Yulei Wang, Kai Li, Chongyang Ren, Hsiaopei Mok, Li Cao, Lingzhu Wen, Minghan Jia, Cheukfai Li, Liping Guo, Guangnan Wei, Jiali Lin, Jiangguo Lai, Honglin Guo, Wenjing Wang, Shiyue Zhang, Zhijian Song, Jian Wang, Hui Chen, Jinwei Hu, Weifeng Wang, Weiwei Shi, Kai Wang. Comprehensive genomic analysis of Chinese breast cancer and clinical application [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-07-03.

Neurochemical Evidence of Preclinical and Clinical Reports on Target-Based Therapy in Alcohol Used Disorder.

Alcohol use disorder (AUD) is a chronic relapsing disorder, which enforces a person to compulsively seek alcohol, restricting control over alcohol intake leads to emergence of an undesired emotional state during abstinence. There are recent advances for better understanding of neurocircuitry involved in the pathophysiology of AUD. Alcohol interaction with neuronal membrane proteins results in changes in neuronal circuits. It is also linked with the potential medication and their clinical validation concerning their pharmacological targets for alcoholic abstinence. This review covers research work from the past few decades on the therapeutic advances on treatment of alcohol dependence; further detailing the fundamental neurochemical mechanisms after alcohol administration. It also covers interaction of alcohol with GABAergic, glutaminergic, dopaminergic, serotonergic and opioid systems. This review further elaborated the neurobiology of noradrenergic, cholinergic and cannabinoid systems and their interaction with AUD. Elaborative information of potential drug targets under current exploration for AUD treatment with their mechanisms are reported here along with clinical outcomes and the associated side effects.

Tamoxifen-zinc(II) phthalocyanine conjugates for target-based photodynamic therapy and hormone therapy

Although photodynamic therapy has been extensively studied in recent years and preclinical studies have shown promising results, strategies for enhancing PDT outcomes and reducing side effects still urgently need to be developed. In this study, a series of Tamoxifen-zinc(II) phthalocyanine conjugates have been designed and synthesized. In these “double-headed” conjugates, photodynamic therapy agent zinc(II) phthalocyanine and hormone therapy drug Tamoxifen were combined via oligoethylene glycol linkers. The conjugates show high specificity, and some of them show cytotoxic effects against the MCF-7 cells overexpressed Estrogen receptor, due to the targeting and cytostatic Tamoxifen moiety. Upon illumination, all these conjugates show high cytotoxicity due to the photosensitizing phthalocyanine unit. Their structure-activity relationship was also assessed. The results show that [Formula: see text]-substituted Tamoxifen-zinc(II) phthalocyanine conjugates are highly promising anticancer targeting agents which exhibit additive effects of photodynamic therapy and hormone therapy.

Evaluation of Pro-Inflammatory Markers IL-6 and TNF-a and their Correlation with Non-Alcoholic Fatty Liver Disease

Background: Non-Alcoholic Fatty Liver Disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient with no history of alcohol abuse or other causes for secondary hepatic steatosis. The pathogenesis of NAFLD and Non-Alcoholic Steatohepatitis (NASH) has not been fully elucidated. Non-Alcoholic Fatty Liver Disease (NAFLD) consists of a complex spectrum of diseases, ranging from asymptomatic steatosis with possible aminotransferase alterations to Non-Alcoholic Steato-Hepatitis (NASH), cirrhosis, and also hepatocellular carcinoma. Pro inflammatory cytokines like IL-1, IL-6 and TNF-α play a major role in the pathogenesis of NAFLD. These cytokines also play a crucial role in the development of insulin resistance, which is a key factor in the pathogenesis of NAFLD. There is limited data on the association of IL-6 and TNF-α with NAFLD from India. Hence, we aim to assess the correlation of IL-6 and TNF-α with NAFLD. Materials and Methods: It was a cross sectional observational study which was conducted on 40 cases of NAFLD and 40 healthy controls. All relevant investigations and serum levels of IL-6 and TNF-α were measured. Statistical analysis was done using Pearson chi-square/ fisher exact test, student t-test (un-paired). Pearson correlation test was used to see the relationship between the variables. Result: The serum levels of IL-6 and TNF-α correlated significantly with NAFLD with a p-value of <0.001. The serum levels of IL-6 showed a significant correlation with the severity of NAFLD (p<0.001), but the same was not seen with TNF-α. Conclusion: Our study showed significant correlation of TNF-α and IL-6 with NAFLD, which suggested a proven role of these pro-inflammatory markers in the pathogenesis of this disease as shown in past studies. In future target-based therapy is new field of research.

Near-infrared spectroscopy in vegetables and humans: An observational study.

Cerebral near-infrared spectroscopy (NIRS) of tissue oxygen saturation is claimed to be a surrogate marker for global cerebral perfusion. Increasingly, NIRS target-based therapy has been used during cardiac surgery in the hope of decreasing the incidence of adverse neurological outcome. We report NIRS values for some common vegetables and faculty at a world-class medical institution. Observational nonblinded study. Single tertiary care institution and local urban vegetable market. Five yams (Dioscorea cayenensis), five courgettes (Cucurbita pepo) and five butternut squashes (Cucurbita moschata) were studied. Five cardiothoracic surgeons and anaesthesiologists were the control group. None. NIRS value of each species. Mean NIRS value for the control group was 71% [95% confidence interval (CI) 68 to 74] and was similar to that of the yellow squashes [75% (95% CI 74 to 76)]. These values were significantly greater than the NIRS measurements of both the butternut squash and yam [63% (95% CI 62 to 64) and 64% (95% CI 63 to 65), respectively, P < 0.01]. Commonly eaten vegetables have NIRS measurements similar to those seen in healthy humans.

Abstract 1674: Novel direct AMPK activator suppresses non-small cell lung cancer through inhibition of lipid metabolism

Abstract Lung cancer is the leading cause of cancer mortality. While non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer and dominates almost 85% of all lung cancer cases. Conventional therapy, such as surgery, chemotherapy, or radiotherapy, scarify normal cells during the curing progress are becoming unfavorable. To avoid harmful side-effect on normal cell, target-based therapy is the mainstream of modern cancer therapy. For example, gefitinib is a clinically-marketed drug which acts as tyrosine kinase inhibitor to inhibit epidermal growth factor receptor (EGFR) activating signaling pathway. For the NSCLC patients who harbor activating substitution from leucine to arginine at amino acid 858 (L858R) point mutation and in-frame exon 19 deletion on EGFR, response well to gefitinib and these two common mutation are used a biomarkers for gefitinib prescription. However, gefitinib-resistance commonly happens due to further substitution mutation from threonine to methionine at amino acid position 790 (T790M) occurred after one year or less gefitinib treatment. Therefore, developing new treatment strategy to tackle gefitinib-resistance is urgently. Abnormal energy metabolism is accepted as new cancer hallmark. Recently, a metabolism rate-limiting enzyme 5'-adenosine menophosphate-activated protein kinase (AMPK) has become a promising anti-cancer target. In this study, we have applied computational docking to perform in silico virtual screening, and we have identified a novel direct AMPK agonist, D561-0775 from a compound library. Using enzyme activation assay, we demonstrated that D561-0775 activates directly on AMPK α subunit. In addition, D561-0775 exhibited significant inhibitory effect on gefitinib-resistant NSCLC cell lines but is less cytotoxicity on normal lung fibroblast cells. D561-0775 also activates AMPK/mTOR signaling pathway, resulting in induction of apoptosis, cell cycle arrest, suppressing glycolysis and cholesterol synthesis in gefitinib-resistant H1975 lung cancer cells. Taken together, D561-0775 has provided clue on a new chemical structure that could be developed as cancer drug for gefitinib-resistant NSCLC patients through inhibition lipid metabolism by directly targeting at AMPK directly. Acknowledgments: This work was supported by Macau Science and Technology Development Fund (Project No: 021/2013/A1, 074/2011/A3 &amp; 082/2013/A3) Citation Format: Xi Chen, Chun Xie, Xing Xing Fan, Ze Bo Jiang, Vincent Wong, Jia Hui Xu, Xiao Jun Yao, Liang Liu, Elaine L. Leung. Novel direct AMPK activator suppresses non-small cell lung cancer through inhibition of lipid metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1674.

Upregulation of FOXP1 is a new independent unfavorable prognosticator and a specific predictor of lymphatic dissemination in cutaneous melanoma patients.

BackgroundFOXP1 is a pleiotropic protein that plays important roles in immune responses (B-cell development regulation and differentiation of monocyte), organ development (cardiac valves, lung, and esophagus), and neuronal development. Besides being the primary regulator of normal human tissue development, FOXP1 also plays a role in tumorigenesis. However, the potential value of FOXP1 expression in tumor prognosis remains controversial. FOXP1 expression was assessed in tumor cells (TCs) and stromal cells (SCs) of cutaneous melanomas with the aim of analyzing the associations between FOXP1 expression and clinicopathological characteristics. We believe this article to be the first report analyzing the correlations between FOXP1 expression and clinicopathological, as well as histological, characteristics in melanoma.Materials and methodsIn total, 96 formalin-fixed, paraffin-embedded primary cutaneous melanoma tissue specimens were subjected to immunohistochemical analysis for FOXP1, and the results were correlated with classical clinicopathological features and patient survival.ResultsFOXP1 overexpression in TCs was strongly associated with the presence of metastases in sentinel lymph nodes (p=0.0003, OR=11.66) and positive status of regional lymph nodes (p=0.0006, OR=22.15). In 96% (52 of 54) of patients presenting with low FOXP1 expression, no clinical or histopathological features of lymphatic dissemination were observed. However, thinner and nonulcerated tumors were reported to have increased numbers of FOXP1-positive SCs. In addition, a strong association was observed between FOXP1 upregulation in SCs and the absence of regional lymph node metastases. There was a significant correlation between FOXP1 upregulation in TCs and shorter cancer-specific overall survival (log-rank test, p=0.0040) and disease-free survival (log-rank test, p=0.0021). FOXP1 expression was confirmed in multivariate analysis as a factor that significantly unfavorably impacts prognosis in melanoma patients (HR=3.14, p=0.0299, adjusted for age, Breslow thickness, and sex).ConclusionThe findings from this study indicate that FOXP1 has a major role in melanoma progression, which makes it a candidate for molecular target-based cancer therapy.

GRO-α and IL-8 enhance ovarian cancer metastatic potential via the CXCR2-mediated TAK1/NFκB signaling cascade.

Intraperitoneal metastasis is a common occurrence and is usually involved in the poor prognosis of ovarian cancer. Its specific metastatic pattern implies that certain indispensable microenvironmental factors secreted in the peritoneal cavity can direct metastatic ovarian cancer cells to permissive niches for secondary lesion formation. However, the underlying molecular mechanisms are ill defined. Herein, we report that GRO-α and IL-8 are predominately upregulated in culture media derived from either normal or cancerous omenta and are associated with increased ovarian cancer aggressiveness.Methods: OCM was established from culture medium of fresh human omental tissues. Primary and metastatic ovarian cancer cell lines were generated from human tumor tissues and verified by specific antibodies. The functional roles of GRO-α, IL-8, and their specific receptor CXCR2 were examined by neutralizing antibodies, shRNA gene knockdown, CRISPR/Cas9 gene knockout and pharmaceutical CXCR2 inhibitor SB225002. The oncogenic properties of ovarian cancer cells were examined by in vitro and in vivo mouse models.Results: Both GRO-α and IL-8 can activate TAK1/NFκB signaling via the CXCR2 receptor. Intriguingly, TAK1/NFκB signaling activity was higher in metastatic ovarian cancer cells; this higher activity makes them more susceptible to OCM-induced tumor aggressiveness. Treatment of ovarian cancer cells with GRO-α and IL-8 neutralizing antibodies or ablation of CXCR2 by shRNA gene knockdown, CRISPR/Cas9 gene knockout, or CXCR2 inhibitor SB225002 treatment significantly attenuated TAK1/NFκB signaling and decreased in vitro and in vivo oncogenic and metastatic potential, suggesting CXCR2 plays a key role in the GRO-α and IL-8-governed metastatic spreading of ovarian cancer cells in the intraperitoneal cavity.Conclusion: This study highlights the significance of GRO-α and IL-8 as the key chemokines in the peritoneal tumor microenvironment and suggests the utility of targeting their receptor CXCR2 as a potential target-based therapy for peritoneal metastases of ovarian cancer.