Assessing the Occurrence and Influence of Cancer Chemotherapy-Related Pharmacogenetic Alleles in the Chilean Population.

BACKGROUND: Pharmacogenomic knowledge as a biomarker for cancer care has transformed clinical practice, however, as current guidelines are primarily derived from Eurocentric populations, this limits their application in Latin America, particularly among Hispanic or Latino groups. Despite advancements, systemic chemotherapy still poses challenges in drug toxicity and suboptimal response. This study explores pharmacogenetic markers related to anticancer drugs in a Chilean cohort, filling a gap in Latin American research. Notably, the influence of native South American Mapuche-Huilliche ancestry. METHODS: To explore pharmacogenetic markers related to anticancer drugs, we utilized an ethnically Admixed Chilean genome-wide association studies (GWAS) dataset of 1095 unrelated individuals. Pharmacogenomic markers were selected from PharmGKB, totaling 36 level 1 and 2 evidence single nucleotide polymorphisms (SNPs) and 571 level 3 SNPs. Comparative analyses involved assessing SNP frequencies across diverse populations from the 1000 Genomes Project. Haplotypes were estimated, and linkage disequilibrium was examined. Ancestry-based association analyses explored relationships between SNPs and Mapuche-Huilliche and European ancestries. Chi-square distribution with p ≤ 0.05 and Bonferroni's multiple adjustment tests determined statistical differences between allele frequencies. RESULTS: Our study reveals significant disparities in SNP frequency within the Chilean population. Notably, dihydropyrimidine dehydrogenase (DPYD) variants (rs75017182 and rs67376798), linked to an increased risk of severe fluoropyrimidine toxicity, exhibit an exceptionally low frequency (minor allele frequency (MAF) < 0.005). Nudix hydrolase 15 (NUDT15) rs116855232, associated with hematological mercaptopurine toxicity, is relatively common (MAF = 0.062), and is further linked to Mapuche-Huilliche ancestry. Thiopurine methyltransferase enzyme (TPMT), implicated in severe toxicity to mercaptopurines, SNPs rs1142345 and rs1800460 of TMPT gene demonstrate higher MAFs in Admixed Americans and the Chilean population (MAF range 0.031-0.057). Finally, the variant in the UDP-glucuronosyltransferase 1 gene (UGT1A1) rs4148323, correlated with irinotecan neutropenia, exhibits the highest MAF in East Asian (MAF = 0.136) and Chilean (MAF = 0.025) populations, distinguishing them from other investigated populations. CONCLUSIONS: This study provides the first comprehensive pharmacogenetic characterization of cancer therapy-related SNPs and highlights significant disparities in SNP frequencies within the Chilean population. Our findings underscore the necessity for inclusive research and personalized therapeutic strategies to ensure the equitable and effective application of precision medicine across diverse global communities.

Obesity is associated with early recurrence on breast cancer patients that achieved pathological complete response to neoadjuvant chemotherapy.

Pathological complete response (pCR) after neoadjuvant chemotherapy (NCT) is associated with good long-term prognosis in breast cancer (BC) patients. However, some patients still recur and eventually die from this disease. For years, clinical stage at diagnosis has been consistently linked to recurrence and survival in the pCR setting. Herein, we aimed to identify other potential predictors of recurrence and survival in patients that achieved pCR. We performed a retrospective analysis of patients diagnosed between 2011 and 2020 in our center. We calculated overall survival (OS), invasive disease-free survival (IDFS), distant disease-free survival (DDFS), and BC-specific survival (BCSS). Among the 241 patients included into our study 36% were obese (Body Mass Index (BMI) > 29.9 kg/m2) and 47% were stage III. Multivariate analysis confirmed that obesity was a significant risk factor associated with early recurrence and poorer survival in these patients. In summary, obesity and clinical stage predict early recurrence and poorer survival in patients that achieved pCR after NCT. Pending further investigation and based on our findings we speculate that weight management could be beneficial for this subset of patients. To our knowledge, this is the first Latin American report linking obesity and recurrence within this setting.

Proteogenomic analysis in an early onset diffuse gastric cancer patient revealed alterations in PIK3R1, TP53, SMAD4 and a potential role of the PI3K-AKT and EGFR pathways: a case report.

Background: Early-onset gastric cancers (EOGC) are poor prognosis hard-to treat malignancies that affect young individuals (<45 years old). Case Description: Herein we describe the case of a 26-year-old female EOGC patient that initially displayed stable disease after first-line CAPOX plus immunotherapy. However, patient eventually developed progressive disease and was consecutively switched to paclitaxel plus ramucirumab, and palliative irinotecan. In search for therapeutic alternatives a proteo-genomic analysis was performed in a tissue biopsy taken after the first progression. Our analyses found a total of 18 somatic mutations, including TP53 and PIK3R1, and a previously unreported germline alteration in the tumor suppressor SMAD4. Also, our proteomic analysis found 62 proteins previously documented as "enriched in stomach cancer" and AKT/mTOR and EGFR as pathways with therapeutic potential. Unfortunately, the clinical utility of AKT/mTOR inhibitors or EGFR targeted therapies could not be assessed. Conclusions: As explained above EOGC is a growing health concern that affects young individuals. Furthermore, the reported case displayed a poor response to standard therapy including checkpoint inhibitors and chemotherapy despite the presence of biomarkers that predict a favorable outcome. Future studies should adopt alternative approaches to find novel, more effective therapies.

Contrast-enhanced mammography predicts pathological response after neoadjuvant chemotherapy in locally advanced breast cancer.

Introduction: Recently, contrast-enhanced mammography (CEM) has emerged as a reliable alternative to breast magnetic resonance imaging (MRI) for the assessment of pathological response in breast cancer patients. Our study sought to determine the diagnostic accuracy of CEM to predict pathological complete response (pCR) in patients who received neoadjuvant chemotherapy (NACT). Methods: We retrieved the medical records of patients who underwent NACT at our institution. Using post-surgery pCR, morphological evidence and CEM enhancement tumours were classified as follows: 1) radiologic complete response (rCR); 2) functional radiological complete response (frCR); and 3) non-complete response. Initially, we used multivariate analyses adjusted by clinical variables and frCR or rCR to determine which variables affected pathological response. Then, CEM diagnostic accuracy to discriminate pCR was assessed using receiver operating characteristic curves in univariate and multivariate models including either frCR or rCR. Results: A total of 48 patients were included in our study. Most patients (68.7%) were hormone receptor (HR)+ and 41.6% (20) of the patients achieved pCR. Using univariate logistic regression analyses we found that HR status, HER2 status, rCR and frCR had a significant impact on CEM diagnostic accuracy. Exploratory analyses found that CEM sensitivity was higher for HR- tumours. Multivariate logistic regression analyses found 60% sensitivity, 92.9% specificity and 79.2% accuracy in a model that included clinical variables and rCR. Conclusion: CEM is a reliable alternative to high-cost, time-consuming breast MRI that predicts pCR in patients undergoing NACT; CEM diagnostic accuracy was higher among patients who harboured HR- tumours.

Mutational Landscape and Actionable Target Rates on Advanced Stage Refractory Cancer Patients: A Multicenter Chilean Experience.

Major advances in sequencing technologies and targeted therapies have accelerated the incorporation of oncology into the era of precision medicine and "biomarker-driven" treatments. However, the impact of this approach on the everyday clinic has yet to be determined. Most precision oncology reports are based on developed countries and usually involve metastatic, hard-to-treat or incurable cancer patients. Moreover, in many cases race and ethnicity in these studies is commonly unreported and real-world evidence in this topic is scarce. Herein, we report data from a total of 202 Chilean advanced stage refractory cancer patients. Retrospectively, we collected patient data from NGS tests and IHC in order to determine the proportion of patients that would benefit from targeted treatments. Overall >20 tumor types were included in our cohort and 37% of patients (n = 74) displayed potentially actionable alterations, including on-label, off-label and immune checkpoint inhibitor recommendations. Our findings were in-line with previous reports such as the cancer genome atlas (TCGA). To our knowledge, this is the first report of its kind in Latin America delivering real-world evidence to estimate the percentage of refractory tumor patients that might benefit from precision oncology. Although this approach is still in its infancy in Chile, we strongly encourage the implementation of mutational tumor boards in our country in order to provide more therapeutic options for advanced stage refractory patients.

Differentially Expressed Genes and Signaling Pathways Potentially Involved in Primary Resistance to Chemo-Immunotherapy in Advanced-Stage Gastric Cancer Patients.

Recently, the combination of chemotherapy plus nivolumab (chemo-immunotherapy) has become the standard of care for advanced-stage gastric cancer (GC) patients. However, despite its efficacy, up to 40% of patients do not respond to these treatments. Our study sought to identify variations in gene expression associated with primary resistance to chemo-immunotherapy. Diagnostic endoscopic biopsies were retrospectively obtained from advanced GC patients previously categorized as responders (R) or non-responders (NR). Thirty-four tumor biopsies (R: n = 16, NR: n = 18) were analyzed by 3' massive analysis of cDNA ends (3'MACE). We found >30 differentially expressed genes between R and NRs. Subsequent pathway enrichment analyses demonstrated that angiogenesis and the Wnt-ß-catenin signaling pathway were enriched in NRs. Concomitantly, we performed next generation sequencing (NGS) analyses in a subset of four NR patients that confirmed alterations in genes that belonged to the Wnt/ß-catenin and the phosphoinositide 3-kinase (PI3K) pathways. We speculate that angiogenesis, the Wnt, and the PI3K pathways might offer actionable targets. We also discuss therapeutic alternatives for chemo-immunotherapy-resistant advanced-stage GC patients.

FRI-1 Is an Anti-Cancer Isoquinolinequinone That Inhibits the Mitochondrial Bioenergetics and Blocks Metabolic Shifts by Redox Disruption in Breast Cancer Cells.

Since breast cancer (BC) cells are dependent on mitochondrial bioenergetics for promoting proliferation, survival, and metastasis, mitochondria highlight as an important target for anticancer drug discovery. FRI-1, methyl 1, 3-dimethyl-5, 8-dioxo-5, 8-dihydro-4-isoquinolinecarboxylate, was previously described as a selective cytotoxic compound on cancer cell lines, however, details on the mechanism of action remain unknown. In this work, we describe that FRI-1 inhibits mitochondrial bioenergetics, producing apoptosis in MCF7 and MDA-MB-231 BC cell lines. FRI-1 decreases the maximal oxygen consumption rate (OCR), Δψm, NADH, and ATP levels, with a notable increase of mitochondrial reactive oxygen species (ROS) production, promoting AMPK activation with pro-survival effects. Moreover, FRI-1 inhibits the metabolic remodeling to glycolysis induced by oligomycin. In isolated tumoral mitochondria, FRI-1 increases Complex I and III-dependent OCR state 2, and this is sensitive to rotenone and antimycin A inhibitor additions, suggesting a redox cycling event. Remarkably, α-ketoglutarate and lipoic acid supplementation reversed and promoted, respectively, the FRI-1-induced apoptosis, suggesting that mitochondrial redox disruption affects 2-oxoglutarate dehydrogenase (OGDH) activity, and this is involved in their anticancer mechanism. Consistent with this, the combination of FRI-1 and CPI-613, a dual inhibitor of redox-sensible tricarboxylic acid (TCA) cycle enzymes PDH and OGDH, produced extensive BC cell death. Taken together, our results suggest that FRI-1 exhibits anticancer effects through inhibition of mitochondrial bioenergetics by redox disruption in BC cells.

A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer.

BACKGROUND: Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3-4 toxicity. METHODS: Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms. RESULTS: Reported grade ≤ 2 and 3-4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70-10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19-1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity. CONCLUSION: Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.

Screen-detected breast cancer is associated with better prognosis and survival compared to self-detected/symptomatic cases in a Chilean cohort of female patients.

PURPOSE: The implementation of national breast cancer (BC) screening programs in Latin America has been rather inconsistent. Instead, most countries have opted for "opportunistic" mammogram screenings on the population at risk. Our study assessed and compared epidemiological, clinical factors, and survival rates associated with BC detected by screening (SDBC) or self-detected/symptomatic (non-SDBC) in Chilean female patients. METHODS: Registry-based cohort study that included non-metastatic BC (stage I/II/III) patients diagnosed between 1993 and 2020, from a public hospital (PH) and a private university cancer center (PC). Epidemiological and clinical data were obtained from medical records. RESULTS: A total of 4559 patients were included. Most patients (55%; n = 2507) came from PH and were diagnosed by signs/symptoms (non-SDBC; n = 3132, 68.6%); these patients displayed poorer overall (OS) and invasive disease-free survival (iDFS) compared to SDBC. Importantly, the proportion of stage I and "luminal" BC (HR + /HER2 -) were significantly higher in SDBC vs. non-SDBC. Finally, using a stage/subset-stratified age/insurance-adjusted model, we found that non-SDBC cases are at a higher risk of death (HR:1.75; p < 0.001). In contrast, patients with PC health insurance have a lower risk of death (HR: 0.60; p < 0.001). CONCLUSION: We confirm previous studies that report better prognosis/survival on SDBC patients. This is probably due to a higher proportion of stage I and luminal-A cases versus non-SDBC. In turn, the survival benefit observed in patients with PC health insurance might be attributed to a larger proportion of SDBC. Our data support the implementation of a systematic BC screening program in Chile to improve patient prognosis and survival rates.

Oncological resection, myasthenia gravis and staging as prognostic factors in thymic tumours: a Chilean case series.

BACKGROUND: Thymic epithelial tumours are rare and highly heterogeneous. Reports from the United States suggest an overall incidence of 0.15 per 100,000/year. In contrast, the incidence of these tumours in Latin America is largely unknown and reports are scarce, somewhat limited to case reports. METHODS: Herein, we report a series of 38 thymic tumours from a single institution, retrospectively incorporated into this study. Patient characteristics and outcomes including age, sex, stage, paraneoplastic syndromes, treatment regimens and the date of decease were obtained from medical records. RESULTS: Most cases in our series were females and young age (<50 years old) and early stage by Masaoka-Koga or the Moran staging systems. Also, a 34% of patients had myasthenia gravis (MG). Next, we analysed overall survival rates in our series and found that the quality of surgery (R0, R1 or R2), MG status and staging (Masaoka-Koga, Moran or TNM) were prognostic factors. Finally, we compared our data to larger thymic tumour series. CONCLUSIONS: Overall, our study confirms complete surgical resection as the standard, most effective treatment for thymic epithelial tumours. Also, the Masaoka-Koga staging system remains as a reliable prognostic factor but also the Moran staging system should be considered for thymomas.

Case Report: Molecular Features and Treatment Options for Small Bowel Adenocarcinoma.

Small bowel adenocarcinoma (SBA) is a rare malignancy characterized by poor prognosis. Recent efforts have sought to elucidate the genetic landscape and the molecular drivers behind this disease. Herein, we report the main molecular alterations in two metastatic (stage IV) SBA patients. Interestingly, one of them had gene alterations that affected signaling pathways previously described for SBA. However, a second patient displayed previously unreported alterations in this particular tumor type. Based on these findings we discuss potential treatment options for patients affected by this rare, aggressive disease.

The Reprimo-Like Gene Is an Epigenetic-Mediated Tumor Suppressor and a Candidate Biomarker for the Non-Invasive Detection of Gastric Cancer.

Reprimo-like (RPRML) is an uncharacterized member of the Reprimo gene family. Here, we evaluated the role of RPRML and whether its regulation by DNA methylation is a potential non-invasive biomarker of gastric cancer. RPRML expression was evaluated by immunohistochemistry in 90 patients with gastric cancer and associated with clinicopathologic characteristics and outcomes. The role of RPRML in cancer biology was investigated in vitro, through RPRML ectopic overexpression. Functional experiments included colony formation, soft agar, MTS, and Ki67 immunofluorescence assays. DNA methylation-mediated silencing was evaluated by the 5-azacytidine assay and direct bisulfite sequencing. Non-invasive detection of circulating methylated RPRML DNA was assessed in 25 gastric cancer cases and 25 age- and sex-balanced cancer-free controls by the MethyLight assay. Downregulation of RPRML protein expression was associated with poor overall survival in advanced gastric cancer. RPRML overexpression significantly inhibited clonogenic capacity, anchorage-independent growth, and proliferation in vitro. Circulating methylated RPRML DNA distinguished patients with gastric cancer from controls with an area under the curve of 0.726. The in vitro overexpression results and the poor patient survival associated with lower RPRML levels suggest that RPRML plays a tumor-suppressive role in the stomach. Circulating methylated RPRML DNA may serve as a biomarker for the non-invasive detection of gastric cancer.

A Molecular Stratification of Chilean Gastric Cancer Patients with Potential Clinical Applicability.

Gastric cancer (GC) is a complex and heterogeneous disease. In recent decades, The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) defined GC molecular subtypes. Unfortunately, these systems require high-cost and complex techniques and consequently their impact in the clinic has remained limited. Additionally, most of these studies are based on European, Asian, or North American GC cohorts. Herein, we report a molecular classification of Chilean GC patients into five subtypes, based on immunohistochemical (IHC) and in situ hybridization (ISH) methods. These were Epstein-Barr virus positive (EBV+), mismatch repair-deficient (MMR-D), epithelial to mesenchymal transition (EMT)-like, and accumulated (p53+) or undetected p53 (p53-). Given its lower costs this system has the potential for clinical applicability. Our results confirm relevant molecular alterations previously reported by TCGA and ACRG. We confirm EBV+ and MMR-D patients had the best prognosis and could be candidates for immunotherapy. Conversely, EMT-like displayed the poorest prognosis; our data suggest FGFR2 or KRAS could serve as potential actionable targets for these patients. Finally, we propose a low-cost step-by-step stratification system for GC patients. To the best of our knowledge, this is the first Latin American report on a molecular classification for GC. Pending further validation, this stratification system could be implemented into the routine clinic.

Retrospective Analysis of Chilean and Mexican GI Stromal Tumor Registries: A Tale of Two Latin American Realities.

PURPOSE: Like other malignancies, GI stromal tumors (GIST) are highly heterogeneous. This not only applies to histologic features and malignant potential, but also to geographic incidence rates. Several studies have reported GIST incidence and prevalence in Europe and North America. In contrast, GIST incidence rates in South America are largely unknown, and only a few studies have reported GIST prevalence in Latin America. PATIENTS AND METHODS: Our study was part of a collaborative effort between Chile and Mexico, called Salud con Datos. We sought to determine GIST prevalence and patients' clinical characteristics, including survival rates, through retrospective analysis. RESULTS: Overall, 624 patients were included in our study. Our results found significant differences between Mexican and Chilean registries, such as stage at diagnosis, primary tumor location, CD117-positive immunohistochemistry status, mitotic index, and tumor size. Overall survival (OS) times for Chilean and Mexican patients with GIST were 134 and 156 months, respectively. No statistically significant differences in OS were detected by sex, age, stage at diagnosis, or recurrence status in both cohorts. As expected, patients categorized as being at high risk of recurrence displayed a trend toward poorer progression-free survival in both registries. CONCLUSION: To the best of our knowledge, this is the largest report from Latin America assessing the prevalence, clinical characteristics, postsurgery risk of recurrence, and outcomes of patients with GIST. Our data confirm surgery as the standard treatment of localized disease and confirm a poorer prognosis in patients with regional or distant disease. Finally, observed differences between registries could be a result of registration bias.

High Proportion of Potential Candidates for Immunotherapy in a Chilean Cohort of Gastric Cancer Patients: Results of the FORCE1 Study.

Gastric cancer (GC) is a heterogeneous disease. This heterogeneity applies not only to morphological and phenotypic features but also to geographical variations in incidence and mortality rates. As Chile has one of the highest mortality rates within South America, we sought to define a molecular profile of Chilean GCs (ClinicalTrials.gov identifier: NCT03158571/(FORCE1)). Solid tumor samples and clinical data were obtained from 224 patients, with subsets analyzed by tissue microarray (TMA; n = 90) and next generation sequencing (NGS; n = 101). Most demographic and clinical data were in line with previous reports. TMA data indicated that 60% of patients displayed potentially actionable alterations. Furthermore, 20.5% were categorized as having a high tumor mutational burden, and 13% possessed micro-satellite instability (MSI). Results also confirmed previous studies reporting high Epstein-Barr virus (EBV) positivity (13%) in Chilean-derived GC samples suggesting a high proportion of patients could benefit from immunotherapy. As expected, TP53 and PIK3CA were the most frequently altered genes. However, NGS demonstrated the presence of TP53, NRAS, and BRAF variants previously unreported in current GC databases. Finally, using the Kendall method, we report a significant correlation between EBV+ status and programmed death ligand-1 (PDL1)+ and an inverse correlation between p53 mutational status and MSI. Our results suggest that in this Chilean cohort, a high proportion of patients are potential candidates for immunotherapy treatment. To the best of our knowledge, this study is the first in South America to assess the prevalence of actionable targets and to examine a molecular profile of GC patients.

Chilean Registry for Neuroendocrine Tumors: A Latin American Perspective.

Neuroendocrine tumors (NETs) are relatively rare and highly heterogeneous neoplasms. Despite this, recent studies from North America and Central Europe have suggested an increase in incidence. In Latin America, NET data are scarce and scattered with only a few studies reporting registries. Our goal was to establish a NET registry in Chile. Here, we report the establishment and our first 166 NET patients. We observed a slight preponderance of males, a median age at diagnosis of 53 years and a median overall survival of 110 months. As anticipated, most tumors were gastroenteropancreatic (GEP). Survival analyses demonstrated that non-GEP or stage IV tumors presented significantly lower overall survival (OS). Similarly, patients with surgery classified as R0 had better OS compared to R1, R2, or no surgery. Furthermore, patients with elevated chromogranin A (CgA) or high Ki67 showed a trend to poorer OS; however, these differences did not reach statistical significance (log-rank test p = 0.07). To the best of our knowledge, this is the first report of a NET registry in Chile. Median OS in our registry (110 months) is in line with other registries from Argentina and Spain. Other variables including age at diagnosis and gender were similar to previous studies; however, our data indicate a high proportion of small-bowel NETs compared to other cohorts, reflecting the need for NET regional registries. Indeed, these registries may explain regional discrepancies in incidence and distribution, adding to our knowledge on this seemingly rare, highly heterogeneous disease.

FR58P1a; a new uncoupler of OXPHOS that inhibits migration in triple-negative breast cancer cells via Sirt1/AMPK/ß1-integrin pathway.

Highly malignant triple-negative breast cancer (TNBC) cells rely mostly on glycolysis to maintain cellular homeostasis; however, mitochondria are still required for migration and metastasis. Taking advantage of the metabolic flexibility of TNBC MDA-MB-231 cells to generate subpopulations with glycolytic or oxidative phenotypes, we screened phenolic compounds containing an ortho-carbonyl group with mitochondrial activity and identified a bromoalkyl-ester of hydroquinone named FR58P1a, as a mitochondrial metabolism-affecting compound that uncouples OXPHOS through a protonophoric mechanism. In contrast to well-known protonophore uncoupler FCCP, FR58P1a does not depolarize the plasma membrane and its effect on the mitochondrial membrane potential and bioenergetics is moderate suggesting a mild uncoupling of OXPHOS. FR58P1a activates AMPK in a Sirt1-dependent fashion. Although the activation of Sirt1/AMPK axis by FR58P1a has a cyto-protective role, selectively inhibits fibronectin-dependent adhesion and migration in TNBC cells but not in non-tumoral MCF10A cells by decreasing ß1-integrin at the cell surface. Prolonged exposure to FR58P1a triggers a metabolic reprograming in TNBC cells characterized by down-regulation of OXPHOS-related genes that promote cell survival but comprise their ability to migrate. Taken together, our results show that TNBC cell migration is susceptible to mitochondrial alterations induced by small molecules as FR58P1a, which may have therapeutic implications.

Chilean Gastric Cancer Task Force: A study protocol to obtain a clinical and molecular classification of a cohort of gastric cancer patients.

Gastric cancer (GC) is the world's second-leading cause of neoplastic mortality. Genetic alterations, response to treatments, and mortality rates are highly heterogeneous across different regions. Within Latin America, GC is the leading cause of cancer death in Chile, affecting 17.6 per 100,000 people and causing >3000 deaths/y. Clinical outcomes and response to "one size fits all" therapies are highly heterogeneous and thus a better stratification of patients may aid cancer treatment and response.The Gastric Cancer Task Force is a Chilean collaborative, noninterventional study that seeks to stratify gastric adenocarcinomas using clinical outcomes and genomic, epigenomic, and protein alterations in a cohort of 200 patients. Tumor samples from the Pathology Department and the Cancer Center at UC-Christus healthcare network, Pontificia Universidad Católica de Chile will be analyzed using a panel of 143 known cancer genes (Oncomine Comprehensive Assay) at the Center of Excellence in Precision Medicine in Santiago, Chile. In addition, promoter methylation for selected genes will be performed along with tissue microarray for clinically relevant proteins (e.g., PD-L1, Erb-2, VEGFR2, among others) and Helicobacter pylori and Epstein-Barr virus status. Obtained data will be correlated to 120 clinical parameters retrieve from medical records, including general patient information, cancer history, laboratory studies, comorbidity index, chemotherapy, targeted therapies, efficacy, and follow-up.The development of a clinically meaningful classification that encompasses comprehensive clinical and molecular parameters may improve patient treatment, predict clinical outcomes, aid patient selection/stratification for clinical trials and may offer insights into future preventive and/or therapeutic strategies in patients from Latin America region. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03158571, Registered on May 18, 2017.

Small structural changes on a hydroquinone scaffold determine the complex I inhibition or uncoupling of tumoral oxidative phosphorylation.

Mitochondria participate in several distinctiveness of cancer cell, being a promising target for the design of anti-cancer compounds. Previously, we described that ortho-carbonyl hydroquinone scaffold 14 inhibits the complex I-dependent respiration with selective anti-proliferative effect on mouse mammary adenocarcinoma TA3/Ha cancer cells; however, the structural requirements of this hydroquinone scaffold to affect the oxidative phosphorylation (OXPHOS) of cancer cells have not been studied in detail. Here, we characterize the mitochondrial metabolism of TA3/Ha cancer cells, which exhibit a high oxidative metabolism, and evaluate the effect of small structural changes of the hydroquinone scaffold 14 on the respiration of this cell line. Our results indicate that these structural changes modify the effect on OXPHOS, obtaining compounds with three alternative actions: inhibitors of complex I-dependent respiration, uncoupler of OXPHOS and compounds with both actions. To confirm this, the effect of a bicyclic hydroquinone (9) was evaluated in isolated mitochondria. Hydroquinone 9 increased mitochondrial respiration in state 4o without effects on the ADP-stimulated respiration (state 3ADP), decreasing the complexes I and II-dependent respiratory control ratio. The effect on mitochondrial respiration was reversed by 6-ketocholestanol addition, indicating that this hydroquinone is a protonophoric uncoupling agent. In intact TA3/Ha cells, hydroquinone 9 caused mitochondrial depolarization, decreasing intracellular ATP and NAD(P)H levels and GSH/GSSG ratio, and slightly increasing the ROS levels. Moreover, it exhibited selective NAD(P)H availability-dependent anti-proliferative effect on cancer cells. Therefore, our results indicate that the ortho-carbonyl hydroquinone scaffold offers the possibility to design compounds with specific actions on OXPHOS of cancer cells.