Acute myeloid leukemia (AML) is one of the most common hematopoietic malignancies and the development of new drugs is crucial for the treatment of this lethal disease. Iheyamine A is a nonmonoterpenoid azepinoindole alkaloid from the ascidian Polycitorella sp., and its anticancer mechanism has not been investigated in leukemias. Herein, we showed the significant antileukemic activity of L42 in AML cell lines HEL, HL-60 and THP-1. The IC50 values were 0.466±0.099 µM, 0.356±0.023 µM, 0.475±0.084 µM in the HEL, HL-60 and THP-1 cell lines, respectively, which were lower than the IC50 (2.594±0.271 µM) in the normal liver cell line HL-7702. Furthermore, L42 significantly inhibited the growth of peripheral blood mononuclear cells (PBMCs) from an AML patient. In vivo, L42 effectively suppressed leukemia progression in a mouse model induced by Friend murine leukemia virus (F-MuLV). Mechanistically, we showed that L42 induced cell cycle arrest and apoptosis in leukemia cell lines. RNA sequencing analysis of L42-treated THP-1 cells revealed that the differentially expressed genes (DEGs) were enriched in the cell cycle and apoptosis and predominantly enriched in the PI3K/AKT pathway. Accordingly, L42 decreased the expression of the phospho-PI3K (p85), phospho-AKT and phospho-FOXO3a. Docking and CETSA analysis indicated that L42 bound to the PI3K isoform p110α (PIK3CA), which was implicated in the suppression of the PI3K/AKT pathway. L42 was also shown to initiate the TNF signaling-mediated apoptosis. Moreover, L42 exhibited stronger anti-leukemia activity and sensitivity in IDH2-mutant HEL cells than in IDH2-wild-type control. In conclusion, L42 effectively suppresses cell proliferation and triggers apoptosis in AML cell lines in part through inhibition of the PI3K/AKT signaling pathway to restore FOXO3a expression and activation of the TNF signaling pathway. Thus, the iheyamine A derivative L42 represents a novel candidate for AML therapy.

The aggressive characteristics of triple-negative breast cancer (TNBC) and the absence of targeted medicines make TNBC a challenging clinical case. The molecular landscape of TNBC has been well-understood thanks to recent developments in multi-omic analysis, which have also revealed dysregulated pathways and possible treatment targets. This review summarizes the utilization of multi-omic approaches in elucidating TNBC\'s complex biology and therapeutic avenues. Dysregulated pathways including cell cycle progression, immunological modulation, and DNA damage response have been uncovered in TNBC by multi-omic investigations that integrate genomes, transcriptomics, proteomics, and metabolomics data. Methods like this pave the door for the discovery of new therapeutic targets, such as the EGFR, PARP, and mTOR pathways, which in turn direct the creation of more precise treatments. Recent developments in TNBC treatment strategies, including immunotherapy, PARP inhibitors, and antibody-drug conjugates, show promise in clinical trials. Emerging biomarkers like MUC1, YB-1, and immune-related markers offer insights into personalized treatment approaches and prognosis prediction. Despite the strengths of multi-omic analysis in offering a more comprehensive view and personalized treatment strategies, challenges exist. Large sample sizes and ensuring high-quality data remain crucial for reliable findings. Multi-omic analysis has revolutionized TNBC research, shedding light on dysregulated pathways, potential targets, and emerging biomarkers. Continued research efforts are imperative to translate these insights into improved outcomes for TNBC patients.

The PI3K/AKT pathway plays a pivotal role in cellular processes, and its dysregulation is implicated in various cancers, including colorectal cancer. The present study correlates the expression levels of critical genes (PIK3CA, PTEN, AKT1, FOXO1, and FRAP) in 60 tumor tissues with clinicopathological and demographic characteristics. The results indicate age-related variation in FOXO1 gene expression, with higher levels observed in patients aged 68 and above. In addition, tumors originating from the rectum exhibit higher FOXO1 expression compared to colon tumors, suggesting region-specific differences in expression. The results also identify the potential correlation between PTEN, PIK3CA gene expression, and parameters such as tumor grade and neuroinvasion. The bioinformatic comparative analysis found that PTEN and FOXO1 expressions were downregulated in colorectal cancer tissue compared to normal colon tissue. Relapse-free survival analysis based on gene expression identified significant correlations, highlighting PTEN and FRAP as potential indicators of favorable outcomes. Our findings provide a deeper understanding of the role of the PI3K/AKT pathway in colorectal cancer and the importance of understanding the molecular basis of colorectal cancer development and progression.

OBJECTIVE: Our aim was to compare the PIK3CA mutation status in matched primary and recurrent tumors of hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer (BC) to gain insight into the optimization of patient selection and detection time for PIK3CA-targeted therapy.
METHODS: The data were from 3035 patients with BC diagnosed at the Breast Disease Center, Peking University First Hospital, between January 2008 and December 2017. Matched primary and recurrent samples were profiled using amplification-refractory mutation system-polymerase chain reaction covering 11 mutational hotspots in PIK3CA.
RESULTS: PIK3CA mutations were detected in 54.3% primary tumors and 48.6% corresponding recurrences. PIK3CA mutation was detected in 37.5% cases in the locoregional recurrent group and 40.0% of distant metastasis, without a statistical difference. Besides, PIK3CA mutations were concordant in 88.6% of the matched pairs. For patients treated with neoadjuvant chemotherapy, 100% concordance was observed. However, PIK3CA mutation was neither correlated with clinicopathological features nor associated with clinical outcomes.
CONCLUSIONS: Mutations in PIK3CA in HR+/HER2- BC generally progressed to recurrent tumors. The high concordance rate of PIK3CA mutation status between primary tumors and corresponding recurrences suggests that the detection of primary tumors could be a substitute approach when recurrent samples are not easily obtainable.

Breast cancer has distinct causes and molecular characteristics at premenopausal and postmenopausal ages. The age-standardized incidence rate for postmenopausal breast cancer is more than 10 times higher than in premenopausal breast cancer. Here, we showed that the expression of 10 out of 20 most frequently mutated genes in breast cancer (namely, PIK3CA, CDH1, MUC16, PTEN, FAT3, FAT1, SPEN, ARID1A, LRP1B and RUNX1) is higher in premenopausal women with breast cancer than in postmenopausal women with breast cancer. The most significant differences in the expression in terms of menopause status were observed for RUNX1 and FAT1. Furthermore, we found that the majority of these 10 genes also show ER (estrogen receptor) or PR (progesterone receptor) status-dependent expression in both premenopausal and postmenopausal breast cancer patients. Unlike what we observed in the case of ER or PR status, the expression of most of these genes does not change depending on HER2 (human epidermal growth factor receptor 2) status in both premenopausal and postmenopausal breast cancer patients. Combined, our analysis suggests that menopause status might influence the expression of most frequently mutated genes in breast cancer, and that the most of these genes whose expression differ between pre- and post-menopausal women with breast cancer also show ER or PR status-dependent expression in women with breast cancer.

PIK3CA is one among the several mutated genes in cancer, including head and neck squamous cell carcinoma (HNSCC). H1047R is a hotspot somatic mutation in PIK3CA that occurs most frequently in several forms of cancers. Distribution of PIK3CA H1047R mutation in Indian HNSCC patients was screened and its effect on disease progression and response to treatment was analysed in this study. Genomic DNA was extracted from tumour biopsies of HNSCC patients (n = 48) and polymerase chain reaction coupled restriction fragment length polymorphism (PCR-RFLP) technique was used to screen for the mutation. Overall survival (OS) and Progression-free survival (PFS) of the patients were calculated in order to study effect of this mutation on survival and response to treatment respectively. Results showed that irrespective of patients\' criteria, twenty-five patients (52 %) carried a heterozygous form of mutation (His/Arg) and the rest (48 %) were wild type (His/His). The mean OS of the cohort with the mutation was 20.451 months (SE ± 1.710 months) while 26.31 months (SE ± 2.431) was in wild type population. PFS of the patients with the mutation was 18.612 months (SE ± 2.072), and for the wild type population, it was 26.31 months (SE ± 2.431). These observations suggest that Indian HNSCC patients with PIK3CA H1047R mutation have poor prognosis.

Lipomatoses are benign proliferation of adipose tissue. Lipomas (benign fat tumors) are the most common component of lipomatosis. They may be unique or multiple, encapsulated or not, subcutaneous or sometimes visceral. In some cases, they form large areas of non-encapsulated fat hypertrophy, with a variable degree of fibrosis. They can develop despite the absence of obesity. They may be familial or acquired. At difference with lipodystrophy syndromes, they are not associated with lipoatrophy areas, except in some rare cases such as type 2 familial partial lipodystrophy syndromes (FPLD2). Their metabolic impact is variable in part depending on associated obesity. They may have functional or aesthetic consequences. Lipomatosis may be isolated, be part of a syndrome, or may be visceral. Isolated lipomatoses include multiple symmetrical lipomatosis (Madelung disease or Launois-Bensaude syndrome), familial multiple lipomatosis, the painful Dercum\'s disease also called Adiposis Dolorosa or Ander syndrome, mesosomatic lipomatosis also called Roch-Leri lipomatosis, familial angiolipomatosis, lipedema and hibernomas. Syndromic lipomatoses include PIK3CA-related disorders, Cowden/PTEN hamartomas-tumor syndrome, some lipodystrophy syndromes, and mitochondrial diseases, especially MERRF, multiple endocrine neoplasia type 1, neurofibromatosis type 1, Wilson disease, Pai or Haberland syndromes. Finally, visceral lipomatoses have been reported in numerous organs and sites: pancreatic, adrenal, abdominal, epidural, mediastinal, epicardial… The aim of this review is to present the main types of lipomatosis and their physiopathological component, when it is known.

Borderline ovarian tumours (BOTs) show intriguing characteristics distinguishing them from other ovarian tumours. The aim of the systematic review was to analyse the spectrum of molecular changes found in BOTs and discuss their significance in the context of the overall therapeutic approach. The systematic review included articles published between 2000 and 2023 in the databases: PubMed, EMBASE, and Cochrane. After a detailed analysis of the available publications, we qualified for the systematic review: 28 publications on proto-oncogenes: BRAF, KRAS, NRAS, ERBB2, and PIK3CA, 20 publications on tumour suppressor genes: BRCA1/2, ARID1A, CHEK2, PTEN, 4 on adhesion molecules: CADM1, 8 on proteins: B-catenin, claudin-1, and 5 on glycoproteins: E-Cadherin. In addition, in the further part of the systematic review, we included eight publications on microsatellite instability and three describing loss of heterozygosity in BOT. Molecular changes found in BOTs can vary on a case-by-case basis, identifying carcinogenic mutations through molecular analysis and developing targeted therapies represent significant advancements in the diagnosis and treatment of ovarian malignancies. Molecular studies have contributed significantly to our understanding of BOT pathogenesis, but substantial research is still required to elucidate the relationship between ovarian neoplasms and extraneous disease, identify accurate prognostic indicators, and develop targeted therapeutic approaches.

BACKGROUND: In most patients with advanced human epidermal growth factor receptor-2-positive (HER2+) breast cancer, anti-HER2 therapies fail due to the development of acquired resistance, potentially mediated through phosphoinositide-3-kinase (PI3K) signaling. We investigated adding taselisib, an α-selective potent oral inhibitor of PI3K, to different HER2-directed regimens in order to improve disease control.
METHODS: Patients (n = 68) with advanced HER2+ breast cancer were enrolled to this open-label, dose-escalation phase Ib study. The primary endpoint was defining the maximal tolerated dose (MTD) for the various taselisib-containing combinations. The secondary endpoint was safety. Exploratory endpoints included circulating tumor DNA analysis. The study included four cohorts: (A) taselisib + trastuzumab emtansine (T-DM1), (C) taselisib + trastuzumab and pertuzumab (TP), (D) taselisib + TP + paclitaxel, and (E) taselisib + TP + fulvestrant.
RESULTS: Following dose escalation, the taselisib MTD was defined as 4 mg once daily. Treatment was associated with significant toxicities, as 34 out of 68 patients experienced grade ≥3 adverse events (AEs) attributed to taselisib, the most common all-grade AEs being diarrhea, fatigue, and oral mucositis. At a median follow-up of 43.8 months, median progression-free survival (PFS) for the MTD-treated population in cohorts A, C, and E was 6.3 [95% confidence interval (CI) 3.2-not applicable (NA)] months, 1.7 (95% CI 1.4-NA) months, and 10.6 (95% CI 8.3-NA) months, respectively. The median PFS for patients in cohort A with prior T-DM1 use was 10.4 (95% CI 2.7-NA) months.
CONCLUSIONS: PIK3CA targeting with taselisib in combination with HER2-targeted therapies was associated with both promising efficacy and substantial toxicities.

Around 75% of breast cancer (BC) patients have tumors expressing the predictive biomarker estrogen receptor α (ER) and are offered endocrine therapy. One-third eventually develop endocrine resistance, a majority with retained ER expression. Mutations in the phosphatidylinositol bisphosphate 3-kinase (PI3K) catalytic subunit encoded by PIK3CA is a proposed resistance mechanism and a pharmacological target in the clinical setting. Here we explore the frequency of PIK3CA mutations in endocrine-resistant BC before and during treatment and correlate to clinical features. Patients with ER-positive (ER +), human epidermal growth factor receptor 2 (HER2)-negative primary BC with an ER + relapse within 5 years of ongoing endocrine therapy were retrospectively assessed. Tissue was collected from primary tumors (n = 58), relapse tumors (n = 54), and tumor-free lymph nodes (germline controls, n = 62). Extracted DNA was analyzed through panel sequencing. Somatic mutations were observed in 50% (31/62) of the patients, of which 29% occurred outside hotspot regions. The presence of PIK3CA mutations was significantly associated with nodal involvement and mutations were more frequent in relapse than primary tumors. Our study shows the different PIK3CA mutations in endocrine-resistant BC and their fluctuations during therapy. These results may aid investigations of response prediction, facilitating research deciphering the mechanisms of endocrine resistance.