E-Cadherin-Deficient Epithelial Cells Are Sensitive to HDAC Inhibitors

Inactivating germline mutations in the CDH1 gene (encoding the E-cadherin protein) are the genetic hallmark of hereditary diffuse gastric cancer (HDGC), and somatic CDH1 mutations are an early event in the development of sporadic diffuse gastric cancer (DGC) and lobular breast cancer (LBC). In this study, histone deacetylase (HDAC) inhibitors were tested for their ability to preferentially inhibit the growth of human cell lines (MCF10A and NCI-N87) and murine organoids lacking CDH1 expression. CDH1−/− breast and gastric cells were more sensitive to the pan-HDAC inhibitors entinostat, pracinostat, mocetinostat and vorinostat than wild-type cells, with an elevated growth inhibition that was, in part, attributable to increased apoptosis. CDH1-null cells were also sensitive to more class-specific HDAC inhibitors, but compared to the pan-inhibitors, these effects were less robust to genetic background. Increased sensitivity to entinostat was also observed in gastric organoids with both Cdh1 and Tp53 deletions. However, the deletion of Tp53 largely abrogated the sensitivity of the Cdh1-null organoids to pracinostat and mocetinostat. Finally, entinostat enhanced Cdh1 expression in heterozygous Cdh1+/− murine organoids. In conclusion, entinostat is a promising drug for the chemoprevention and/or treatment of HDGC and may also be beneficial for the treatment of sporadic CDH1-deficient cancers.

The role of AKR1 family in tamoxifen resistant invasive lobular breast cancer based on data mining

Background Tamoxifen (TAM) resistance to invasive lobular cell carcinoma is a challenge for breast cancer treatment. This study explored the role of Aldo-keto reductase family 1 (AKR1) family in tamoxifen-resistant aggressive lobular breast cancer based on data mining. Methods TAM-resistant invasive lobular breast cancer gene chip was downloaded from the Gene Expression Omnibus (GEO) database (accession-numbered as GSE96670). The online analytical tool GEO2R was used to screen for differentially expressed genes in TAM-resistant invasive lobular breast cancer cells and TAM-sensitive counterparts. A protein-protein interaction (PPI) networks were constructed using the STRING online platform and the Cytoscape software. GeneMANIA and GSCALite online tools were used to reveal the potential role of these hub genes in breast cancer progression and TAM resistance development. And the used the GSE67916 microarray data set to verify the differentially expression of these hub genes in breast cancer. The protein expression levels of AKR1C1, AKR1C2 and AKR1C3 in TAM-sensitive and resistant breast cancer cells were compared. The TAM sensitivity of breast cancer cells with or without AKR1C1, AKR1C2 or AKR1C3 gene manipulation was evaluated by cell viability assay. Results A total of 184 differentially expressed genes were screened. Compared with TAM sensitive breast cancer cells, 162 were up-regulated and 22 were down-regulated. The study identified several hub genes in the PPI network that may be involved in the development of TAM resistance of breast cancer, including signal transducer and activator of transcription 1 (STAT1), estrogen receptor alpha (ESR1), fibronectin1 (FN1), cytochrome P4501B1 (CYP1B1), AKR1C1, AKR1C2, AKR1C3 and uridine diphosphate glucuronosyltransferase (UGT) 1A family genes (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10). Compared with TAM-sensitive counterparts, the expression levels of AKR1C1, AKR1C2, and AKR1C3 were up-regulated in TAM-resistant breast cancer cells. Conclusions Overexpression of each of these three genes significantly increased the resistance of breast cancer cells to TAM treatment, while their knockdown showed opposite effects, indicating that they are potential therapeutic target for the treatment of TAM-resistant breast cancer.

A Rare Metastatic Site of Invasive Lobular Breast Carcinoma: A Case Report

Here, we report a case of a 42-year-old female patient with left lobular breast cancer-gastric metastasis (initially misdiagnosed five years ago as an invasive ductal carcinoma) presenting with dyspepsia, weight loss, and persistent vomiting lasting for four weeks. Upper GI endoscopy revealed evidence of linitis plastica, and histological and immunocytochemical analyses of the biopsy confirmed gastric metastasis secondary to invasive lobular breast carcinoma.

397 A phase I/II trial of intracerebroventricular 177Lu DTPA omburtamab radioimmunotherapy for leptomeningeal metastasis from solid tumors

BackgroundLeptomeningeal metastasis (LM) from solid tumors may be diagnosed in approximately 10% of patients with metastatic cancer and can occur with virtually all malignant tumors. Median overall survival (OS) is poor and limited to a few months with LM-directed treatment, including available targeted therapy, immunotherapy and radiation therapy. Omburtamab specifically binds to B7-H3 (CD276), a transmembrane glycoprotein of the immunoglobulin superfamily. The limited expression of B7-H3 on normal cells, including normal brain, combined with the broad expression in various types of solid tumors, makes B7-H3 a target for radioimmunotherapy of LM from solid tumors. In this first-in-human trial the safety and efficacy of intracerebroventricular administration of radiolabeled omburtamab, 177Lu-DTPA-omburtamab, will be evaluated in patients with LM from ductal or lobular breast cancer, non-small cell lung cancer, or melanoma.MethodsThis is an open-label phase I/II study. Part 1 is a dose-escalation phase to be conducted at ~4 sites (US/Europe) with a primary objective of identifying the maximum tolerated dose and/or recommended phase II dose for Part 2 (RP2D). It will follow a 3+3 design with pts receiving up to five 5-week cycles of 177Lu-DTPA-omburtamab. Part 2 is a cohort-expansion phase at ~9 sites (US/Europe) in which a maximum of 48 patients in 3 cohorts (ductal or lobular breast cancer [cohort A], non-small cell lung cancer [cohort B], and melanoma [cohort C]) with up to 16 patients in each will receive up to five 5 week cycles of treatment with intracerebroventricular 177Lu DTPA omburtamab at the RP2D determined in Part 1. The primary objective of Part 2 is to establish the safety of repeat doses of 177Lu-omburtamab. Additional objectives of Parts 1/2 include the evaluation of absorbed radiation doses, PK profile, investigator-assessed response, duration of response, progression-free survival, and OS. Key inclusion criteria include diagnosis of either ductal or lobular breast cancer, non-small cell lung cancer, or malignant melanoma and diagnosis of recurrent or refractory LM; prior standard of care treatment of leptomeningeal disease; acceptable hematological, liver and kidney status; and a life expectancy of >2 months. The study has been approved by each institution’s ethics board, and patients provided informed consent before taking part.Trial RegistrationNCT04315246Ethics ApprovalThe study has been approved by each institution’s ethics board, and patients provided informed consent before taking part.