Chemical perturbations impacting histone acetylation govern colorectal cancer differentiation.

Dysregulated epigenetic programs that restrict differentiation, reactivate fetal genes, and confer phenotypic plasticity are critical to colorectal cancer (CRC) development. By screening a small molecule library targeting epigenetic regulators using our dual reporter system, we found that inhibiting histone deacetylase (HDAC) 1/2 promotes CRC differentiation and anti-tumor activity. Comprehensive biochemical, chemical, and genetic experiments revealed that on-target blockade of the HDAC1/2 catalytic domain mediated the differentiated phenotype.

First-in-Human Dose-Escalation Study of Fianlimab, an Antilymphocyte Activation Gene-3 Antibody, with Cemiplimab in Patients with Advanced Malignancies.

Purpose: Preclinical data indicate that fianlimab (antilymphocyte activation gene-3) plus cemiplimab (anti-PD-1) enhances antitumor activity. Here, we report prespecified final analyses of the dose-escalation part of a first-in-human, phase 1 study (NCT03005782) of fianlimab as monotherapy and in combination with cemiplimab in patients with advanced malignancies.

Patients And Methods: Adult patients received 1 to 40 mg/kg of fianlimab plus 350 mg of cemiplimab every 3 weeks (Q3W) across various dose-escalation schedules.

Ramucirumab plus FOLFIRI or irinotecan as second-line treatment for patients with gastroesophageal adenocarcinoma: a review and meta-analysis of an emerging option.

Introduction: The aim of this study was to provide a review of the clinical evidence for use of ramucirumab (RAM) plus folinic acid (leucovorin), fluorouracil (5-FU), and irinotecan (FOLFIRI) or irinotecan as second-line treatment in gastroesophageal adenocarcinoma (GEA).

Methods: A systematic and comprehensive search of PubMed was performed to identify phase 2 clinical trials or retrospective studies using RAM plus FOLFIRI or irinotecan in GEA, including abstracts from major congresses, in addition to published manuscripts. An aggregated review and meta-analysis was performed to assess the effectiveness (overall response rate [ORR] as primary outcome) and safety data of RAM plus FOLFIRI or irinotecan.

PD-L1 has a heterogeneous and dynamic expression in gastric cancer with implications for immunoPET.

Introduction: This study aimed to investigate the dynamics of programmed death-ligand 1 (PD-L1) expression, spatial heterogeneity, and binding affinity of FDA-approved anti-PD-L1 antibodies (avelumab and atezolizumab) in gastric cancer. Additionally, we determined how PD-L1 glycosylation impacts antibody accumulation in gastric cancer cells.

Methods: Dynamic PD-L1 expression was examined in NCIN87 gastric cancer cells.

Transferrin receptor in primary and metastatic breast cancer: Evaluation of expression and experimental modulation to improve molecular targeting.

Background: Conjugation of transferrin (Tf) to imaging or nanotherapeutic agents is a promising strategy to target breast cancer. Since the efficacy of these biomaterials often depends on the overexpression of the targeted receptor, we set out to survey expression of transferrin receptor (TfR) in primary and metastatic breast cancer samples, including metastases and relapse, and investigate its modulation in experimental models.

Methods: Gene expression was investigated by datamining in twelve publicly-available datasets.

Chemotherapy and Immune Checkpoint Blockade for Gastric and Gastroesophageal Junction Adenocarcinoma.

Importance: Combining immune checkpoint blockade (ICB) with chemotherapy improves outcomes in patients with metastatic gastric and gastroesophageal junction (G/GEJ) adenocarcinoma; however, whether this combination has activity in the perioperative setting remains unknown.

Objective: To evaluate the safety and preliminary activity of perioperative chemotherapy and ICB followed by maintenance ICB in resectable G/GEJ adenocarcinoma.

Design, Setting, And Participants: This investigator-initiated, multicenter, open-label, single-stage, phase 2 nonrandomized controlled trial screened 49 patients and enrolled 36 patients with resectable G/GEJ adenocarcinoma from February 10, 2017, to June 17, 2021, with a median (range) follow-up of 35.

A Pilot Study of Paricalcitol plus Nanoliposomal Irinotecan and 5-FU/LV in Advanced Pancreatic Cancer Patients after Progression on Gemcitabine-Based Therapy.

Purpose: Vitamin D analogues remodel the desmoplastic stroma, and improve vascularity and efficacy of chemotherapy in preclinical pancreas cancer models.

Patients And Methods: We conducted a pilot study to evaluate the safety and preliminary efficacy of the vitamin D analogue paricalcitol in combination with nanoliposomal irinotecan (Nal-iri) plus 5-fluorouracil/leucovorin (5-FU/LV) in patients with advanced pancreatic cancer who had progressed on gemcitabine-based therapy. Two dose levels (DL) of paricalcitol were tested: fixed dose weekly (75 mcg, DL1) and weight-based weekly (7 mcg/kg, /DL2).

Impact of BMI in Patients With Early Hormone Receptor-Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS Trial.

Purpose: BMI affects breast cancer risk and prognosis. In contrast to cytotoxic chemotherapy, CDK4/6 inhibitors are given at a fixed dose, irrespective of BMI or weight. This preplanned analysis of the global randomized PALLAS trial investigates the impact of BMI on the side-effect profile, treatment adherence, and efficacy of palbociclib.

Context-dependent activation of STING-interferon signaling by CD11b agonists enhances anti-tumor immunity.

Chronic activation of inflammatory pathways and suppressed interferon are hallmarks of immunosuppressive tumors. Previous studies have shown that CD11b integrin agonists could enhance anti-tumor immunity through myeloid reprograming, but the underlying mechanisms remain unclear. Herein we find that CD11b agonists alter tumor-associated macrophage (TAM) phenotypes by repressing NF-κB signaling and activating interferon gene expression simultaneously.

Circulating Tumor DNA as a Predictive Biomarker for Clinical Outcomes With Margetuximab and Pembrolizumab in Pretreated HER2-Positive Gastric/ Gastroesophageal Adenocarcinoma.

Purpose: To assess the ability of circulating tumor DNA (ctDNA)-based testing to identify patients with HER2 (encoded by ERBB2)-positive gastric/gastroesophageal adenocarcinoma (GEA) who progressed on or after trastuzumab-containing treatments were treated with combination therapy of anti-HER2 and anti-PD-1 agents.

Methods: ctDNA analysis was performed retrospectively using plasma samples collected at study entry from 86 patients participating in the phase 1/2 CP-MGAH22-05 study (NCT02689284).

Results: Objective response rate (ORR) was significantly higher in evaluable ERBB2 amplification-positive vs - negative patients based on ctDNA analysis at study entry (37% vs 6%, respectively; P = .

Antitumour activity of neratinib in patients with HER2-mutant advanced biliary tract cancers.

HER2 mutations are infrequent genomic events in biliary tract cancers (BTCs). Neratinib, an irreversible, pan-HER, oral tyrosine kinase inhibitor, interferes with constitutive receptor kinase activation and has activity in HER2-mutant tumours. SUMMIT is an open-label, single-arm, multi-cohort, phase 2, 'basket' trial of neratinib in patients with solid tumours harbouring oncogenic HER2 somatic mutations (ClinicalTrials.

Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline.

Purpose: To develop recommendations involving targeted therapies for patients with advanced gastroesophageal cancer.

Methods: The American Society of Clinical Oncology convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice.

Results: Eighteen randomized controlled trials met the inclusion criteria for the systematic review.

Manufacturing-dependent change in biological activity of the TLR4 agonist GSK1795091 and implications for lipid A analog development.

A phase I trial (NCT03447314; 204686) evaluated the safety and efficacy of GSK1795091, a Toll-like receptor 4 (TLR4) agonist, in combination with immunotherapy (GSK3174998 [anti-OX40 monoclonal antibody], GSK3359609 [anti-ICOS monoclonal antibody], or pembrolizumab) in patients with solid tumors. The primary endpoint was safety; other endpoints included efficacy, pharmacokinetics, and pharmacodynamics (PD). Manufacturing of GSK1795091 formulation was modified during the trial to streamline production and administration, resulting in reduced PD (cytokine) activity.

Screening of Carbofuran-Degrading Bacteria sp. BSC2-3 and Unveiling the Change in Metabolome during Carbofuran Degradation.

Carbofuran is one of the most commonly used N-methylcarbamate-based pesticides and is excellent for controlling pests; however, carbofuran also causes soil and water pollution. Although various studies have been conducted on the bioremediation of pesticide-contaminated soil, the changes occurring in the metabolome during the bioremediation of carbofuran are not fully understood. In this study, the intracellular and extracellular metabolites of the sp.

Phase 1b trial of anti-VEGF/PDGFR vorolanib combined with immune checkpoint inhibitors in patients with advanced solid tumors.

Purpose: Vorolanib is a multi-target tyrosine kinase inhibitor with anti-angiogenic properties. This study aimed to evaluate the tolerability, safety and efficacy of vorolanib when added to checkpoint inhibitors (CPIs) in patients with advanced solid tumors.

Methods: We conducted a phase 1b study of vorolanib (300 or 400 mg orally once daily) plus pembrolizumab or nivolumab using a standard 3 + 3 design to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D).

Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Gastric cancer is the third leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage.

Durvalumab plus tremelimumab alone or in combination with low-dose or hypofractionated radiotherapy in metastatic non-small-cell lung cancer refractory to previous PD(L)-1 therapy: an open-label, multicentre, randomised, phase 2 trial.

Background: Patients with non-small-cell lung cancer (NSCLC) that is resistant to PD-1 and PD-L1 (PD[L]-1)-targeted therapy have poor outcomes. Studies suggest that radiotherapy could enhance antitumour immunity. Therefore, we investigated the potential benefit of PD-L1 (durvalumab) and CTLA-4 (tremelimumab) inhibition alone or combined with radiotherapy.

A phase II study of everolimus in patients with advanced solid malignancies with or mutations.

Background: Activation of the mTOR pathway has been implicated in the development of several malignancies and alterations in and , can lead to the dysregulation of this pathway. Furthermore, mutations in and are known to confer sensitivity to everolimus-an mTOR inhibitor. Based on these data, a single-arm, open label, single-institution phase II basket study was designed to assess the activity of everolimus in patients with solid malignancies whose tumors harbored mutations in , or .

Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer.

Background: The PI3K/AKT/mTOR (PAM) pathway is a key regulator of tumor therapy resistance. We investigated M2698, an oral p70S6K/AKT dual inhibitor, in patients with advanced cancer who failed standard therapies.

Methods: M2698 was administered as monotherapy (escalation, 15-380 mg daily; food effect cohort, 240-320 mg daily) and combined with trastuzumab or tamoxifen.