HER2 Alterations across Solid Tumors: Implications for Comprehensive Testing.

Purpose: ERBB2 (HER2) alterations (e.g., overexpression, amplification, and mutations) are known to drive tumor progression.

Phase I trial of ADP-A2AFP TCR T-cell therapy in patients with advanced hepatocellular or gastric hepatoid carcinoma.

Background & Aims: Patients with advanced hepatocellular carcinoma (HCC) generally experience poor outcomes despite current therapies; alternative treatments are needed. ADP-A2AFP is an investigational autologous T-cell therapy with an affinity-enhanced T-cell receptor (TCR) targeting alpha-fetoprotein (AFP).

Methods: We describe a phase I, open-label, first-in-human clinical trial of ADP-A2AFP (NCT03132792) in human leukocyte antigen-eligible participants with AFP-expressing HCC (or other tumor) not amenable to transplant/resection that progressed on, were intolerant to, or refused prior systemic therapy.

Paricalcitol plus hydroxychloroquine enhances gemcitabine activity and induces mesenchymal to epithelial transition in pancreatic ductal adenocarcinoma: A single cell RNA-seq analysis.

Epithelial-mesenchymal transition (EMT) describes a process by which epithelial cells acquire mesenchymal properties associated with increased migration, invasion, and resistance to therapy. In pancreatic ductal adenocarcinoma (PDAC), targeting the molecular and intercellular communication pathways that drive EMT represents a promising therapeutic strategy. Here, we investigate the effects of combined treatment with gemcitabine (G), paricalcitol (P), and hydroxychloroquine (GPH) in KPC-Luc orthotopic mouse models of PDAC, using single-cell RNA sequencing (scRNA-seq), high-dimensional weighted gene co-expression network analysis (hdWGCNA), and cell-cell communication analysis.

Paricalcitol and hydroxychloroquine modulates extracellular matrix and enhance chemotherapy efficacy in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis and limited therapeutic options. In a previous publication, our group defined some of the mechanisms that vitamin D analogue paricalcitol (P) and hydroxychloroquine (H) potentiated the effects of gemcitabine-based chemotherapy in PDAC. Based on this, we hypothesized that PH may potentiate 5-fluorouracil (5FU) and oxaliplatin-based chemotherapy, and this may involve a novel mechanism of extracellular matrix (ECM) modulation.

Molecular Characterization and Clinical Outcomes of Pancreatic Neuroendocrine Neoplasms Harboring PAK4-NAMPT Alterations.

Purpose: The mammalian target of rapamycin (mTOR) inhibitor everolimus is US Food and Drug Administration-approved for advanced pancreatic neuroendocrine neoplasms (pNENs), yet resistance is common, necessitating the identification of resistance mechanisms for effective treatment strategies. Previous studies suggest that targeting the aberrant expression of mTOR regulators p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyl transferase (NAMPT) sensitizes pNENs to everolimus. In this study, we queried a large real-world data set of pNENs, characterizing the molecular and immune landscapes, as well as the clinical outcomes associated with aberrant PAK4 and NAMPT expression.

CRISPR/Cas9-directed epigenetic editing in colorectal cancer.

Colorectal cancer (CRC) remains a leading cause of cancer-related illness and death worldwide, arising from a complex interplay of genetic predisposition, environmental influences, and epigenetic dysregulation. Among these factors, epigenetic modifications-reversible and heritable changes in gene expression-serve as crucial regulators of CRC progression. Understanding these modifications is essential for identifying potential biomarkers for early diagnosis and developing targeted therapeutic strategies.

ADT-1004: a first-in-class, oral pan-RAS inhibitor with robust antitumor activity in preclinical models of pancreatic ductal adenocarcinoma.

Background: Oncogenic KRAS mutations occur in nearly, 90% of patients with pancreatic ductal adenocarcinoma (PDAC). Targeting KRAS has been complicated by mutational heterogeneity and rapid resistance. We developed a novel pan-RAS inhibitor, ADT-1004 (an oral prodrug of ADT-007) and evaluated antitumor activity in murine and human PDAC models.

XL888 and pembrolizumab modulate the immune landscape of colorectal tumors in a phase Ib/II clinical trial.

We conducted a phase Ib/II clinical trial to evaluate the safety, feasibility, and clinical activity of combining pembrolizumab (anti-PD-1) with XL888 (Hsp90 inhibitor) in patients with advanced colorectal cancer (CRC). We hypothesized that this regimen would modulate soluble and cellular immune mediators and enhance clinical outcomes. The trial employed a 3 + 3 open-label design, with an expansion cohort at the recommended phase II dose (RP2D) in treatment-refractory, mismatch repair-proficient CRC patients.

Artificial intelligence in gastrointestinal cancers: Diagnostic, prognostic, and surgical strategies.

GI (Gastrointestinal) malignancies are one of the most common and lethal cancers globally. The dawn of precision medicine and developing technologies have reduced the mortality rates for GI malignancies, underscoring the main role of early detection methods for survival rate improvement. Artificial intelligence (AI) is a new technology that may improve GI cancer screening, treatment, and therapeutic efficiency for better patient care.

Mechanism of enhancing chemotherapy efficacy in pancreatic ductal adenocarcinoma with paricalcitol and hydroxychloroquine.

Pancreatic ductal adenocarcinoma (PDAC) has a minimal (<15%) 5-year existence, in part due to resistance to chemoradiotherapy. Previous research reveals the impact of paricalcitol (P) and hydroxychloroquine (H) on altering the lysosomal fusion, decreasing stromal burden, and triggering PDAC to chemotherapies. This investigation aims to elucidate the molecular properties of the H and P combination and their potential in sensitizing PDAC to gemcitabine (G).

A Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth and Induces Antitumor Immunity in Gastrointestinal Cancer.

Activated RAS is a common driver of cancer that was considered undruggable for decades. Recent advances have enabled the development of RAS inhibitors, but the efficacy of these inhibitors remains limited by resistance. In this study, we developed a pan-RAS inhibitor, ADT-007, (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide, that binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis.

RCC1 regulation of subcellular protein localization via Ran GTPase drives pancreatic ductal adenocarcinoma growth.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, with limited therapeutic options. Here, we evaluated the role of regulator of chromosome condensation 1 (RCC1) in PDAC. RCC1 functions as a guanine exchange factor for GTP-binding nuclear protein Ran (Ran) GTPase and is involved in nucleocytoplasmic transport.

Spatial transcriptomic analysis of primary and metastatic pancreatic cancers highlights tumor microenvironmental heterogeneity.

Although the spatial, cellular and molecular landscapes of resected pancreatic ductal adenocarcinoma (PDAC) are well documented, the characteristics of its metastatic ecology remain elusive. By applying spatially resolved transcriptomics to matched primary and metastatic PDAC samples, we discovered a conserved continuum of fibrotic, metabolic and immunosuppressive spatial ecotypes across anatomical regions. We observed spatial tumor microenvironment heterogeneity spanning beyond that previously appreciated in PDAC.

Mesothelin expression correlates with elevated inhibitory immune activity in patients with colorectal cancer.

The expression of the protein Mesothelin (MSLN) is highly variable in several malignancies, including colorectal cancer (CRC), and high levels are associated with aggressive clinicopathological features and worse patient survival. Colorectal cancer is both a common and deadly cancer; being the third most common in incidence and second most common cause of cancer-related death. While systemic therapy remains the primary therapeutic option for most patients with stage IV (metastatic; m) CRC, their disease eventually becomes treatment refractory, and 85% succumb within 5 years.

Association between frailty and overall survival among older adults with hepatocellular carcinoma.

Introduction: Older adults undergoing cancer treatment often experience more treatment-related toxicities and increased risk of mortality compared to younger patients. The role of frailty among older individuals as a predictor of outcomes has gained growing significance. We evaluated the association between frailty and overall survival (OS) in patients with hepatocellular carcinoma (HCC) ≥60 years.

Nivolumab plus relatlimab in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study.

Background: Programmed death-1 (PD-1) inhibitors, including nivolumab, have demonstrated long-term survival benefit in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (CRC). PD-1 and lymphocyte-activation gene 3 (LAG-3) are distinct immune checkpoints that are often co-expressed on tumor-infiltrating lymphocytes and contribute to tumor-mediated T-cell dysfunction. Relatlimab is a LAG-3 inhibitor that has demonstrated efficacy in combination with nivolumab in patients with melanoma.

Transposon DNA sequences facilitate the tissue-specific gene transfer of circulating tumor DNA between human cells.

The exchange of genes between cells is known to play an important physiological and pathological role in many organisms. We show that circulating tumor DNA (ctDNA) facilitates cell-specific gene transfer between human cancer cells and explain part of the mechanisms behind this phenomenon. As ctDNA migrates into the nucleus, genetic information is transferred.

A Case Series of Choroidal and Orbital Neuroendocrine Tumors: Metastasis: Two Patients Treated With Peptide Radionuclide Therapy.

Neuroendocrine tumors (NETs) are rare cancers with heterogeneous histologies, response to treatments, and prognoses. Majority of these cancers originate in the gastrointestinal tract and metastasize to the liver. We report the cases of 5 patients with low-grade NET disease with rare metastases to the choroids.

A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer.

Unlabelled: Here, we describe a novel pan-RAS inhibitor, ADT-007, that potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme. RAS cancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RAS cancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007.

Deciphering cellular plasticity in pancreatic cancer for effective treatments.

Cellular plasticity and therapy resistance are critical features of pancreatic cancer, a highly aggressive and fatal disease. The pancreas, a vital organ that produces digestive enzymes and hormones, is often affected by two main types of cancer: the pre-dominant ductal adenocarcinoma and the less common neuroendocrine tumors. These cancers are difficult to treat due to their complex biology characterized by cellular plasticity leading to therapy resistance.

Advancing Inclusive Research (AIR) Site Alliance: Facilitating the inclusion of historically underrepresented people in oncology and ophthalmology clinical research.

Background: The Advancing Inclusive Research (AIR) Site Alliance is composed of clinical research centers that partner with Genentech, a biotechnology company, to advance the representation of diverse patient populations in its oncology and ophthalmology clinical trials, test recruitment, and retention approaches and establish best practices to leverage across the industry to achieve health equity.

Methods: Through a data-driven selection process, Genentech identified 6 oncology and 3 ophthalmology partners that focus on reaching historically underrepresented patients in clinical trials and worked collaboratively to share knowledge and explore original ways of increasing clinical study access for every patient, including sites co-creation of a Protocol Entry Criteria Guideline with inclusion principles.

Results: For patients, three publicly available educational videos about clinical trials were created in multiple languages.

Advances in Immunotherapy for Hepatocellular Carcinoma (HCC).

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related deaths in the world. More than half of patients with HCC present with advanced stage, and highly active systemic therapies are crucial for improving outcomes. Immune checkpoint inhibitor (ICI)-based therapies have emerged as novel therapy options for advanced HCC.