Polyamine metabolism in prostate cancer.

Purpose Of Review: Normal and malignant prostate engage in high rates of de novo polyamine synthesis. This review considers how polyamine metabolism regulates prostate cancer initiation and progression.

Recent Findings: The androgen receptor (AR) establishes a metabolic program to drive robust polyamine synthesis in the normal prostate.

Metabolic landscape in bladder cancer.

Purpose Of Review: This review examines the existing literature on metabolic pathways associated with bladder cancer (BC) and investigates four domains: (1) diagnoses, (2) cancer classification (staging & grading), (3) tracking, and (4) treatment.

Recent Findings: A systematic search of relevant databases identified studies meeting predefined inclusion criteria. A diverse array of metabolic pathways was found to hold significant biological and clinical relevance to BC, with particular emphasis on amino acid (AA), lipid, nucleic acid (NA), and bioenergetic pathways.

An engineered Treg selective immunocytokine induces sustained immune modulation in a pre-clinical model of hemophilia A.

Background: The development of inhibitory antibodies (inhibitors) is a serious complication in the treatment of hemophilia A with clotting factor VIII (FVIII) replacement therapy. Inhibitor formation critically depends on T cell help and modulation by regulatory T cells (Tregs).

Objective: In this study, we evaluated the F5111 immunocytokine (IC), a single chain fusion between the human interleukin-2 (IL-2) cytokine and an IL-2 antibody that biases cytokine activity towards cells with high IL-2 receptor alpha (IL-2Rα) expression, leading to extended IL-2 half-life and selective expansion of Tregs.

Impact of chromatin on HIV-1 latency: a multi-dimensional perspective.

Human immunodeficiency virus type 1 (HIV-1) is a retrovirus that infects multiple immune cell types and integrates into host cell DNA termed provirus. Under antiretroviral control, provirus in cells is able to evade targeting by both host immune surveillance and antiretroviral drug regimens. Additionally, the provirus remains integrated for the life of the cell, and clonal expansion establishes a persistent reservoir.

Society for Immunotherapy of Cancer (SITC) consensus statement on essential biomarkers for immunotherapy clinical protocols.

Immunotherapy of cancer is now an essential pillar of treatment for patients with many individual tumor types. Novel immune targets and technical advances are driving a rapid exploration of new treatment strategies incorporating immune agents in cancer clinical practice. Immunotherapies perturb a complex system of interactions among genomically unstable tumor cells, diverse cells within the tumor microenvironment including the systemic adaptive and innate immune cells.

CLINICAL DEVELOPMENT OF IMMUNO-ONCOLOGY THERAPEUTICS.

Immuno-oncology (IO) is one of the fastest growing therapeutic areas within oncology. IO agents work indirectly via the host's adaptive and innate immune system to recognize and eradicate tumor cells. Despite checkpoint inhibitors being only introduced to the market since 2011, they have become the second most approved product category.

Phase 1 study of IMCnyeso, a T cell receptor bispecific ImmTAC targeting NY-ESO-1-expressing malignancies.

IMCnyeso, an immune mobilizing monoclonal T cell receptor against cancer (ImmTAC) bispecific (New York esophageal squamous cell carcinoma [NY-ESO]×CD3) T cell engager, targets an NY-ESO-1/L-antigen family member-1 isoform A (LAGE-1A) peptide presented by histocompatibility leukocyte antigen (HLA)-A∗02:01. In this phase 1 study, 28 HLA-A∗02:01+ patients with advanced NY-ESO-1/LAGE-1A-positive advanced tumors (n = 28) receive IMCnyeso weekly intravenously (dose range: 3-300 μg; 7 dose-escalation cohorts). The primary objective is to identify the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D); additional objectives include preliminary anti-tumor activity, pharmacokinetics, immunogenicity, and pharmacodynamic changes.

Tumour-agnostic kinase inhibitors.

Protein kinases are crucial targets for cancer treatment as they orchestrate important signals for oncogenesis and are often aberrantly activated owing to genomic alterations. In the past two decades, multiple kinase inhibitors have been developed, including those that are clinically effective regardless of tumour location, provided that the tumour harbours the aberrantly activated kinase. Consequently, a biomarker-based therapy model, untethered from tumour histology and organ of origin, has been established, which has led to transformative regulatory approvals of tumour-agnostic kinase inhibitors such as larotrectinib, selpercatinib, dabrafenib-trametinib and pemigatinib.

A composite F-FDG PET/CT and HER2 tissue-based biomarker to predict response to neoadjuvant pertuzumab and trastuzumab in HER2-positive breast cancer (TBCRC026).

Background: Early metabolic change on PET/CT was predictive of response to neoadjuvant trastuzumab/pertuzumab (HP) in TBCRC026. We hypothesized that a composite biomarker incorporating PET/CT and HER2 tissue-based biomarkers could improve biomarker performance.

Methods: 83 patients with estrogen receptor-negative/HER2-positive breast cancer received neoadjuvant HP alone [pathologic complete response (pCR) 22 %].

Evaluation of Immunosuppression Levels and Risk of Graft-Versus-Host Disease in Allogeneic Blood or Marrow Transplantation with Post-Transplant Cyclophosphamide.

Post-transplantation cyclophosphamide (PTCy) is standard graft-versus-host disease (GVHD) prophylaxis for allogeneic blood or marrow transplantation (alloBMT), although optimal therapeutic levels of immunosuppression (IS) therapy combined with PTCy remain contested. Previously, with tacrolimus and methotrexate GVHD prophylaxis, week 1 tacrolimus levels >12 ng/mL were associated with a decreased incidence of grade 2-4 acute GVHD (aGVHD). We evaluated if associations between aGVHD and early IS levels were observed amongst patients receiving PTCy.

5-hydroxymethylcytosine sequencing of plasma cell-free DNA identifies epigenomic features in prostate cancer patients receiving androgen deprivation therapies.

Background: We evaluated whether 5hmC signatures in cell-free DNA (cfDNA) are associated with treatment failure to androgen-deprivation therapies (ADT) among men with hormone-naive prostate cancer.

Methods: We collected a total of 139 serial plasma samples from 55 prostate cancer patients receiving ADT at 3 time points including baseline (before initiating ADT, n = 55); 3 months (after initiating ADT, n = 55); and disease progression (n = 15) within 24 months or 24 months if no progression was detected (n = 14). We used selective chemical labeling sequencing to quantify 5hmC abundance across the genome and Kaplan-Meier analysis to assess survival association.

Genomic and fragmentomic landscapes of cell-free DNA for early cancer detection.

Genomic analyses of cell-free DNA (cfDNA) in plasma are enabling noninvasive blood-based biomarker approaches to cancer detection and disease monitoring. Current approaches for identification of circulating tumour DNA typically use targeted tumour-specific mutations or methylation analyses. An emerging approach is based on the recognition of altered genome-wide cfDNA fragmentation in patients with cancer.

Pre- and post-diagnostic use of antihypertensive medications and stage I-III colorectal cancer survival: prospective cohort study.

Antihypertensive medications have been investigated in relation to colorectal cancer (CRC)-specific survival. To address limitations and important unanswered questions in the existing evidence, we investigated associations of pre- and post-diagnostic use of antihypertensive classes-beta-blockers, calcium channel blockers, thiazide diuretics, angiotensin-converting enzyme inhibitors, furosemide, and other antihypertensives-with CRC-specific mortality among 2,182 patients with stage I-III CRC in the Nurses' Health Study and Health Professionals Follow-up Study in a prospective cohort study with long-term follow-up, repeat assessments of antihypertensive use, and rigorous confounding control. Pre- and post-diagnostic use of each antihypertensive class studied was not clearly associated with stage I-III CRC survival compared with either non-users or with patients with high blood pressure who used any other antihypertensives.

Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3.

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Dynamic Modulation of IRE1α-XBP1 Signaling by Adenovirus.

The abundant production of foreign proteins and nucleic acids during viral infection elicits a variety of stress responses in host cells. Viral proteins that accumulate in the endoplasmic reticulum (ER) can trigger the unfolded protein response (UPR), a coordinated signaling program that culminates in the expression of downstream genes that collectively restore protein homeostasis. The model pathogen adenovirus serotype 5 (HAdV5) activates the UPR via the signaling axis formed by inositol-requiring enzyme type 1 (IRE1α) and the X-box binding protein 1 (XBP1), a transcription factor required for immune function.

Tumor immune microenvironment alterations associated with progression in human intraductal papillary mucinous neoplasms.

Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to late-stage diagnoses. To improve patient outcomes, early intervention in precursor lesions such as intraductal papillary mucinous neoplasm (IPMN) is crucial. However, early intervention must be balanced against overtreatment of low-risk lesions that are unlikely to progress, underscoring the need to better understand molecular alterations in neoplastic cells and changes in the tumor microenvironment (TME) that drive the progression of IPMNs.

Navigating confinement: Mechanotransduction and metabolic adaptation.

Cell migration through confined spaces is a critical process influenced by the complex three-dimensional (3D) architecture of the local microenvironment and the surrounding extracellular matrix (ECM). Cells in vivo experience diverse fluidic signals, such as extracellular fluid viscosity, hydraulic resistance, and shear forces, as well as solid cues, like ECM stiffness and viscoelasticity. These fluidic and solid stressors activate mechanotransduction processes and regulate cell migration.

A phase 1 study of the combination of BH3-mimetic, navitoclax, and mTORC1/2 inhibitor, vistusertib, in patients with advanced solid tumors.

Purpose: To determine the, safety, tolerability and recommended phase 2 dosing of the combination of navitoclax, a dual Bcl-2/xL inhibitor, and vistusertib, a TORC1/2 inhibitor.

Methods: Patients with advanced solid tumors received navitoclax plus vistusertib following a 3 + 3 dose escalation design. To mitigate thrombocytopenia, a known toxicity of navitoclax, all patients received lead-in dosing of navitoclax alone at 150 mg orally daily for a minimum of 7 days.

Haploidentical Bone Marrow Transplantation for Sickle Cell Disease.

Background: Related human leukocyte antigen (HLA)-haploidentical bone marrow transplantation (BMT) with posttransplant cyclophosphamide may be curative for sickle cell disease. However, graft failure, severe graft-versus-host disease (GVHD), infections, and mortality remain a concern. We evaluated a novel conditioning regimen followed by related HLA-haploidentical BMT in adults with sickle cell disease.

TOMM20 as a driver of cancer aggressiveness via oxidative phosphorylation, maintenance of a reduced state, and resistance to apoptosis.

Chondrosarcomas are common bone sarcomas frequently resistant to radiation and chemotherapy, with high recurrence rates, development of metastatic disease, and death. Fibrosarcomas are soft tissue sarcomas associated with poor outcomes. Translocase of outer mitochondrial membrane receptor 20 (TOMM20) is a mitochondrial receptor protein associated with cancer aggressiveness in many cancer subtypes, but the mechanisms remain poorly understood.

Six events that shaped antibody approvals in oncology.

A little over twenty-five years ago, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) approved the chimeric antibody rituximab which fundamentally altered the landscape of anti-cancer drugs. While only a few antibodies were approved in the immediate years that followed the rituximab approval, the last decade saw a wave of antibody-drug approvals in the oncology arena. In the last three years, the EMA and FDA greenlighted eighteen antibodies, the majority of them designed in the formats of antibody-drug conjugates (ADC) and bispecific antibodies (BsAb).