The transcriptomic fingerprint of cancer response to Tumor Treating Fields (TTFields).

Tumor Treating Fields (TTFields) therapy is an approved cancer treatment modality, based on non-invasive application of electric fields to the tumor region. Proteomic and cell biology methods revealed a versatile mechanism of action to be involved in the response to TTFields. In the current research we performed whole transcriptome analysis across tumor types to identify pan-cancer responses to TTFields.

Tumor treating fields utilization and efficacy for glioblastoma at a large multicenter academic practice.

Purpose: Despite Tumor Treating Fields (TTF) being included in NCCN guidelines as standard treatment for GBM after improving overall survival in a prospective randomized trial, adoption has been limited. We sought to describe utilization, validate the efficacy, and compare patterns of failure after TTF for GBM patients in a real-world dataset.

Methods: We identified patients with newly diagnosed GBM between 2014-2023 who received standard fractionation external beam radiotherapy (EBRT).

Immune stromal components impede biological effectiveness of carbon ion therapy in a preclinical model of pancreatic ductal adenocarcinoma.

The tumor landscape of pancreatic ductal adenocarcinoma (PDAC) is refractory to conventional photon radiotherapy (RT) due to a fibrotic tumor microenvironment (TME) that promotes chronic hypoxia and reduced immune surveillance. The radiobiological factors unique to carbon ion radiotherapy (CIRT), such as high linear energy transfer (LET) and less dependence on oxygen, make it well-suited to overcome the PDAC TME. Here, we utilized clonal syngeneic KPC pancreatic tumor cell lines and tumors to examine this postulate and to identify underlying factors that impact the response of PDAC to CIRT.

Defective homologous recombination and genomic instability predict increased responsiveness to carbon ion radiotherapy in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is notably resistant to conventional chemotherapy and radiation treatment. However, clinical trials indicate that carbon ion radiotherapy (CIRT) with concurrent gemcitabine is effective for unresectable locally advanced PDAC. This study aimed to identify patient characteristics predictive of CIRT response.

Particle Beam Radiobiology Status and Challenges: A PTCOG Radiobiology Subcommittee Report.

Particle therapy (PT) represents a significant advancement in cancer treatment, precisely targeting tumor cells while sparing surrounding healthy tissues thanks to the unique depth-dose profiles of the charged particles. Furthermore, their linear energy transfer and relative biological effectiveness enhance their capability to treat radioresistant tumors, including hypoxic ones. Over the years, extensive research has paved the way for PT's clinical application, and current efforts aim to refine its efficacy and precision, minimizing the toxicities.

NRG Oncology White Paper on the Relative Biological Effectiveness in Proton Therapy.

This position paper, led by the NRG Oncology Particle Therapy Work Group, focuses on the concept of relative biologic effect (RBE) in clinical proton therapy (PT), with the goal of providing recommendations for the next-generation clinical trials with PT on the best practice of investigating and using RBE, which could deviate from the current standard proton RBE value of 1.1 relative to photons. In part 1, current clinical utilization and practice are reviewed, giving the context and history of RBE.

A single photodynamic priming protocol augments delivery of ⍺-PD-L1 mAbs and induces immunogenic cell death in head and neck tumors.

Photodynamic priming (PDP) leverages the photobiological effects of subtherapeutic photodynamic therapy (PDT) regimens to modulate the tumor vasculature and stroma. PDP also sensitizes tumors to secondary therapies, such as immunotherapy by inducing a cascade of molecular events, including immunogenic cell death (ICD). We and others have shown that PDP improves the delivery of antibodies, among other theranostic agents.

Biomimetic Human Lung Alveolar Interstitium Chip with Extended Longevity.

Determining the mechanistic causes of lung diseases, developing new treatments thereof, and assessing toxicity whether from chemical exposures or engineered nanomaterials would benefit significantly from a preclinical human lung alveolar interstitium model of physiological relevance. The existing preclinical models have limitations because they fail to replicate the key anatomical and physiological characteristics of human alveoli. Thus, a human lung alveolar interstitium chip was developed to imitate key alveolar microenvironmental factors including an electrospun nanofibrous membrane as the analogue of the basement membrane for co-culture of epithelial cells with fibroblasts embedded in 3D collagenous gels, physiologically relevant interstitial matrix stiffness, interstitial fluid flow, and 3D breathing-like mechanical stretch.

Orthologs of human circulating miRNAs associated with hepatocellular carcinoma are elevated in mouse plasma months before tumour detection.

Research examining the potential for circulating miRNA to serve as markers for preneoplastic lesions or early-stage hepatocellular carcinoma (HCC) is hindered by the difficulties of obtaining samples from asymptomatic individuals. As a surrogate for human samples, we identified hub miRNAs in gene co-expression networks using HCC-bearing C3H mice. We confirmed 38 hub miRNAs as associated with HCC in F2 hybrid mice derived from radiogenic HCC susceptible and resistant founders.

Evaluation of the Response of HNSCC Cell Lines to γ-Rays and C Ions: Can Radioresistant Tumors Be Identified and Selected for C Ion Radiotherapy?

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. Thirty percent of patients will experience locoregional recurrence for which median survival is less than 1 year. Factors contributing to treatment failure include inherent resistance to X-rays and chemotherapy, hypoxia, epithelial to mesenchymal transition, and immune suppression.

Mitotic phosphorylation of tumor suppressor DAB2IP maintains spindle assembly checkpoint and chromosomal stability through activating PLK1-Mps1 signal pathway and stabilizing mitotic checkpoint complex.

Chromosomal instability (CIN) is a driving force for cancer development. The most common causes of CIN include the dysregulation of the spindle assembly checkpoint (SAC), which is a surveillance mechanism that prevents premature chromosome separation during mitosis by targeting anaphase-promoting complex/cyclosome (APC/C). DAB2IP is frequently silenced in advanced prostate cancer (PCa) and is associated with aggressive phenotypes of PCa.

Facile and direct detection of human papillomavirus (HPV) DNA in cells using loop-mediated isothermal amplification (LAMP).

Human papillomavirus (HPV)-mediated cancers, particularly cervical and oropharyngeal cancer, lead to hundreds of thousands of deaths worldwide each year. Simple, straightforward, and cost-effective detection of HPV DNA from patients with these malignancies or at risk for developing cancer can improve outcomes for patients, serving as a tool for early detection, monitoring treatment response, and assessment of cancer recurrence. Loop-mediated isothermal amplification (LAMP) is a simple and robust method for the detection and amplification of DNA in a single tube, utilizing the Bst strand-displacing DNA polymerase.

Associations between lipids in selected brain regions, plasma miRNA, and behavioral and cognitive measures following Si ion irradiation.

The space radiation environment consists of multiple species of charged particles, including Si ions, that may impact brain function during and following missions. To develop biomarkers of the space radiation response, BALB/c and C3H female and male mice and their F2 hybrid progeny were irradiated with Si ions (350 MeV/n, 0.2 Gy) and tested for behavioral and cognitive performance 1, 6, and 12 months following irradiation.

Transcriptomic analysis links hepatocellular carcinoma (HCC) in HZE ion irradiated mice to a human HCC subtype with favorable outcomes.

High-charge, high-energy ion particle (HZE) radiations are extraterrestrial in origin and characterized by high linear energy transfer (high-LET), which causes more severe cell damage than low-LET radiations like γ-rays or photons. High-LET radiation poses potential cancer risks for astronauts on deep space missions, but the studies of its carcinogenic effects have relied heavily on animal models. It remains uncertain whether such data are applicable to human disease.

Avasopasem manganese synergizes with hypofractionated radiation to ablate tumors through the generation of hydrogen peroxide.

Avasopasem manganese (AVA or GC4419), a selective superoxide dismutase mimetic, is in a phase 3 clinical trial (NCT03689712) as a mitigator of radiation-induced mucositis in head and neck cancer based on its superoxide scavenging activity. We tested whether AVA synergized with radiation via the generation of hydrogen peroxide, the product of superoxide dismutation, to target tumor cells in preclinical xenograft models of non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma, and pancreatic ductal adenocarcinoma. Treatment synergy with AVA and high dose per fraction radiation occurred when mice were given AVA once before tumor irradiation and further increased when AVA was given before and for 4 days after radiation, supporting a role for oxidative metabolism.

An overview of potential novel mechanisms of action underlying Tumor Treating Fields-induced cancer cell death and their clinical implications.

Traditional cancer therapy choices for clinicians are surgery, chemotherapy, radiation and immune therapy which are used either standalone therapies or in various combinations. Other physical modalities beyond ionizing radiation include photodynamic therapy and heating and the more recent approach referred to as Tumor Treating Fields (TTFields). TTFields are intermediate frequency, low-intensity, alternating electric fields that are applied to tumor regions and cells using noninvasive arrays.

Dose rate determination for preclinical total body irradiation.

The accuracy of delivered radiation dose and the reproducibility of employed radiotherapy methods are key factors for preclinical radiobiology applications and research studies. In this work, ionization chamber (IC) measurements and Monte Carlo (MC) simulations were used to accurately determine the dose rate for total body irradiation (TBI), a classic radiobiologic and immunologic experimental method. Several phantom configurations, including large solid water slab, small water box and rodentomorphic mouse and rat phantoms were simulated and measured for TBI setup utilizing a preclinical irradiator XRad320.

The Long and Short of It: The Emerging Roles of Non-Coding RNA in Small Extracellular Vesicles.

Small extracellular vesicles (EVs) play a significant role in intercellular communication through their non-coding RNA (ncRNA) cargo. While the initial examination of EV cargo identified both mRNA and miRNA, later studies revealed a wealth of other types of EV-related non-randomly packed ncRNAs, including tRNA and tRNA fragments, Y RNA, piRNA, rRNA, and lncRNA. A number of potential roles for these ncRNA species were suggested, with strong evidence provided in some cases, whereas the role for other ncRNA is more speculative.

Tumor treating fields cause replication stress and interfere with DNA replication fork maintenance: Implications for cancer therapy.

Tumor treating fields (TTFields) is a noninvasive physical modality of cancer therapy that applies low-intensity, intermediate frequency, and alternating electric fields to a tumor. Interference with mitosis was the first mechanism describing the effects of TTFields on cancer cells; however, TTFields was shown to not only reduce the rejoining of radiation-induced DNA double-strand breaks (DSBs), but to also induce DNA DSBs. The mechanism(s) by which TTFields generates DNA DSBs is related to the generation of replication stress including reduced expression of the DNA replication complex genes MCM6 and MCM10 and the Fanconi's Anemia pathway genes.

miR-125a-5p Functions as Tumor Suppressor microRNA And Is a Marker of Locoregional Recurrence And Poor prognosis in Head And Neck Cancer.

MicroRNAs (miRNAs) are short single-stranded RNAs, measuring 21 to 23 nucleotides in length and regulate gene expression at the post-transcriptional level through mRNA destabilization or repressing protein synthesis. Dysregulation of miRNAs can lead to tumorigenesis through changes in regulation of key cellular processes such as cell proliferation, cell survival, and apoptosis. miR-125a-5p has been implicated as a tumor suppressor miRNA in malignancies such as non-small cell lung cancer and colon cancer.

Radiation-Induced DNA Damage Cooperates with Heterozygosity of TP53 and PTEN to Generate High-Grade Gliomas.

Glioblastomas are lethal brain tumors that are treated with conventional radiation (X-rays and gamma rays) or particle radiation (protons and carbon ions). Paradoxically, radiation is also a risk factor for GBM development, raising the possibility that radiotherapy of brain tumors could promote tumor recurrence or trigger secondary gliomas. In this study, we determined whether tumor suppressor losses commonly displayed by patients with GBM confer susceptibility to radiation-induced glioma.

Ionizing radiation affects the composition of the proteome of extracellular vesicles released by head-and-neck cancer cells in vitro.

Exosomes and other extracellular vesicles are key players in cell-to-cell communication, and it has been proposed that they are involved in different aspects of the response to ionizing radiation, including transmitting the radiation-induced bystander effect and mediating radioresistance. The functional role of exosomes depends on their molecular cargo, including proteome content. Here we aimed to establish the proteome profile of exosomes released in vitro by irradiated UM-SCC6 cells derived from human head-and-neck cancer and to identify processes associated with radiation-affected proteins.