A novel lineage-tracing tool reveals that hypoxic tumor cells drive tumor relapse after radiotherapy.

Purpose: Tumor hypoxia imposes a main obstacle to the efficacy of anti-cancer therapy. Understanding the cellular dynamics of individual hypoxic cells before, during and post-treatment has been hampered by the technical inability to identify and trace these cells over time.

Methods And Materials: Here, we present a novel lineage-tracing reporter for hypoxic cells based on the conditional expression of a HIF1a-CreER-UnaG biosensor that can visualize hypoxic cells in a time-dependent manner and trace the fate of hypoxic cells over time.

Promising Diagnostic and Therapeutic Approaches Based on VHHs for Cancer Management.

The discovery of the distinctive structure of heavy chain-only antibodies in species belonging to the Camelidae family has elicited significant interest in their variable antigen binding domain (VHH) and gained attention for various applications, such as cancer diagnosis and treatment. This article presents an overview of the characteristics, advantages, and disadvantages of VHHs as compared to conventional antibodies, and their usage in diverse applications. The singular properties of VHHs are explained, and several strategies that can augment their utility are outlined.

Surface modification effect on contrast agent efficiency for X-ray based spectral photon-counting scanner/luminescence imaging: from fundamental study to proof of concept.

X-Ray imaging techniques are among the most widely used modalities in medical imaging and their constant evolution has led to the emergence of new technologies. The new generation of computed tomography (CT) systems - spectral photonic counting CT (SPCCT) and X-ray luminescence optical imaging - are examples of such powerful techniques. With these new technologies the rising demand for new contrast agents has led to extensive research in the field of nanoparticles and the possibility to merge the modalities appears to be highly attractive.

Prognostic biomarkers for the response to the radiosensitizer nimorazole combined with RCTx: a pre-clinical trial in HNSCC xenografts.

Background: Tumor hypoxia is associated with resistance to radiotherapy and chemotherapy. In head and neck squamous cell carcinoma (HNSCC), nimorazole, an oxygen mimic, combined with radiotherapy (RT) enabled to improve loco-regional control (LRC) in some patients with hypoxic tumors but it is unknown whether this holds also for radiochemotherapy (RCTx). Here, we investigated the impact of nimorazole combined with RCTx in HNSCC xenografts and explored molecular biomarkers for its targeted use.

Overcoming radioresistance with the hypoxia-activated prodrug CP-506: A pre-clinical study of local tumour control probability.

Background And Purpose: Tumour hypoxia is an established radioresistance factor. A novel hypoxia-activated prodrug CP-506 has been proven to selectively target hypoxic tumour cells and to cause anti-tumour activity. The current study investigates whether CP-506 improves outcome of radiotherapy in vivo.

Polyphenols as Potential Protectors against Radiation-Induced Adverse Effects in Patients with Thoracic Cancer.

Radiotherapy is one of the standard treatment approaches used against thoracic cancers, occasionally combined with chemotherapy, immunotherapy and molecular targeted therapy. However, these cancers are often not highly sensitive to standard of care treatments, making the use of high dose radiotherapy necessary, which is linked with high rates of radiation-induced adverse effects in healthy tissues of the thorax. These tissues remain therefore dose-limiting factors in radiation oncology despite recent technological advances in treatment planning and delivery of irradiation.

Picomolar fluorescent probes for compound affinity determination to carbonic anhydrase IX expressed in live cancer cells.

Numerous human cancers, especially hypoxic solid tumors, express carbonic anhydrase IX (CAIX), a transmembrane protein with its catalytic domain located in the extracellular space. CAIX acidifies the tumor microenvironment, promotes metastases and invasiveness, and is therefore considered a promising anticancer target. We have designed a series of high affinity and high selectivity fluorescein-labeled compounds targeting CAIX to visualize and quantify CAIX expression in cancer cells.

Homologous Recombination Deficiency Scar: Mutations and Beyond-Implications for Precision Oncology.

Homologous recombination deficiency (HRD) is a prevalent in approximately 17% of tumors and is associated with enhanced sensitivity to anticancer therapies inducing double-strand DNA breaks. Accurate detection of HRD would therefore allow improved patient selection and outcome of conventional and targeted anticancer therapies. However, current clinical assessment of HRD mainly relies on determining germline mutational status and is insufficient for adequate patient stratification as mechanisms of HRD occurrence extend beyond functional BRCA1/2 loss.

Selectively Targeting Tumor Hypoxia With the Hypoxia-Activated Prodrug CP-506.

Hypoxia-activated prodrugs (HAP) are a promising class of antineoplastic agents that can selectively eliminate hypoxic tumor cells. This study evaluates the hypoxia-selectivity and antitumor activity of CP-506, a DNA alkylating HAP with favorable pharmacologic properties. Stoichiometry of reduction, one-electron affinity, and back-oxidation rate of CP-506 were characterized by fast-reaction radiolytic methods with observed parameters fulfilling requirements for oxygen-sensitive bioactivation.

Value of functional in-vivo endpoints in preclinical radiation research.

Background: Cancer research faces the problem of high rates of clinical failure of new treatment approaches after positive preclinical data. We hypothesize that a major confounding factor to this problem in radiooncology is the choice of the preclinical endpoint.

Methods: We present a comprehensive re-evaluation of large-scale preclinical in-vivo data on fractionated irradiation alone or simultaneously with Epidermal Growth Factor Receptor inhibition.

A novel co-culture assay to assess anti-tumor CD8 T cell cytotoxicity via luminescence and multicolor flow cytometry.

T cell immunotherapies have shown great promise in patients with advanced cancer disease, revolutionizing treatment. T cell cytotoxicity is crucial in its efficacy, therefore developing ex vivo methods testing tumor and T cell interactions is pivotal. Increasing efforts have been made in developing co-culture assays with sophisticated materials and platforms aiming to mimic the tumor microenvironment (TME), but its complexity makes it difficult to develop the ideal model.

Combining hypoxia-activated prodrugs and radiotherapy in silico: Impact of treatment scheduling and the intra-tumoural oxygen landscape.

Hypoxia-activated prodrugs (HAPs) present a conceptually elegant approach to not only overcome, but better yet, exploit intra-tumoural hypoxia. Despite being successful in vitro and in vivo, HAPs are yet to achieve successful results in clinical settings. It has been hypothesised that this lack of clinical success can, in part, be explained by the insufficiently stringent clinical screening selection of determining which tumours are suitable for HAP treatments.

Stereotactic ablative body radiotherapy (SABR) combined with immunotherapy (L19-IL2) versus standard of care in stage IV NSCLC patients, ImmunoSABR: a multicentre, randomised controlled open-label phase II trial.

Background: About 50% of non-small cell lung cancer (NSCLC) patients have metastatic disease at initial diagnosis, which limits their treatment options and, consequently, the 5-year survival rate (15%). Immune checkpoint inhibitors (ICI), either alone or in combination with chemotherapy, have become standard of care (SOC) for most good performance status patients. However, most patients will not obtain long-term benefit and new treatment strategies are therefore needed.

Hypoxia PET Imaging with [18F]-HX4-A Promising Next-Generation Tracer.

Hypoxia-a common feature of the majority of solid tumors-is a negative prognostic factor, as it is associated with invasion, metastasis and therapy resistance. To date, a variety of methods are available for the assessment of tumor hypoxia, including the use of positron emission tomography (PET). A plethora of hypoxia PET tracers, each with its own strengths and limitations, has been developed and successfully validated, thereby providing useful prognostic or predictive information.

Human fibronectin extra domain B as a biomarker for targeted therapy in cancer.

The extracellular matrix protein fibronectin contains a domain that is rarely found in healthy adults and is almost exclusively expressed by newly formed blood vessels in tumours, particularly in solid tumours, different types of lymphoma and some leukaemias. This domain, called the extra domain B (ED-B), thus has broad therapeutic potential. The antibody L19 has been developed to specifically target ED-B and has shown therapeutic potential when combined with cytokines, such as IL-2.

Nitroglycerin as a radiosensitizer in non-small cell lung cancer: Results of a prospective imaging-based phase II trial.

Background: Nitroglycerin is proposed as an agent to reduce tumour hypoxia by improving tumour perfusion. We investigated the potential of nitroglycerin as a radio-sensitizer in non-small cell lung cancer (NSCLC) and the potential of functional imaging for patient selection.

Material And Methods: Trial NCT01210378 is a single arm phase II trial, designed to detect 15% improvement in 2-year overall survival (primary endpoint) in stage IB-IV NSCLC patients treated with radical (chemo-) radiotherapy and a Transiderm-Nitro 5 patch during radiotherapy.

Hypoxia-activated prodrugs and (lack of) clinical progress: The need for hypoxia-based biomarker patient selection in phase III clinical trials.

Hypoxia-activated prodrugs (HAPs) are designed to specifically target the hypoxic cells of tumors, which are an important cause of treatment resistance to conventional therapies. Despite promising preclinical and clinical phase I and II results, the most important of which are described in this review, the implementation of hypoxia-activated prodrugs in the clinic has, so far, not been successful. The lack of stratification of patients based on tumor hypoxia status, which can vary widely, is sufficient to account for the failure of phase III trials.

HIF-1α and HIF-2α Differently Regulate the Radiation Sensitivity of NSCLC Cells.

The hypoxia-inducible transcription factors (HIF)-1/2α are the main oxygen sensors which regulate the adaptation to intratumoral hypoxia. The aim of this study was to assess the role of the HIF proteins in regulating the radiation response of a non-small cell lung cancer (NSCLC) in vitro model. To directly assess the unique and overlapping functions of HIF-1α and HIF-2α, we use CRISPR gene-editing to generate isogenic H1299 non-small cell lung carcinoma cells lacking HIF-1α, HIF-2α or both.

An orthotopic non-small cell lung cancer model for image-guided small animal radiotherapy platforms.

Methods:: An orthotopic non-small cell lung cancer model in NMRI-nude mice was established to investigate the complementary information acquired from 80 kVp microcone-beam CT (micro-CBCT) and bioluminescence imaging (BLI) using different angles and filter settings. Different micro-CBCT-based radiation-delivery plans were evaluated based on their dose-volume histogram metrics of tumor and organs at risk to select the optimal treatment plan.

Results:: H1299 cell suspensions injected directly into the lung render exponentially growing single tumor nodules whose CBCT-based volume quantification strongly correlated with BLI-integrated intensity.

Synergistic Effects of NOTCH/γ-Secretase Inhibition and Standard of Care Treatment Modalities in Non-small Cell Lung Cancer Cells.

Lung cancer is the leading cause of cancer death worldwide. More effective treatments are needed to increase durable responses and prolong patient survival. Standard of care treatment for patients with non-operable stage III-IV NSCLC is concurrent chemotherapy and radiation.

Prognostic Role of Hypoxia-Inducible Factor-2α Tumor Cell Expression in Cancer Patients: A Meta-Analysis.

Hypoxia-inducible factor-2α (HIF-2α) plays an important role in tumor progression and metastasis. A number of studies have evaluated the correlation between HIF-2α overexpression and clinical outcome in cancer patients but yielded inconsistent results. To comprehensively and quantitatively summarize the evidence on the capability of HIF-2α to predict the prognosis of cancer patients with solid tumors, a meta-analysis was carried out.