Eco-evolutionary Guided Pathomics Analysis to Predict DCIS Upstaging.

Cancers evolve in a dynamic ecosystem. Thus, characterizing cancer's ecological dynamics is crucial to understanding cancer evolution and can lead to discovering novel biomarkers to predict disease progression. Ductal carcinoma in situ (DCIS) is an early-stage breast cancer characterized by abnormal epithelial cell growth confined within the milk ducts.

L-DOS47 Elevates Pancreatic Cancer Tumor pH and Enhances Response to Immunotherapy.

Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials.

L-DOS47 enhances response to immunotherapy in pancreatic cancer tumor.

Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials.

Intraperitoneal Delivery of Iopamidol to Assess Extracellular pH of Orthotopic Pancreatic Tumor Model by CEST-MRI.

The extracellular pH (pHe) of solid tumors is often acidic, as a consequence of the Warburg effect, and an altered metabolic state is often associated with malignancy. It has been shown that acidosis can promote tumor progression; thus, many therapeutic strategies have been adopted against tumor metabolism; one of these involves alkalinization therapies to raise tumor pH to inhibit tumor progression, improve immune surveillance, and overcome resistance to chemotherapies. Chemical exchange saturation transfer-magnetic resonance imaging (CEST-MRI) is a noninvasive technique that can measure pH using pH-sensitive contrast agents.

Evolutionary Analysis of TCGA Data Using Over- and Under- Mutated Genes Identify Key Molecular Pathways and Cellular Functions in Lung Cancer Subtypes.

We identify critical conserved and mutated genes through a theoretical model linking a gene’s fitness contribution to its observed mutational frequency in a clinical cohort. “Passenger” gene mutations do not alter fitness and have mutational frequencies determined by gene size and the mutation rate. Driver mutations, which increase fitness (and proliferation), are observed more frequently than expected.

Back to basic: Trials and tribulations of alkalizing agents in cancer.

Unlabelled: "Dysregulated" metabolism is a characteristic of the cancer cell phenotype. This includes persistent use of glycolytic metabolism in normoxic environments (Warburg effect) leading to increased acid production and accumulation of protons in the interstitial space. Although often thought to be disordered, altered cancer metabolism is the outcome of intense Darwinian selection and, thus, must have evolved to maximize cancer cell fitness.

A simulation of parental and glycolytic tumor phenotype competition predicts observed responses to pH changes and increased glycolysis after anti-VEGF therapy.

Clinical cancers are typically spatially and temporally heterogeneous, containing multiple microenvironmental habitats and diverse phenotypes and/or genotypes, which can interact through resource competition and direct or indirect interference. A common intratumoral evolutionary pathway, probably initiated as adaptation to hypoxia, leads to the "Warburg phenotype" which maintains high glycolytic rates and acid production, even in normoxic conditions. Since individual cancer cells are the unit of Darwinian selection, intraspecific competition dominates intratumoral evolution.

Proton export upregulates aerobic glycolysis.

Introduction: Aggressive cancers commonly ferment glucose to lactic acid at high rates, even in the presence of oxygen. This is known as aerobic glycolysis, or the "Warburg Effect." It is widely assumed that this is a consequence of the upregulation of glycolytic enzymes.

Images Are Data: Challenges and Opportunities in the Clinical Translation of Radiomics.

Radiomics provides an opportunity to uncover image-based biomarkers through the conversion and analysis of standard-of-care medical images into high-dimensional mineable data. In the last decade, thousands of studies have been published on different clinical applications, novel analysis algorithms, and the stability and reproducibility of radiomics. Despite this, interstudy comparisons are challenging because there is not a generally accepted analytic and reporting standard.

Lipogenesis mediated by OGR1 regulates metabolic adaptation to acid stress in cancer cells via autophagy.

Malignant tumors exhibit altered metabolism resulting in a highly acidic extracellular microenvironment. Here, we show that cytoplasmic lipid droplet (LD) accumulation, indicative of a lipogenic phenotype, is a cellular adaption to extracellular acidity. LD marker PLIN2 is strongly associated with poor overall survival in breast cancer patients.

Volume doubling time and radiomic features predict tumor behavior of screen-detected lung cancers.

Background: Image-based biomarkers could have translational implications by characterizing tumor behavior of lung cancers diagnosed during lung cancer screening. In this study, peritumoral and intratumoral radiomics and volume doubling time (VDT) were used to identify high-risk subsets of lung patients diagnosed in lung cancer screening that are associated with poor survival outcomes.

Methods: Data and images were acquired from the National Lung Screening Trial.

AI-Radiomics Can Improve Inclusion Criteria and Clinical Trial Performance.

Success of clinical trials increasingly relies on effective selection of the target patient populations. We hypothesize that computational analysis of pre-accrual imaging data can be used for patient enrichment to better identify patients who can potentially benefit from investigational agents. This was tested retrospectively in soft-tissue sarcoma (STS) patients accrued into a randomized clinical trial (SARC021) that evaluated the efficacy of evofosfamide (Evo), a hypoxia activated prodrug, in combination with doxorubicin (Dox).

Modeling Tumor: Lymphatic Interactions in Lymphatic Metastasis of Triple Negative Breast Cancer.

Breast cancer frequently metastasizes to lymphatics and the presence of breast cancer cells in regional lymph nodes is an important prognostic factor. Delineating the mechanisms by which breast cancer cells disseminate and spatiotemporal aspects of interactions between breast cancer cells and lymphatics is needed to design new therapies to prevent lymphatic metastases. As triple-negative breast cancer (TNBC) has a high incidence of lymphatic metastasis, we used a three-dimensional (3D) coculture model of human TNBC cells and human microvascular lymphatic endothelial cells (LECs) to analyze TNBC:LEC interactions.

Integrated Biomarkers for the Management of Indeterminate Pulmonary Nodules.

Patients with indeterminate pulmonary nodules (IPNs) at risk of cancer undergo high rates of invasive, costly, and morbid procedures. To train and externally validate a risk prediction model that combined clinical, blood, and imaging biomarkers to improve the noninvasive management of IPNs. In this prospectively collected, retrospective blinded evaluation study, probability of cancer was calculated for 456 patient nodules using the Mayo Clinic model, and patients were categorized into low-, intermediate-, and high-risk groups.

Hypoxia-Related Radiomics and Immunotherapy Response: A Multicohort Study of Non-Small Cell Lung Cancer.

Background: Immunotherapy yields survival benefit for some advanced stage non-small cell lung cancer (NSCLC) patients. Because highly predictive biomarkers of immunotherapy response are an unmet clinical need, we used pretreatment radiomics and clinical data to train and validate a parsimonious model associated with survival outcomes among NSCLC patients treated with immunotherapy.

Methods: Three cohorts of NSCLC patients treated with immunotherapy were analyzed: training (n = 180), validation 1 (n = 90), and validation 2 (n = 62).

Macrophage-Derived Cholesterol Contributes to Therapeutic Resistance in Prostate Cancer.

Castration-resistant prostate cancer (CRPC) is a lethal stage of disease in which androgen receptor (AR) signaling is persistent despite androgen deprivation therapy (ADT). Most studies have focused on investigating cell-autonomous alterations in CRPC, while the contributions of the tumor microenvironment are less well understood. Here we sought to determine the role of tumor-associated macrophages in CRPC, based upon their role in cancer progression and therapeutic resistance.

Non-invasive measurement of PD-L1 status and prediction of immunotherapy response using deep learning of PET/CT images.

Background: Currently, only a fraction of patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) experience a durable clinical benefit (DCB). According to NCCN guidelines, Programmed death-ligand 1 (PD-L1) expression status determined by immunohistochemistry (IHC) of biopsies is the only clinically approved companion biomarker to trigger the use of ICI therapy. Based on prior work showing a relationship between quantitative imaging and gene expression, we hypothesize that quantitative imaging (radiomics) can provide an alternative surrogate for PD-L1 expression status in clinical decision support.

Extracellular Acidification Induces Lysosomal Dysregulation.

Many invasive cancers emerge through a years-long process of somatic evolution, characterized by an accumulation of heritable genetic and epigenetic changes and the emergence of increasingly aggressive clonal populations. In solid tumors, such as breast ductal carcinoma, the extracellular environment for cells within the nascent tumor is harsh and imposes different types of stress on cells, such as hypoxia, nutrient deprivation, and cytokine inflammation. Acidosis is a constant stressor of most cancer cells due to its production through fermentation of glucose to lactic acid in hypoxic or normoxic regions (Warburg effect).

Cancer heterogeneity and metastasis: life at the edge.

There is abundant evidence that the phenotype of cells the tumor at the stromal interface is distinct from the tumor cells that are within the core. Molecular phenotyping of cells at the edge show that they express higher levels of proteins associated with elevated glycolytic metabolism, including GLUT-1, HIF-1, and CA-IX. An end product of glycolysis is the production of acid, and acidosis of tumors is strongly associated with increased metastatic potential across a wide variety of tumor types.

F-FDG PET/CT Habitat Radiomics Predicts Outcome of Patients with Cervical Cancer Treated with Chemoradiotherapy.

Purpose: To determine if quantitative features extracted from pretherapy fluorine 18 fluorodeoxyglucose (F-FDG) PET/CT estimate prognosis in patients with locally advanced cervical cancer treated with chemoradiotherapy.

Materials And Methods: In this retrospective study, PET/CT images and outcomes were curated from 154 patients with locally advanced cervical cancer, who underwent chemoradiotherapy from two institutions between March 2008 and June 2016, separated into independent training ( = 78; mean age, 51 years ± 13 [standard deviation]) and testing ( = 76; mean age, 50 years ± 10) cohorts. Radiomic features were extracted from PET, CT, and habitat (subregions with different metabolic characteristics) images that were derived by fusing PET and CT images.

Radiomics predicts risk of cachexia in advanced NSCLC patients treated with immune checkpoint inhibitors.

Background: Approximately 50% of cancer patients eventually develop a syndrome of prolonged weight loss (cachexia), which may contribute to primary resistance to immune checkpoint inhibitors (ICI). This study utilised radiomics analysis of F-FDG-PET/CT images to predict risk of cachexia that can be subsequently associated with clinical outcomes among advanced non-small cell lung cancer (NSCLC) patients treated with ICI.

Methods: Baseline (pre-therapy) PET/CT images and clinical data were retrospectively curated from 210 ICI-treated NSCLC patients from two institutions.

Cycling hypoxia selects for constitutive HIF stabilization.

Tumors experience temporal and spatial fluctuations in oxygenation. Hypoxia inducible transcription factors (HIF-α) respond to low levels of oxygen and induce re-supply oxygen. HIF-α stabilization is typically facultative, induced by hypoxia and reduced by normoxia.