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.

Metabolic Imaging as a Tool to Characterize Chemoresistance and Guide Therapy in Triple-Negative Breast Cancer (TNBC).

After an initial response to chemotherapy, tumor relapse is frequent. This event is reflective of both the spatiotemporal heterogeneities of the tumor microenvironment as well as the evolutionary propensity of cancer cell populations to adapt to variable conditions. Because the cause of this adaptation could be genetic or epigenetic, studying phenotypic properties such as tumor metabolism is useful as it reflects molecular, cellular, and tissue-level dynamics.

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.

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.

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).

Targeting of Evolutionarily Acquired Cancer Cell Phenotype by Exploiting pHi-Metabolic Vulnerabilities.

Evolutionary dynamics can be used to control cancers when a cure is not clinically considered to be achievable. Understanding Darwinian intratumoral interactions of microenvironmental selection forces can be used to steer tumor progression towards a less invasive trajectory. Here, we approach intratumoral heterogeneity and evolution as a dynamic interaction among subpopulations through the application of small, but selective biological forces such as intracellular pH (pHi) and/or extracellular pH (pHe) vulnerabilities.

Causes and Consequences of Variable Tumor Cell Metabolism on Heritable Modifications and Tumor Evolution.

When cancer research advanced into the post-genomic era, it was widely anticipated that the sought-after cure will be delivered promptly. Instead, it became apparent that an understanding of cancer genomics, alone, is unable to translate the wealth of information into successful cures. While gene sequencing has significantly improved our understanding of the natural history of cancer and identified candidates for therapeutic targets, it cannot predict the impact of the biological response to therapies.

Integrative Analysis of Breast Cancer Cells Reveals an Epithelial-Mesenchymal Transition Role in Adaptation to Acidic Microenvironment.

Early ducts of breast tumors are unequivocally acidic. High rates of glycolysis combined with poor perfusion lead to a congestion of acidic metabolites in the tumor microenvironment, and pre-malignant cells must adapt to this acidosis to thrive. Adaptation to acidosis selects cancer cells that can thrive in harsh conditions and are capable of outgrowing the normal or non-adapted neighbors.