Systems biology informed neural networks (SBINN) predict response and novel combinations for PD-1 checkpoint blockade.

Anti-PD-1 immunotherapy has recently shown tremendous success for the treatment of several aggressive cancers. However, variability and unpredictability in treatment outcome have been observed, and are thought to be driven by patient-specific biology and interactions of the patient's immune system with the tumor. Here we develop an integrative systems biology and machine learning approach, built around clinical data, to predict patient response to anti-PD-1 immunotherapy and to improve the response rate.

Nanoengineered Disruption of Heat Shock Protein 90 Targets Drug-Induced Resistance and Relieves Natural Killer Cell Suppression in Breast Cancer.

Drug-induced resistance, or tolerance, is an emerging yet poorly understood failure of anticancer therapy. The interplay between drug-tolerant cancer cells and innate immunity within the tumor, the consequence on tumor growth, and therapeutic strategies to address these challenges remain undescribed. Here, we elucidate the role of taxane-induced resistance on natural killer (NK) cell tumor immunity in triple-negative breast cancer (TNBC) and the design of spatiotemporally controlled nanomedicines, which boost therapeutic efficacy and invigorate "disabled" NK cells.

Integrating Systems Biology and an Ex Vivo Human Tumor Model Elucidates PD-1 Blockade Response Dynamics.

Ex vivo human tumor models have emerged as promising, yet complex tools to study cancer immunotherapy response dynamics. Here, we present a strategy that integrates empirical data from an ex vivo human system with computational models to interpret the response dynamics of a clinically prescribed PD-1 inhibitor, nivolumab, in head and neck squamous cell carcinoma (HNSCC) biopsies (N = 50). Using biological assays, we show that drug-induced variance stratifies samples by T helper type 1 (Th1)-related pathways.

Cooperative adaptation to therapy (CAT) confers resistance in heterogeneous non-small cell lung cancer.

Understanding intrinsic and acquired resistance is crucial to overcoming cancer chemotherapy failure. While it is well-established that intratumor, subclonal genetic and phenotypic heterogeneity significantly contribute to resistance, it is not fully understood how tumor sub-clones interact with each other to withstand therapy pressure. Here, we report a previously unrecognized behavior in heterogeneous tumors: cooperative adaptation to therapy (CAT), in which cancer cells induce co-resistant phenotypes in neighboring cancer cells when exposed to cancer therapy.

Targeting tumor phenotypic plasticity and metabolic remodeling in adaptive cross-drug tolerance.

Metastable phenotypic state transitions in cancer cells can lead to the development of transient adaptive resistance or tolerance to chemotherapy. Here, we report that the acquisition of a phenotype marked by increased abundance of CD44 (CD44) by breast cancer cells as a tolerance response to routinely used cytotoxic drugs, such as taxanes, activated a metabolic switch that conferred tolerance against unrelated standard-of-care chemotherapeutic agents, such as anthracyclines. We characterized the sequence of molecular events that connected the induced CD44 phenotype to increased activity of both the glycolytic and oxidative pathways and glucose flux through the pentose phosphate pathway (PPP).

Perspective on nanochannels as cellular mediators in different disease conditions.

Tunnelling nanotubes (TNTs), also known as membrane nanochannels, are actin-based structures that facilitate cytoplasmic connections for rapid intercellular transfer of signals, organelles and membrane components. These dynamic TNTs can form de novo in animal cells and establish complex intercellular networks between distant cells up to 150 μm apart. Within the last decade, TNTs have been discovered in different cell types including tumor cells, macrophages, monocytes, endothelial cells and T cells.

Perspectives on the role of brain cellular players in cancer-associated brain metastasis: translational approach to understand molecular mechanism of tumor progression.

Brain metastasis is one of the leading causes of death among cancer patients. Cancer cells migrate to various sites and harbor different niche in the body which help cancer cells in their survival. The brain is one of the safest place where cancer cells are protected from immune cells.

Insights into exchange factor directly activated by cAMP (EPAC) as potential target for cancer treatment.

Cancer remains a global health problem and approximately 1.7 million new cancer cases are diagnosed every year worldwide. Although diverse molecules are currently being explored as targets for cancer therapy the tumor treatment and therapy is highly tricky.

Cancer Immunotherapy and Personalized Medicine: Emerging Technologies and Biomarker-Based Approaches.

Purpose Of Review: The vision and strategy for the 21st century treatment of cancer calls for a personalized approach in which therapy selection is designed for each individual patient. While genomics has led the field of personalized cancer medicine over the past several decades by connecting patient-specific DNA mutations with kinase-targeted drugs, the recent discovery that tumors evade immune surveillance has created unique challenges to personalize cancer immunotherapy. In this mini-review we will discuss how personalized medicine has evolved recently to accommodate the emerging era of cancer immunotherapy.

Preclinical Cancer Models and Biomarkers for Drug Development: New Technologies and Emerging Tools.

Background And Purpose: Predicting the efficacy of anticancer therapy is the holy grail of drug development and treatment selection in the clinic. To achieve this goal, scientists require pre-clinical models that can reliably screen anticancer agents with robust clinical correlation. However, there is increasing challenge to develop models that can accurately capture the diversity of the tumor ecosystem, and therefore reliably predict how tumors respond or resistant to treatment.