Target Identification in Cancer Using RNA interference – Accelerated Therapy Development in Leukemias
The challenge in drug development has been the implementation of novel active treatment regimens in cancer. Despite a deeper understanding of molecular oncogenesis many therapeutic strategies have failed in the clinic, raising the questions if currently developed drugs are not active enough against the targets or the “true” molecular targets – the synthetic lethal vulnerabilities in cancer genomes – have not been discovered yet.
A conceptual framework successfully developed for quantitatively understanding and predicting many physiological and dynamical properties of mammals and plants, including metabolic rates, ontogenetic growth trajectories and vascular structure, is extended to tumors. The theory presumes that life at all scales from intra- to multi-cellular levels is sustained by space-filling, fractal-like, hierarchical branching networks whose “universal” geometric and dynamical properties provide a mathematical framework that captures the essential features of these diverse systems.
Cancer is widespread among eukaryotes, and can be successfully tackled only by understanding its place in the story of life itself – especially the evolution of multi-cellularity. In this seminar I will propose a new theory of cancer, drawing on insights from astrobiology. The central hypothesis is that cancer is an organized pre-programmed process driven by a cassette of highly conserved, deeply-evolved ancient genes – genes that are active in early-stage embryo development, and which become inappropriately re-awakened in the adult form
Cancer results from a process of cellular evolution. Key cancer defenses and vulnerabilities
both arose from the ancient evolutionary transition from single-celled to multicellular
organisms. Because cellular evolution leads inexorably to cancer, organismal evolution has
led to adaptations that organize cell reproduction into patterns that are less subject to cellular
evolution. We used an agent-based computational model of evolution inside tissues to test the
hypothesis that cell differentiation is crucial to suppressing cellular evolution within the body.
Neoplastic progression is a process of somatic evolution. Cells mutate and some mutations increase the fitness (survival or reproduction) of the clone, leading to a clonal expansion. The evolutionary theory of cancer is now 36 years old, but the dynamics of the process are still poorly understood.
One of the most exciting breakthroughs in cell biology over the past decade is the recognition that micromechanical inputs to cells from the solid-state extracellular matrix (ECM), such as those encoded in ECM geometry, topography, and elasticity, can influence cell and tissue physiology and pathology in profound and specific ways.
The major recent advances in genomic sequencing provide unparalleled opportunities to identify novel mechanisms that regulate susceptibility to human diseases, as well as disease pathogenesis and progression. However, the heterogeneity of human populations leads to complexity that complicates these analyses.
Cancer does not exist in a vacuum: the host immune system continuously monitors cells for alterations in protein content and structure. Several key questions in cancer immunology are the identification of antigens associated with tumor destruction, optimal timing and method of antigen delivery, and the identification of the regulatory pathways and tumor heterogeneity that limit effective immunity. The design of future vaccines requires understanding both the targets and the biology of effective anti-tumor immune responses.
Dr. Henikoff will talk about histone variants, nucleosome dynamics and epigenetics.
To a physicist, epigenetics – the passing of heritable traits to daughter cells without alteration of the genome – seems like magic. Yet it surely lies at the heart of cancer, as cancerous phenotypes can be switched on and off without alteration of the genome. Together with the Henikoff lab at Fred Hutchinson Cancer Research Center, we have been looking for physical manifestations of epigenetic coding.