Dr. Robert Gatenby - Ecology and evolution in control and cure of metastatic cancers скачать в хорошем качестве

Dr. Robert Gatenby - Ecology and evolution in control and cure of metastatic cancers

#CATMO2020 Cancer Adaptive Therapy Models -- 2020 Workshop An online workshop on models of Adaptive Therapy. It was held from Dec. 7th to 10th, 2020. For more information please visit the website: http://catmo2020.org/. Speaker: Dr. Robert Gatenby, Moffitt Cancer Center Title: Ecology and evolution in control and cure of metastatic cancers Abstract: Increasing numbers of effective therapies are available for metastatic cancers. For example, there are currently 52 drugs approved for use in metastatic prostate cancer. However, of the 37,000 men who are diagnosed with metastatic prostate cancer each year in the US, none are cured. Although most metastatic cancers now have at least one effective therapy, evolution of resistance almost invariably leads to treatment failure and patient death. Investigating tumor progression during treatment has generally focused on defining the molecular machinery that permits resistance. While often viewed as the result of a “resistance mutation,” many adaptive strategies simply involve increased expression of genes (e.g. xenobiotic metabolism) already in the human genome. Furthermore, clinical treatments to block the resistance mechanism (e.g. the MDR proteins) have generally been unsuccessful reflecting the multiplicity of available strategies. In an evolutionary context, however, the mere presence of a resistant phenotype is not sufficient for treatment failure. Rather, tumor progression requires proliferation of the resistant phenotype at a rate sufficient to produce the billions of cells necessary for clinically evident progressive disease. Importantly, the necessary molecular, cellular, and population dynamics necessary for cancer progression during treatment are deeply connected because there are often significant phenotypic costs from synthesis, maintenance, and operation of the molecular machinery of resistance that can reduce cellular proliferation and invasion particularly in the substrate-poor environment often present in clinical cancers. Evolution-based cancer treatment assumes that resistant phenotypes are invariably present prior to initiation of therapy and seeks to exploit evolutionary dynamics to delay or prevent proliferation of these cells. A specific example of this approach is adaptive therapy which is used in clinical settings in which cure is not achievable. Similar to widely accepted practices in pest management, adaptive therapy reduces or periodically withdraws treatment to maintain a stable population of treatment-sensitive cells that can use their fitness advantage (i.e. absence of the cost of resistance) to suppress proliferation of resistant phenotypes. This approach has been investigated in both pre-clinical and clinical conditions. A clinical trial in metastatic castrate-resistant prostate cancer (mCRPC) has been completed and will be discussed. Finally, when cure from a cancer treatment is possible but rare, evolutionary dynamics, based on observations in background extinctions, can theoretically be used to increase the probability of complete eradication of the malignant population.