A theoretical quantitative model for evolution of cancer chemotherapy resistance

<p>Abstract</p> <p>Background</p> <p>Disseminated cancer remains a nearly uniformly fatal disease. While a number of effective chemotherapies are available, tumors inevitably evolve resistance to these drugs ultimately resulting in treatment failure and cancer progression. Causes for chemotherapy failure in cancer treatment reside in multiple levels: poor vascularization, hypoxia, intratumoral high interstitial fluid pressure, and phenotypic resistance to drug-induced toxicity through upregulated xenobiotic metabolism or DNA repair mechanisms and silencing of apoptotic pathways. We propose that in order to understand the evolutionary dynamics that allow tumors to develop chemoresistance, a comprehensive quantitative model must be used to describe the interactions of cell resistance mechanisms and tumor microenvironment during chemotherapy.</p> <p>Ultimately, the purpose of this model is to identify the best strategies to treat different types of tumor (tumor microenvironment, genetic/phenotypic tumor heterogeneity, tumor growth rate, etc.). We predict that the most promising strategies are those that are both cytotoxic and apply a selective pressure for a phenotype that is less fit than that of the original cancer population. This strategy, known as double bind, is different from the selection process imposed by standard chemotherapy, which tends to produce a resistant population that simply upregulates xenobiotic metabolism. In order to achieve this goal we propose to simulate different tumor progression and therapy strategies (chemotherapy and glucose restriction) targeting stabilization of tumor size and minimization of chemoresistance.</p> <p>Results</p> <p>This work confirms the prediction of previous mathematical models and simulations that suggested that administration of chemotherapy with the goal of tumor stabilization instead of eradication would yield better results (longer subject survival) than the use of maximum tolerated doses. Our simulations also indicate that the simultaneous administration of chemotherapy and 2-deoxy-glucose does not optimize treatment outcome because when simultaneously administered these drugs are antagonists. The best results were obtained when 2-deoxy-glucose was followed by chemotherapy in two separate doses.</p> <p>Conclusions</p> <p>These results suggest that the maximum potential of a combined therapy may depend on how each of the drugs modifies the evolutionary landscape and that a rational use of these properties may prevent or at least delay relapse.</p> <p>Reviewers</p> <p>This article was reviewed by Dr Marek Kimmel and Dr Mark Little.</p

Whole-Exome sequencing analysis identified TMSB10/TRABD2A locus to be associated with carfilzomib-related cardiotoxicity among patients with multiple myeloma

BackgroundProteasome inhibitor Carfilzomib (CFZ) is effective in treating patients with refractory or relapsed multiple myeloma (MM) but has been associated with cardiovascular adverse events (CVAE) such as hypertension, cardiomyopathy, and heart failure. This study aimed to investigate the contribution of germline genetic variants in protein-coding genes in CFZ-CVAE among MM patients using whole-exome sequencing (WES) analysis.MethodsExome-wide single-variant association analysis, gene-based analysis, and rare variant analyses were performed on 603,920 variants in 247 patients with MM who have been treated with CFZ and enrolled in the Oncology Research Information Exchange Network (ORIEN) at the Moffitt Cancer Center. Separate analyses were performed in European Americans and African Americans followed by a trans-ethnic meta-analysis.ResultsThe most significant variant in the exome-wide single variant analysis was a missense variant rs7148 in the thymosin beta-10/TraB Domain Containing 2A (TMSB10/TRABD2A) locus. The effect allele of rs7148 was associated with a higher risk of CVAE [odds ratio (OR) = 9.3 with a 95% confidence interval of 3.9—22.3, p = 5.42*10−7]. MM patients with rs7148 AG or AA genotype had a higher risk of CVAE (50%) than those with GG genotype (10%). rs7148 is an expression quantitative trait locus (eQTL) for TRABD2A and TMSB10. The gene-based analysis also showed TRABD2A as the most significant gene associated with CFZ-CVAE (p = 1.06*10−6).ConclusionsWe identified a missense SNP rs7148 in the TMSB10/TRABD2A as associated with CFZ-CVAE in MM patients. More investigation is needed to understand the underlying mechanisms of these associations

Classifying the evolutionary and ecological features of neoplasms

The consensus conference was supported by Wellcome Genome Campus Advanced Courses and Scientific Conferences. C.C.M. is supported in part by US NIH grants P01 CA91955, R01 CA149566, R01 CA170595, R01 CA185138 and R01 CA140657 as well as CDMRP Breast Cancer Research Program Award BC132057. M.J. is supported by NIH grant K99CA201606. K.S.A. is supported by NCI 5R21 CA196460. K. Polyak is supported by R35 CA197623, U01 CA195469, U54 CA193461, and the Breast Cancer Research Foundation. K.J.P. is supported by NIH grants CA143803, CA163124, CA093900 and CA143055. D.P. is supported by the European Research Council (ERC-617457- PHYLOCANCER), the Spanish Ministry of Economy and Competitiveness (BFU2015-63774-P) and the Education, Culture and University Development Department of the Galician Government. K.S.A. is supported in part by the Breast Cancer Research Foundation and NCI R21CA196460. C.S. is supported by the Royal Society, Cancer Research UK (FC001169), the UK Medical Research Council (FC001169), and the Wellcome Trust (FC001169), NovoNordisk Foundation (ID 16584), the Breast Cancer Research Foundation (BCRF), the European Research Council (THESEUS) and Marie Curie Network PloidyNet. T.A.G. is a Cancer Research UK fellow and a Wellcome Trust funded Investigator. E.S.H. is supported by R01 CA185138-01 and W81XWH-14-1-0473. M.Gerlinger is supported by Cancer Research UK and The Royal Marsden/ICR National Institute of Health Research Biomedical Research Centre. M.Ge., M.Gr., Y.Y., and A.So. were also supported in part by the Wellcome Trust [105104/Z/14/Z]. J.D.S. holds the Edward B. Clark, MD Chair in Pediatric Research, and is supported by the Primary Children's Hospital (PCH) Pediatric Cancer Research Program, funded by the Intermountain Healthcare Foundation and the PCH Foundation. A.S. is supported by the Chris Rokos Fellowship in Evolution and Cancer. Y.Y. is a Cancer Research UK fellow and supported by The Royal Marsden/ICR National Institute of Health Research Biomedical Research Centre. E.S.H. was supported in part by PCORI grants 1505–30497 and 1503–29572, NIH grants R01 CA185138, T32 CA093245, and U10 CA180857, CDMRP Breast Cancer Research Program Award BC132057, a CRUK Grand Challenge grant, and the Breast Cancer Research Foundation. A.R.A.A. was funded in part by NIH grant U01CA151924. A.R.A.A., R.G. and J.S.B. were funded in part by NIH grant U54CA193489