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Exploiting Gene Expression Kinetics in Conventional Radiotherapy, Hyperfractionation, and Hypofractionation for Targeted Therapy.

ABSTRACT: The dramatic changes in the technological delivery of radiation therapy, the repertoire of molecular targets for which pathway inhibitors are available, and the cellular and immunologic responses that can alter long-term clinical outcome provide a potentially unique role for using the radiation-inducible changes as therapeutic targets. Various mathematical models of dose and fractionation are extraordinarily useful in guiding treatment regimens. However, although the model may fit the clinical outcome, a deeper understanding of the molecular and cellular effect of the individual dose size and the adaptation to repeated exposure, called multifraction (MF) adaptation, may provide new therapeutic targets for use in combined modality treatments using radiochemotherapy and radioimmunotherapy. We discuss the potential of using different radiation doses and MF adaptation for targeting transcription factors, immune and inflammatory response, and cell "stemness." Given the complex genetic composition of tumors before treatment and their adaptation to drug treatment, innovative combinations using both the pretreatment molecular data and also the MF-adaptive response to radiation may provide an important role for focused radiation therapy as an integral part of precision medicine and immunotherapy.

SUBMITTER: Makinde AY

PROVIDER: S-EPMC5023066 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Exploiting Gene Expression Kinetics in Conventional Radiotherapy, Hyperfractionation, and Hypofractionation for Targeted Therapy.

Makinde Adeola Y AY Eke Iris I Aryankalayil Molykutty J MJ Ahmed Mansoor M MM Coleman C Norman CN

Seminars in radiation oncology 20160705 4

The dramatic changes in the technological delivery of radiation therapy, the repertoire of molecular targets for which pathway inhibitors are available, and the cellular and immunologic responses that can alter long-term clinical outcome provide a potentially unique role for using the radiation-inducible changes as therapeutic targets. Various mathematical models of dose and fractionation are extraordinarily useful in guiding treatment regimens. However, although the model may fit the clinical o ...[more]

PMID: 27619247

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Project description:PURPOSE:The limited radiotherapy resources for global cancer control have resulted in increased interest in developing time- and cost-saving innovations to expand access to those resources. Hypofractionated regimens could minimize cost and increase access for limited-resource countries. In this investigation, we estimated the percentage cost-savings per radiotherapy course and increased radiotherapy access in African countries after adopting hypofractionation for breast and prostate radiotherapy. For perspective, results were compared with high-income countries. METHODS:The cost and course of breast and prostate radiotherapy for conventional and hypofractionated regimens in low-resource facilities were calculated using the Radiotherapy Cost Estimator tool developed by the International Atomic Energy Agency (IAEA) and then compared with another activity-based costing model. The potential maximum cost savings in each country over 7 years for breast and prostate radiotherapy were then estimated using cancer incidence data from the Global Cancer Observatory database with use rates applied. The increase in radiotherapy access was estimated by current national capacities from the IAEA directory. RESULTS:The estimated cost per course of conventional and hypofractionated regimens were US$2,232 and $1,339 for breast treatment, and $3,389 and $1,699 for prostate treatment, respectively. The projected potential maximum cost savings with full hypofractionation implementation were $1.1 billion and $606 million for breast and prostate treatment, respectively. The projected increase of radiotherapy access due to implementing hypofractionation varied between +0.3% to 25% and +0.4% to 36.0% for breast and prostate treatments, respectively. CONCLUSION:This investigation demonstrates that adopting hypofractionated regimens as standard treatment of breast and prostate cancers can result in substantial savings and increase radiotherapy access in developing countries. Given reduced delivery cost and treatment times, we anticipate a substantial increase in radiotherapy access with additional innovations that will allow progressive hypofractionation without compromising quality.

Project description:The vascular endothelium is considered as a key cell compartment for the response to ionizing radiation of normal tissues and tumors, and as a promising target to improve the differential effect of radiotherapy in the future. Following radiation exposure, the global endothelial cell response covers a wide range of gene, miRNA, protein and metabolite expression modifications. Changes occur at the transcriptional, translational and post-translational levels and impact cell phenotype as well as the microenvironment by the production and secretion of soluble factors such as reactive oxygen species, chemokines, cytokines and growth factors. These radiation-induced dynamic modifications of molecular networks may control the endothelial cell phenotype and govern recruitment of immune cells, stressing the importance of clearly understanding the mechanisms which underlie these temporal processes. A wide variety of time series data is commonly used in bioinformatics studies, including gene expression, protein concentrations and metabolomics data. The use of clustering of these data is still an unclear problem. Here, we introduce kernels between Gaussian processes modeling time series, and subsequently introduce a spectral clustering algorithm. We apply the methods to the study of human primary endothelial cells (HUVECs) exposed to a radiotherapy dose fraction (2 Gy). Time windows of differential expressions of 301 genes involved in key cellular processes such as angiogenesis, inflammation, apoptosis, immune response and protein kinase were determined from 12 hours to 3 weeks post-irradiation. Then, 43 temporal clusters corresponding to profiles of similar expressions, including 49 genes out of 301 initially measured, were generated according to the proposed method. Forty-seven transcription factors (TFs) responsible for the expression of clusters of genes were predicted from sequence regulatory elements using the MotifMap system. Their temporal profiles of occurrences were established and clustered. Dynamic network interactions and molecular pathways of TFs and differential genes were finally explored, revealing key node genes and putative important cellular processes involved in tissue infiltration by immune cells following exposure to a radiotherapy dose fraction.

Dataset Information

Exploiting Gene Expression Kinetics in Conventional Radiotherapy, Hyperfractionation, and Hypofractionation for Targeted Therapy.

Publications

Exploiting Gene Expression Kinetics in Conventional Radiotherapy, Hyperfractionation, and Hypofractionation for Targeted Therapy.

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