Comprehensive molecular tumor profiling in radiation oncology: How it could be used for precision medicine

Eke, Iris; Makinde, Adeola Y.; Aryankalayil, Molykutty J.; Ahmed, Mansoor M.; Coleman, C. Norman

doi:10.1016/j.canlet.2016.01.041

Cited by 18 publications

(11 citation statements)

References 130 publications

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“…De novo or acquired drug resistance to molecular inhibitors is a highly relevant clinical problem and can be caused by multiple factors, such as decreased target expression, mutations in the target sequence resulting in impaired drug functionality but also changes in downstream molecules or related pathways allowing the cancer cell to bypass the inhibitory effects (51,52). As the complexity of precision medicine including tumor heterogeneity becomes better understood additional strategies are necessary to enhance the clinical efficacy of molecular-targeted therapy (53,54).…”

Section: Discussionmentioning

confidence: 99%

Exploiting Radiation-Induced Signaling to Increase the Susceptibility of Resistant Cancer Cells to Targeted Drugs: AKT and mTOR Inhibitors as an Example

Eke

Makinde

Aryankalayil

et al. 2018

Molecular Cancer Therapeutics

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Implementing targeted drug therapy in radio-oncologic treatment regimens has greatly improved the outcome of cancer patients. However, the efficacy of molecular targeted drugs such as inhibitory antibodies or small molecule inhibitors essentially depends on target expression and activity, which both can change during the course of treatment. Radiotherapy has previously been shown to activate prosurvival pathways, which can help tumor cells to adapt and thereby survive treatment. Therefore, we aimed to identify changes in signaling induced by radiation and evaluate the potential of targeting these changes with small molecules to increase the therapeutic efficacy on cancer cell survival. Analysis of "The Cancer Genome Atlas" database disclosed a significant overexpression of , and genes in human prostate cancer samples compared with normal prostate gland tissue. Multifractionated radiation of three-dimensional-cultured prostate cancer cell lines with a dose of 2 Gy/day as a clinically relevant schedule resulted in an increased protein phosphorylation and enhanced protein-protein interaction between AKT and mTOR, whereas gene expression of , and related kinases was not altered by radiation. Similar results were found in a xenograft model of prostate cancer. Pharmacologic inhibition of mTOR/AKT signaling after activation by multifractionated radiation was more effective than treatment prior to radiotherapy. Taken together, our findings provide a proof-of-concept that targeting signaling molecules after activation by radiotherapy may be a novel and promising treatment strategy for cancers treated with multifractionated radiation regimens such as prostate cancer to increase the sensitivity of tumor cells to molecular targeted drugs.

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Section: Discussionmentioning

confidence: 99%

Exploiting Radiation-Induced Signaling to Increase the Susceptibility of Resistant Cancer Cells to Targeted Drugs: AKT and mTOR Inhibitors as an Example

Eke

Makinde

Aryankalayil

et al. 2018

Molecular Cancer Therapeutics

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“…Broad molecular profiling is expected to be a key component of future advancements in the care of patients with NSCLC. Prospective clinical trials are underway to generate clinical and molecular predictors, including comprehensive molecular profiling and/or primary tumor microRNA expression, to guide selection of patients for oligometastases-directed ablative therapy ( 107 , 108 ). Further investigation, including independent validation, is needed before clinical implementation.…”

Section: Future Directions and Ongoing Prospective Trialsmentioning

confidence: 99%

Radiotherapy for Oligometastatic Lung Cancer

et al. 2017

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Non-small cell lung cancer (NSCLC) typically presents at an advanced stage, which is often felt to be incurable, and such patients are usually treated with a palliative approach. Accumulating retrospective and prospective clinical evidence, including a recently completed randomized trial, support the existence of an oligometastatic disease state wherein select individuals with advanced NSCLC may experience historically unprecedented prolonged survival with aggressive local treatments, consisting of radiotherapy and/or surgery, to limited sites of metastatic disease. This is reflected in the most recent AJCC staging subcategorizing metastatic disease into intra-thoracic (M1a), a single extra thoracic site (M1b), and more diffuse metastases (M1c). In the field of radiation oncology, recent technological advances have allowed for the delivery of very high, potentially ablative, doses of radiotherapy to both intra- and extra-cranial disease sites, referred to as stereotactic radiosurgery and stereotactic body radiotherapy (or SABR), in much shorter time periods compared to conventional radiation and with minimal associated toxicity. At the same time, significant improvements in systemic therapy, including platinum-based doublet chemotherapy, molecular agents targeting oncogene-addicted NSCLC, and immunotherapy in the form of checkpoint inhibitors, have led to improved control of micro-metastatic disease and extended survival sparking newfound interest in combining these agents with ablative local therapies to provide additive, and in the case of radiation and immunotherapy, potentially synergistic, effects in order to further improve progression-free and overall survival. Currently, despite the tantalizing potential associated with aggressive local therapy in the setting of oligometastatic NSCLC, well-designed prospective randomized controlled trials sufficiently powered to detect and measure the possible added benefit afforded by this approach are desperately needed.

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“…For the elucidation of the pathogenesis of the disease, the comprehensive profiling of proteins, DNA, RNA and metabolites has been carried out (3,4). This profiling would provide invaluable information useful for the identification of molecules of therapy, diagnosis and tumor biology.…”

Section: Introductionmentioning

confidence: 99%

Expression of DNA damage response proteins in gastric cancer: Comprehensive protein profiling and histological analysis

et al. 2018

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Gastric cancer is the third major cause of cancer-related mortality in Japan. The aim of this study was to identify a factor implicated in the biology of gastric cancer by comprehensive protein profiling. Protein profiling was carried out by liquid chromatography-tandem mass spectrometry, using formalin-fixed paraffin-embedded specimens of 17 gastric cancer cases. Pathway analysis and orthogonal partial least square-discriminant analysis suggested the significant expression of ribonucleoproteins, heterogeneous nuclear ribonucleoproteins, interleukin binding factor 2 (ILF2), KU70 and KU80, which are involved in DNA damage response (DDR). Thus, the expression and phosphorylation levels of KU70, ILF2, CHK1 and CHK2 were examined by immunohistochemistry in 42 cases of gastric cancer. The expressions of ILF2 and CHK1 were unaffected in all cases. The expression and phosphorylation of CHK2 were absent in 2 cases. Despite the expression of proteins, the phosphorylation of KU70 and CHK2 appeared to be impaired in 1 and 4 cases, respectively. In 7 out of 42 cases (17%), DDR appeared to be impaired. Recurrence was noted in 2 out of these 7 cases (29%), whereas the recurrence was noted in 2 out of the remaining 35 cases (6%). The expression levels of KU70, ILF2, CHK1, CHK2 and TP53 were further examined in 4 gastric cancer cell lines. The expression and phosphorylation levels following exposure to ultraviolet radiation were abnormal in the 3 cell lines. The normal consecutive phosphorylation of CHK1 and CHK2, the upregulation of TP53 and an increase in apoptotic cell death following exposure to ultraviolet radiation was detected only in one cell line, suggesting that the preserved functions of DDR and TP53 are necessary for the determination of cell fate. It is thus suggested that DDR plays an important role in the pathobiology of gastric cancers.

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Comprehensive molecular tumor profiling in radiation oncology: How it could be used for precision medicine

Cited by 18 publications

References 130 publications

Exploiting Radiation-Induced Signaling to Increase the Susceptibility of Resistant Cancer Cells to Targeted Drugs: AKT and mTOR Inhibitors as an Example

Exploiting Radiation-Induced Signaling to Increase the Susceptibility of Resistant Cancer Cells to Targeted Drugs: AKT and mTOR Inhibitors as an Example

Radiotherapy for Oligometastatic Lung Cancer

Expression of DNA damage response proteins in gastric cancer: Comprehensive protein profiling and histological analysis

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