Measurements of Mcl-1 protein dependencies using dimerization-specific antibodies as predictive biomarkers for BH-3 mimetic class therapies in AML.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e19505-e19505
Author(s):  
Michael H. Cardone ◽  
Andrew Kinloch ◽  
Mine Canakci ◽  
Jingping Ge
Keyword(s):  
Cell Lines ◽  
Protein Complexes ◽  
Treatment Options ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Response To Treatment ◽  
Clinical Settings ◽  
Cancer Therapies ◽  
Protein Levels ◽  
Combination Treatments

e19505 Background: The anti-apoptotic Bcl-2 family proteins facilitate pro-survival and resistance to anti-cancer therapies. Measuring the function of these proteins has shown utility in predicting response to treatment. A biomarker platform that assesses the functionality of these proteins by measuring BH3 mediated signaling potential in individual patients’ cancers, could provide a potential guiding platform for treating AML. In AML venetoclax is becoming widely prescribed and highly effective in combination with other drugs. Recent data indicate that Mcl-1 dependence is a resistance factor to venetoclax and that methods for identifying this could provide guidance for combination treatments. We are developing a technology to directly measure the occurrence of heterodimers of Mcl-1, or Bcl-xL, bound to pro-apoptotic BH3-only protein Bim. These measurements are combined in algorithms developed to indicate the cancer cell apoptotic priming state and offer great potential for identifying best AML treatment options. Methods: Monoclonal antibodies against conformation-specific epitopes induced in Mcl-1/Bim and Bcl-xL/Bim protein complexes were made. Selective bonding of Heterodimer Specific Mcl-1 Bim (HSMCB) and Heterodimer Specific Bcl-xL Bim (HSBXB) mabs were confirmed using ELISA, fluorescence polarization, immunofluorescence microscopy and flow, and by immunohistochemistry in genetically defined cell lines and in AML patient biopsied samples. Results: We show that HSMCB signal depends on both Mcl-1 and Bim protein levels while HSBXB requires Bc-xL and Bim levels. The relative signals of HSMCB to unbound Mcl-1 signal ([HsMcB]/[Mcl-1]) provide a biomarker for Mcl-1 dependence. We carefully established binding metrics that correlate to drug response in cell lines. The pharmacological disruption of these complexes is monitored by the ratiometric readouts that serve as predictive biomarkers for BH-3 mimetic drugs in AML cells. Conclusions: Mcl-1 dependence is a predictive biomarker for venetoclax resistance and for response to Mcl-1 targeted therapies. Flow cytometric and IHC based measurements of a heterodimer complex offer a direct and simpler approach that harbors potential for use in clinical settings. Additional antibodies targeting Mcl-1/Bak and Bcl-2/Bim complexes are being tested.

scholarly journals mTOR, p70S6K, AKT, and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids

2013 ◽  
Vol 20 (4) ◽  
pp. 463-475 ◽  
Author(s):  
Teresa Gagliano ◽  
Mariaenrica Bellio ◽  
Erica Gentilin ◽  
Daniela Molè ◽  
Federico Tagliati ◽  
...  
Keyword(s):  
Cell Viability ◽  
Cell Lines ◽  
Mtor Inhibitor ◽  
Primary Cultures ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Response To Treatment ◽  
Akt Activation ◽  
Protein Levels ◽  
Bronchial Carcinoids

Bronchial carcinoids (BCs) are rare neuroendocrine tumors that are still orphans of medical treatment. Human BC primary cultures may display resistance to everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), in terms of cell viability reduction. Our aim was to assess whether the novel dual phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor NVP-BEZ235 is effective in everolimus-resistant human BC tissues and cell lines. In addition, we searched for possible markers of the efficacy of mTOR inhibitors that may help in identifying the patients who may benefit from treatment with mTOR inhibitors, sparing them from ineffective therapy. We found that NVP-BEZ235 is twice as potent as everolimus in reducing cell viability and activating apoptosis in human BC tissues that display sensitivity to mTOR inhibitors, but is not effective in everolimus-resistant BC tissues and cell lines that bypass cyclin D1 downregulation and escape G0/G1 blockade. Rebound AKT activation was not observed in response to treatment with either mTOR inhibitor in the ‘resistant’ BC cells. In addition to total mTOR levels, putative markers of the sensitivity of BCs to mTOR inhibitors are represented by AKT, p70S6K (RPS6KB2), and ERK1/2 (MAPK3/1) protein levels. Finally, we validated these markers in an independent BC group. These data indicate that the dual PI3K/mTOR inhibitor NVP-BEZ235 is more potent than everolimus in reducing the proliferation of human BC cells. ‘Resistant’ cells display lower levels of mTOR, p70S6K, AKT, and ERK1/2, indicating that these proteins may be useful as predictive markers of resistance to mTOR and PI3K/mTOR inhibitors in human BCs.

scholarly journals Identification of early and intermediate biomarkers for ARDS mortality by multi-omic approaches

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
S. Y. Liao ◽  
N. G. Casanova ◽  
C. Bime ◽  
S. M. Camp ◽  
H. Lynn ◽  
...  
Keyword(s):  
Biomarker Discovery ◽  
Association Studies ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Genome Wide Association Studies ◽  
Potential Candidate ◽  
Gene Set ◽  
Protein Levels ◽  
N 93

AbstractThe lack of successful clinical trials in acute respiratory distress syndrome (ARDS) has highlighted the unmet need for biomarkers predicting ARDS mortality and for novel therapeutics to reduce ARDS mortality. We utilized a systems biology multi-“omics” approach to identify predictive biomarkers for ARDS mortality. Integrating analyses were designed to differentiate ARDS non-survivors and survivors (568 subjects, 27% overall 28-day mortality) using datasets derived from multiple ‘omics’ studies in a multi-institution ARDS cohort (54% European descent, 40% African descent). ‘Omics’ data was available for each subject and included genome-wide association studies (GWAS, n = 297), RNA sequencing (n = 93), DNA methylation data (n = 61), and selective proteomic network analysis (n = 240). Integration of available “omic” data identified a 9-gene set (TNPO1, NUP214, HDAC1, HNRNPA1, GATAD2A, FOSB, DDX17, PHF20, CREBBP) that differentiated ARDS survivors/non-survivors, results that were validated utilizing a longitudinal transcription dataset. Pathway analysis identified TP53-, HDAC1-, TGF-β-, and IL-6-signaling pathways to be associated with ARDS mortality. Predictive biomarker discovery identified transcription levels of the 9-gene set (AUC-0.83) and Day 7 angiopoietin 2 protein levels as potential candidate predictors of ARDS mortality (AUC-0.70). These results underscore the value of utilizing integrated “multi-omics” approaches in underpowered datasets from racially diverse ARDS subjects.

scholarly journals CUL4A, ERCC5, and ERCC1 as Predictive Factors for Trabectedin Efficacy in Advanced Soft Tissue Sarcomas (STS): A Spanish Group for Sarcoma Research (GEIS) Study

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1128 ◽  
Author(s):  
David S. Moura ◽  
Paloma Sanchez-Bustos ◽  
Antonio Fernandez-Serra ◽  
María Lopez-Alvarez ◽  
José L. Mondaza-Hernandez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Soft Tissue ◽  
Cell Lines ◽  
Predictive Factors ◽  
Excision Repair ◽  
Soft Tissue Sarcomas ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Expression Levels ◽  
Protein Levels

A translational study was designed to analyze the expression of nucleotide excision repair (NER) and homologous recombination (HR) genes as potential predictive biomarkers for trabectedin in soft-tissue sarcoma (STS). This study is part of a randomized phase II trial comparing trabectedin plus doxorubicin versus doxorubicin in advanced STS. Gene expression levels were evaluated by qRT-PCR, while CUL4A protein levels were quantified by immunohistochemistry. Expression levels were correlated with patients’ progression-free survival (PFS) and overall survival (OS). Gene expression was also evaluated in cell lines and correlated with trabectedin sensitivity. In doxorubicin arm and in the whole series, which includes samples from both arms, no significant differences in terms of PFS were observed amongst the analyzed genes. In the group treated with trabectedin plus doxorubicin, the median of PFS was significantly longer in cases with CUL4A, ERCC1, or ERCC5 overexpression, while BRCA1 expression did not correlated with PFS. Gene expression had no prognostic influence in OS. CUL4A protein levels correlated with worse PFS in doxorubicin arm and in the whole series. In cell lines, only overexpression of ERCC1 was significantly correlated with trabectedin sensitivity. In conclusion, CUL4A, ERCC5, and mainly ERCC1 acted as predictive factors for trabectedin efficacy in advanced STS.

Identifying Mcl-1 protein dependencies using dimerization-specific antibody biomarker for predicting response to targeted apoptosis inducing therapies.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7038-7038
Author(s):  
Michael H. Cardone ◽  
Sae Rin Jean ◽  
Bahriye Karakas ◽  
Sonia Kumar ◽  
Max Narovlyansky ◽  
...  
Keyword(s):  
Leukemia Cell ◽  
Predictive Biomarker ◽  
Response To Therapy ◽  
Cancer Therapies ◽  
Cancer Treatments ◽  
Protein Levels ◽  
Formalin Fixed Paraffin ◽  
Mimetic Peptides ◽  
Formalin Fixed Paraffin Embedded ◽  
Bh3 Mimetic

7038 Background: The anti-apoptotic Bcl-2 family proteins facilitate pro-survival and resistance to anti-cancer therapies. Measuring the function of these proteins has shown utility in predicting response to therapy. A method that expands the principle of BH3 profiling to solid tumors is presented. Measuring the occurrence of heterodimers of Myeloid Leukemia Cell Differentiation Protein (Mcl-1), and pro-apoptotic binding protein Bim is an indicator of cancer cell apoptotic priming state. The readout of Mcl-1 containing complex-specific biomarkers can identify survival dependencies in cancer cells potentially providing clinical utility in guiding cancer treatments. Methods: Engineered immunogens that recapitulate conformation-specific epitopes induced during binding of the Mcl-1/Bim protein complex were used to generate. monoclonal antibodies. One Heterodimer Specific Mcl-1 Bim (HsMcB) was chosen. The selective binding was confirmed using ELISA, fluorescence polarization, immunofluorescence microscopy and flow cytometry in Bim or Mcl-1 knockdown cells, and by immunohistochemistry in formalin-fixed paraffin-embedded patient tissue. Correlation of HsMcB measurements to BH3 profiling readouts from the Mcl-1 restricted Noxa peptide was explored. Results: HsMcB signal depends on both Mcl-1 and Bim protein levels. The ratio of the HsMcB to unbound protein (Mcl-1) signal ([HsMcB]/[Mcl-1]) was measured. Disruption of the complexes by BH3 mimetics targeted to Mcl-1 and depletion of Mcl-1 level using CDK9 inhibitors diminished the [HsMcB]/[Mcl-1] readout. We see correlations between these readouts and BH3 mimetic peptides readouts from the Mcl-1 specific Noxa and MS1 BH3 mimetic peptides in AML patient samples that have been treated with Mcl-1 inhibitors. Conclusions: Mcl-1 dependence is a predictive biomarker for venetoclax resistance and for response to Mcl-1 targeted therapies. Flow cytometric and IHC based measurements of a heterodimer complex offer a direct and simpler approach that harbors potential for use in clinical settings. Additional antibodies targeting Mcl-1/Bak and Mcl-1 Noxa complexes are being tested.

Regulation of drug sensitivity by ribosomal protein S3a

Blood ◽  
2000 ◽  
Vol 95 (3) ◽  
pp. 1047-1055 ◽  
Author(s):  
Z.-B. Hu ◽  
M. D. Minden ◽  
E. A. McCulloch
Keyword(s):  
Ribosomal Protein ◽  
Cell Lines ◽  
Response To Treatment ◽  
Protein Levels ◽  
Cell Extracts ◽  
All Trans Retinoic Acid ◽  
Biologic Effects ◽  
Blast Cells ◽  
Increased Sensitivity ◽  
Myelomonocytic Leukemia

When bcl-2 is immunoprecipitated from 32P-labeled cell extracts of all-trans retinoic acid (ATRA)-treated acute myeloblastic leukemia (AML) blasts, a phosphorylated protein of approximately 30 kd is coprecipitated. This protein has been identified as ribosomal protein S3a. The biologic effects of S3a include favoring apoptosis and enhancing the malignant phenotype. We sought to determine whether S3a, like bcl-2, influenced the response of cells to chemotherapeutic drugs and ATRA. Cell lines were studied in which S3a was genetically increased or disrupted; increased S3a was regularly associated with increased plating efficiency and increased sensitivity to either cytosine arabinoside (ara-C) or doxorubicin (DNR). S3a did not affect the sensitivity of cells to paclitaxel. Pulse exposures to either 3HTdR or ara-C showed a greater percentage of clonogenic cells in the S phase of the cell cycle in cells with increased S3a than in controls. Cells with increased S3a responded to ATRA by increased ara-C or DNR sensitivity, whereas cells with reduced S3a protein were either protected by ATRA or not affected. We studied cryopreserved blast cells from patients with AML or chronic myelomonocytic leukemia (CMML). S3a protein levels were heterogeneous in these populations. In 32 cryopreserved blast populations, S3a levels were significantly correlated with both bcl-2 and with cell growth in culture. As in cell lines, high S3a in cryopreserved blasts was associated with ATRA-induced sensitization to ara-C. No significant association was seen between S3a levels and response to treatment.

scholarly journals The potential of miR-630, an IGF1R regulator, as a predictive biomarker for HER2-targeted drugs.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 620-620
Author(s):  
Claire Corcoran ◽  
Sweta Rani ◽  
Susan Breslin ◽  
Irene M. Ghobrial ◽  
John Crown ◽  
...  
Keyword(s):  
Cell Lines ◽  
Potential Role ◽  
Acquired Resistance ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Targeted Drugs ◽  
Anoikis Resistance ◽  
Her2 Positive ◽  
Resistant Phenotype ◽  
In Cells

620 Background: Innate or acquired resistance to current HER-targeting drugs indicates that their use for HER2-overexpressing breast cancer (BC) treatment may be compromised. miRNAs may have potential as diagnostic, prognostic and predictive biomarkers for treatment response, as well as therapeutic targets and replacement therapies. We aimed to investigate miR-630 as a predictive biomarker for response to a range of HER-drugs and as a potential target for increasing sensitivity to the same. Methods: Following global miRNA profiling using taqman low density arrays, the reduced expression of miR-630 in cells and corresponding conditioned medium (CM) of HER2-positive BC cell lines with acquired/innate lapatinib (L) resistance (SKBR3-LR, HCC1954-LR, MDA-MB-453) was confirmed by qPCR. miR-630 mimics and inhibitors were used to assess cell response to current (L, trastuzumab (T)) and emerging (neratinib (N), afatinib (A)) HER-targeting drugs. Targetscan prediction software and immunoblotting were used to determine miR-630 regulated proteins. Results: miR-630 levels were significantly decreased in cells and CM with acquired lapatinib resistance compared to their age-matched controls. Decreased miR-630 was also observed for innately resistant MDA-MB-453 compared to innately sensitive SKBR3.Administration of miR-630 mimic significantly sensitised resistant cells to all 4 drugs tested. Specifically, miR-630 mimic increased the anti-proliferative effects of L by 31% (SKBR3-LR), 9% (HCC1954-LR) and 9% (MDA-MB-453). Similarly, miR-630 mimic improved the efficacy of T (11-35%), N (4-17%) and A (9-25%); (range for different cell lines). Inhibition of miR-630 in sensitive parent cells induced an insensitive/resistant phenotype, significantly reducing the efficacy of all 4 drugs tested. Interestingly, miR-630 also significantly regulates cell motility, invasion and anoikis resistance implicating this miRNA in overall cell aggressiveness. Conclusions: This data suggests a potential role for miR-630 as a predictive biomarker for HER-targeting drugs as well as an additional therapeutic target for HER2-overexpressing BC. Acknowledgements: MTCI SFI SRC (08/SRC/B1410), MKF and HEA’s PRTLI Cycle 5 to TBSI.

scholarly journals BMI1-Inhibitor PTC596 in Combination with MCL1 Inhibitor S63845 or MEK Inhibitor Trametinib in the Treatment of Acute Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 581
Author(s):  
Katja Seipel ◽  
Basil Kopp ◽  
Ulrike Bacher ◽  
Thomas Pabst
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Unmet Need ◽  
Mek Inhibitor ◽  
Leukemic Cells ◽  
Wild Type ◽  
Protein Levels ◽  
Combination Treatments ◽  
Mutational Status ◽  
Combined Use

Purpose: Prognosis for acute myeloid leukemia (AML) patients is poor, particularly in TP53 mutated AML, secondary, relapsed, and refractory AML, and in patients unfit for intensive treatment, thus highlighting an unmet need for novel therapeutic approaches. The combined use of compounds targeting the stem cell oncoprotein BMI1 and activating the tumor suppressor protein p53 may represent a promising novel treatment option for poor risk AML patients. Experimental Design: The BMI1 inhibitor PTC596, MCL1 inhibitor S63845, and MEK inhibitor trametinib, as well as the p53 activator APR-246 were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells. AML cells represented all major morphologic and molecular subtypes including FLT3-ITD and FLT3 wild type, NPM1 mutant and wild type, as well as TP53 mutant and wild type AML cell lines and a variety of patient derived AML cells. Results: AML cell lines were variably susceptible to PTC596 and to combination treatments with PTC596 and MCL1 inhibitor S63845, MEK inhibitor trametinib, or TP53 activator APR-246, independent of TP53 mutational status. Susceptibility of patient samples for PTC596 in combination with S63845 or trametinib was significant for the majority of adverse risk primary and secondary AML with minimal efficacy in favorable risk AML, and correlated significantly with CD34 positivity of the samples. BMI1 and MN1 gene expression, and MCL1 and MEK1 protein levels were identified as biomarkers for response to PTC596 combination treatments. Conclusions: The combination of PTC596 and S63845 may be an effective treatment in CD34+ adverse risk AML with elevated MN1 gene expression and MCL1 protein levels, while PTC596 and trametinib may be more effective in CD34+ adverse risk AML with elevated BMI1 gene expression and MEK protein levels.

scholarly journals Expression Atlas of FGF and FGFR Genes in Pancancer Uncovered Predictive Biomarkers for Clinical Trials of Selective FGFR Inhibitors

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Yuan Li ◽  
Long Wu ◽  
Weiping Tao ◽  
Dawei Wu ◽  
Fei Ma ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trials ◽  
Tumor Cell ◽  
Cell Lines ◽  
Expression Profiles ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Tumor Cell Lines ◽  
Expression Atlas ◽  
Tumor Types

Background. Clinical trials based on FGFR mutation or amplification as a druggable target of FGFR inhibitors have produced disappointing clinical outcomes. Therefore, the identification of predictive biomarkers for FGFR-targeted agents has remained a crucial issue. Methods. Expression profiles of FGFs and FGFRs in 8,111 patients with 24 types of solid tumors and 879 tumor cell lines along with drug sensitivity data were obtained and followed by integrative bioinformatics analysis. Results. FGFs and FGFRs were frequently dysregulated in pancancer. Most of the expression of FGFs and FGFRs were significantly associated with overall survival in at least two cancer types. Moreover, tumor cell lines with high FGFR1/3 expression were more sensitive to FGFR inhibitor PD173074, especially in breast, liver, lung and ovarian cancer. The predicted positive ratios of FGFR1-4 were generally over 10% in most tumor types, especially in squamous cell carcinoma. High positive FGFR1 or 3 expression ratios were predicted in cholangiocarcinoma (58%), followed by bladder cancer (42%), endometrial carcinoma (35%), and ovarian cancer (34%). Conclusions. FGFR expression was a promising predictive biomarker for FGFR inhibition response in clinical trials, and different combinations of FGFR genes should be used in screening for patients in certain tumor types.

scholarly journals CTNI-17. CLINICAL EFFICACY AND PREDICTIVE BIOMARKERS OF ONC201 IN H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii45-ii46
Author(s):  
Abed Rahman Kawakibi ◽  
Rohinton S Tarapore ◽  
Sharon Gardner ◽  
Chase Thomas ◽  
Rodrigo Cartaxo ◽  
...  
Keyword(s):  
Cell Lines ◽  
Human Cancer ◽  
Resistance Mechanism ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Clinical Analysis ◽  
Mechanism Analysis ◽  
Human Cancer Cell Lines ◽  
Best Response ◽  
Diffuse Midline Glioma

Abstract Patients with diffuse midline glioma (DMG) harboring H3 K27M mutation rarely survive longer than two years and have no proven therapies following first-line radiation. ONC201, a bitopic DRD2 antagonist and allosteric ClpP agonist, has shown encouraging efficacy in early phase studies in H3 K27M-mutant DMG. In order to define response rates in H3 K27M DMG patients and to clarify the genomic, anatomic and molecular predictors of response, we performed an integrated pre-clinical and clinical analysis of ONC201 treatment. ONC201 was effective in intra-uterine electroporation (IUE)-generated H3 K27M-mutant murine glioma models with excellent CNS penetration and survival benefit. Patients with H3 K27M-mutant DMG treated with ONC201 on active clinical trials (n=50, 27 thalamic, 23 brainstem) showed an overall survival (OS) of 28.1 (range: 5.9–105) months from diagnosis (enrollment by 4/29/19, data cut-off 12/28/19), compared to historical median OS of 12 months. Median OS for non-recurrent patients has not been reached (n=16, median follow-up: 16.8 from diagnosis). For non-recurrent thalamic patients (n=8), median PFS is 20.1 (range: 9.3–27.6) months from diagnosis (median time on drug: 14.5 months). Best response for thalamic patients by RANO: 1 CR, 5 PR, 7 SD, 8 PD, 6 not reported. Decreased H3 K27M cell-free tumor DNA in plasma and CSF at 6 months correlated with long-term response. Baseline tumor gene expression profiling in patients treated with ONC201 (n=14) identified EGFR and the cortical developmental transcription factor FOXG1 as the strongest biomarkers of radiographic response to ONC201. Analysis of 541 ONC201-treated human cancer cell lines from DepMap, provided evidence for an EGFR-dependent ONC201 resistance mechanism. Analysis of 38 glioma cell lines further supports FOXG1 as a glioma-specific predictive biomarker of ONC201 response. The unprecedented survival results and radiographic responses to ONC201 in H3K27M DMG make a compelling case for later phase and combinatorial studies.

scholarly journals Radiotherapy and the gut microbiome: facts and fiction

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Jing Liu ◽  
Chao Liu ◽  
Jinbo Yue
Keyword(s):  
Gut Microbiome ◽  
Response To Treatment ◽  
Cancer Therapies ◽  
Functional Changes ◽  
Positive Effects ◽  
Combination Treatments ◽  
Important Player ◽  
Radiation Induced ◽  
Gastrointestinal Mucositis

AbstractAn ever-growing body of evidence has linked the gut microbiome with both the effectiveness and the toxicity of cancer therapies. Radiotherapy is an effective way to treat tumors, although large variations exist among patients in tumor radio-responsiveness and in the incidence and severity of radiotherapy-induced side effects. Relatively little is known about whether and how the microbiome regulates the response to radiotherapy. Gut microbiota may be an important player in modulating “hot” versus “cold” tumor microenvironment, ultimately affecting treatment efficacy. The interaction of the gut microbiome and radiotherapy is a bidirectional function, in that radiotherapy can disrupt the microbiome and those disruptions can influence the effectiveness of the anticancer treatments. Limited data have shown that interactions between the radiation and the microbiome can have positive effects on oncotherapy. On the other hand, exposure to ionizing radiation leads to changes in the gut microbiome that contribute to radiation enteropathy. The gut microbiome can influence radiation-induced gastrointestinal mucositis through two mechanisms including translocation and dysbiosis. We propose that the gut microbiome can be modified to maximize the response to treatment and minimize adverse effects through the use of personalized probiotics, prebiotics, or fecal microbial transplantation. 16S rRNA sequencing is the most commonly used approach to investigate distribution and diversity of gut microbiome between individuals though it only identifies bacteria level other than strain level. The functional gut microbiome can be studied using methods involving metagenomics, metatranscriptomics, metaproteomics, as well as metabolomics. Multiple ‘-omic’ approaches can be applied simultaneously to the same sample to obtain integrated results. That said, challenges and remaining unknowns in the future that persist at this time include the mechanisms by which the gut microbiome affects radiosensitivity, interactions between the gut microbiome and combination treatments, the role of the gut microbiome with regard to predictive and prognostic biomarkers, the need for multi “-omic” approach for in-depth exploration of functional changes and their effects on host-microbiome interactions, and interactions between gut microbiome, microbial metabolites and immune microenvironment.

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