Modeling cellular response in large-scale radiogenomic databases to advance precision radiotherapy

Manem, Venkata SK.; Lambie, Meghan; Смирнов, Петр; Kofia, Victor; Freeman, Mark; Koritzinsky, Marianne; Abazeed, Mohamed E.; Haibe‐Kains, Benjamin; Bratman, Scott V.

doi:10.1101/449793

Cited by 6 publications

(6 citation statements)

References 46 publications

(59 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Breast cancer. The AR has been shown to be a potential mediator of radioresistance and a target for the radiosensitization of AR+ TNBC [100][101][102]200 . Inhibition of AR with enzalutamide results in increased radiosensitization of AR+ breast cancer cells through the inhibition of AR-activated DNA-PKcs-mediated repair 100 .…”

Section: Combination Therapies Ar + Radiation Therapymentioning

confidence: 99%

ARe we there yet? Understanding androgen receptor signaling in breast cancer

et al. 2020

View full text Add to dashboard Cite

The role of androgen receptor (AR) activation and expression is well understood in prostate cancer. In breast cancer, expression and activation of AR is increasingly recognized for its role in cancer development and its importance in promoting cell growth in the presence or absence of estrogen. As both prostate and breast cancers often share a reliance on nuclear hormone signaling, there is increasing appreciation of the overlap between activated cellular pathways in these cancers in response to androgen signaling. Targeting of the androgen receptor as a monotherapy or in combination with other conventional therapies has proven to be an effective clinical strategy for the treatment of patients with prostate cancer, and these therapeutic strategies are increasingly being investigated in breast cancer. This overlap suggests that targeting androgens and AR signaling in other cancer types may also be effective. This manuscript will review the role of AR in various cellular processes that promote tumorigenesis and metastasis, first in prostate cancer and then in breast cancer, as well as discuss ongoing efforts to target AR for the more effective treatment and prevention of cancer, especially breast cancer.

show abstract

Section: Combination Therapies Ar + Radiation Therapymentioning

confidence: 99%

ARe we there yet? Understanding androgen receptor signaling in breast cancer

et al. 2020

View full text Add to dashboard Cite

show abstract

“…We hope and envision that this package will help users to compare their own signature to those in the RadiationGeneSigDB database, and help build better biomarkers by using multiple datasets in the discovery, or pre-clinical phase. Furthermore, RadiationGeneSigDB coupled with RadioGx, a novel computational platform of radiogenomics datasets (Manem et al , 2018) , will enable us to build reliable and clinically-verifiable genomic predictors of radiation response.…”

Section: Resultsmentioning

confidence: 99%

RadiationGeneSigDB: A database of oxic and hypoxic radiation response gene signatures and their utility in identification of hypoxia-regulated MicroRNA

Manem

Dhawan

2018

Preprint

View full text Add to dashboard Cite

Radiation therapy is among the most effective and widely used modalities of cancer therapy in current clinical practice. With the advent of new high throughput genomic technologies and the continuous inflow of transcriptomic data, there has been a paradigm shift in the landscape of radiation oncology. In this era of personalized radiation medicine, genomic datasets hold great promise to investigate novel biomarkers predictive of radiation response. In this regard, the number of available gene expression based signatures built under oxic and hypoxic conditions is getting larger. This poses two main questions in the field, namely, i) how reliable are these signatures when applied across a compendium of datasets in different model systems; and ii) is there redundancy of gene signatures. To address these fundamental radiobiologic questions, we curated a database of gene expression signatures predictive of radiation response under oxic and hypoxic conditions. RadiationGeneSigDB has a collection of 11 oxic and 24 hypoxic signatures with the standardized gene list as a gene symbol, Entrez gene ID, and its function. We present the utility of this database through three case studies: i) comparing breast cancer oxic signatures in cell line data vs. patient data; ii) comparing the similarity of head and neck cancer hypoxia signatures in clinical tumor data; and iii) gaining an understanding of hypoxia-associated miRNA. This valuable, curated repertoire of published gene expression signatures provides a motivating example for how to search for similarities in radiation response for tumors arising from different tissues across model systems under oxic and hypoxic conditions, and how a well-curated set of gene signatures can be used to generate novel hypotheses about the functions of non-coding RNA. Availability and implementation:RadiationGeneSigDB is implemented in R. The source code of this package and signatures can be downloaded from the GitHub: https://github.com/vmsatya/RadiationGeneSigDB

show abstract

“…Intratumoral genomic heterogeneity in GBM has limited the efficacy of personalized targeted therapies. To overcome this barrier, we sought to discover 16 metabolic pathways that caused RT-resistance in GBM independently of genotype. By analyzing how intracellular metabolite levels correlated with GBM RT resistance, we found that low levels of nucleobase-containing metabolites were strongly associated with sensitivity to RT.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, efforts to overcome primary RT-resistance are likely to improve outcomes in patients with GBM. Efforts to develop new strategies to overcome RT-resistance have previously used large-scale genomic profiling data to define candidate oncogenic molecular alterations to target in combination with radiation 14,15,16 . Due to the profound genomic heterogeneity of GBM, we instead sought to define therapeutic strategies that could overcome RT-resistance independently of genotype.…”

Section: Introductionmentioning

confidence: 99%

Purine metabolism regulates DNA repair and therapy resistance in glioblastoma

Zhou

Yao

Scott

et al. 2020

Preprint

View full text Add to dashboard Cite

Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance, and new strategies that are effective independent of genotype are urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens of genomically-distinct models of GBM, we found that purine metabolites strongly correlated with radiation resistance. Inhibiting purine, but not pyrimidine, synthesis radiosensitized GBM cells and patient-derived neurospheres by impairing DNA repair in a nucleoside-dependent fashion. Likewise, administration of exogenous purine nucleosides protected sensitive GBM models from radiation by promoting DNA repair. Combining an FDA-approved inhibitor of de novo purine synthesis with radiation arrested growth in GBM xenograft models and depleted intratumoral guanylates. High expression of the rate-limiting enzyme of de novo GTP synthesis was associated with shorter survival in GBM patients. Together, these findings indicate that inhibiting de novo purine synthesis may be a promising strategy to overcome therapy resistance in this genomically heterogeneous disease.

show abstract

Modeling cellular response in large-scale radiogenomic databases to advance precision radiotherapy

Cited by 6 publications

References 46 publications

ARe we there yet? Understanding androgen receptor signaling in breast cancer

ARe we there yet? Understanding androgen receptor signaling in breast cancer

RadiationGeneSigDB: A database of oxic and hypoxic radiation response gene signatures and their utility in identification of hypoxia-regulated MicroRNA

Purine metabolism regulates DNA repair and therapy resistance in glioblastoma

Contact Info

Product

Resources

About