Novel DNA targeted therapies for head and neck cancers: clinical potential and biomarkers

Glorieux, Mary; Dok, Rüveyda; Nuyts, Sandra

doi:10.18632/oncotarget.20953

Cited by 52 publications

(66 citation statements)

References 99 publications

(257 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings lead us to speculate that prolonged cell cycle arrest after DNA damage may be protective for HNSCC cells in the context of PRT because of increased sublethal DNA damage repair. Because numerous CDK inhibitors and CHK1/2 inhibitors are being developed and tested in clinical trials, our findings may suggest ways of optimizing combinations of these inhibitors with PRT or XRT to improve treatment response in HNSCC.…”

Section: Discussionmentioning

confidence: 94%

“…Our findings agree with those of others that both pathways are active after PRT. Notably, DNA‐PKcs, inhibitors of which are being investigated in clinical trials, were expressed in greater amounts after PRT vs XRT, suggesting that a choice of PRT or XRT to be used in combination with these inhibitors may improve control of HNSCC, especially HPV+ HNSCC. Moreover, thymidylate synthase, which is critical for DDR and is targeted by cancer chemotherapeutic agents such as fluorouracil, was expressed at higher levels after PRT vs XRT; this may imply that the radiosensitization effects of fluorouracil may be stronger for PRT than for XRT.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Patterns of protein expression in human head and neck cancer cell lines differ after proton vs photon radiotherapy

et al. 2019

View full text Add to dashboard Cite

Background: Proton radiotherapy (PRT) may be a less toxic alternative to photon radiotherapy (XRT) for patients with head and neck squamous cell carcinoma (HNSCC). However, the molecular responses of HNSCC cells to PRT vs XRT are unclear. Methods: Proteomics analyses of protein expression profiles by reverse-phase protein arrays were done for two human papillomavirus [HPV]-negative and two HPV+ cell lines. Expression patterns of 175 proteins involved in several signaling pathways were tested.Results: Compared with PRT, XRT tended to induce lower expression of DNA damage repair-and cell cycle arrest-related proteins and higher expression of cell survival-and proliferation-related proteins. Conclusions: Under these experimental conditions, PRT and XRT induced different protein expression and activation profiles. Further preclinical verification is needed, as are studies of tumor pathway mutations as biomarkers for choice of treatment or as radiosensitization targets to improve the response of HNSCC to PRT or XRT. K E Y W O R D Shead & neck cancer, photon radiotherapy, proton radiotherapy, radiation-induced molecular changes, reverse-phase protein array (RPPA)Portions of this work were presented in poster form at the annual Global Academic Programs

show abstract

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Patterns of protein expression in human head and neck cancer cell lines differ after proton vs photon radiotherapy

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Clinical data from SCC patients treated with these drugs could also reveal if SMAD4 status predicts their therapeutic responses. Furthermore, WEE1‐ and CHK1/2 inhibitors also block DNA repair increasing radiosensitivity in head and neck cancer (HNC) models, and may be effective against SMAD4 deficient SCCs.…”

Section: Potential Therapeutic Approaches Against Smad4 Deficient Sccsmentioning

confidence: 99%

Lessons learned from SMAD4 loss in squamous cell carcinomas

Young

Wang

2019

Molecular Carcinogenesis

View full text Add to dashboard Cite

SMAD4 is a potent tumor suppressor and the primary mediator of the TGFß signaling pathway. SMAD4 genetic loss is frequent in squamous cell carcinomas (SCCs). Reports of SMAD4 expression in SCCs vary significantly possibly due to inter-tumor heterogeneity or technical reasons. SMAD4 loss is an initiation event for SCCs. In tumor epithelial cells, SMAD4 mutant SCCs commonly present with increased proliferation, decreased apoptosis, and “Brca-like” genomic instability associated with DNA repair defects. SMAD4 loss also plays a role in expansion of cancer stem cells (CSC). Epithelial SMAD4 loss causes overexpression of TGFß which is released into the tumor microenvironment and contributes to SCC progression through pro-inflammatory and immune evasive mechanisms. SMAD4 loss, while not directly targetable, is associated with multiple targetable pathways that require further studies. Altogether, SMAD4 loss is a potential biomarker in SCCs that should be further studied to gain insight for prognosis and therapeutic approaches to potentially guide future clinical trials and improve SCC patient outcomes.

show abstract

“…One such strategy, now in clinical trials, involves using targeted therapies, including those that affect DNA repair, to enhance the effects of radiotherapy. 8,9 Radiation causes both single-strand breaks (SSBs) and double-strand breaks (DSBs) in DNA. SSBs are more common and can often be repaired; DSBs, in contrast, are a major cause of radiation-induced cell death.…”

Section: Introductionmentioning

confidence: 99%

“…10 Therefore, effective DNA damage repair (DDR) is critical to ensure cell survival after radiation, and drugs or small molecules that target DDR pathways, such as poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors, are being tested in combination with radiation in clinical trials. 9,11 The major functions of PARP include detecting DNA SSBs and DSBs, recruiting DDR-related factors to the lesions, and stabilizing replication forks during DDR. [12][13][14][15] Therefore, PARP inhibitors may enhance antitumor response after radiation by blocking the DDR of radiation-induced SSBs and DSBs.…”

Section: Introductionmentioning

confidence: 99%

Proton and photon radiosensitization effects of niraparib, a PARP‐1/‐2 inhibitor, on human head and neck cancer cells

et al. 2020

View full text Add to dashboard Cite

Background Combining photon or proton radiotherapy with targeted therapy shows promise for head and neck cancer (HNSCC). The poly (adenosine diphosphate [ADP]‐ribose) polymerase‐1/2 inhibitor niraparib targets DNA damage repair (DDR). We evaluated the effects of niraparib in combination with photons or protons, and its effects on the relative biological effectiveness (RBE) of protons, in human HNSCC cell lines. Methods Radiosensitivity was assessed and RBE was calculated with clonogenic survival assays; unrepaired DNA double‐strand breaks were evaluated using immunocytochemical analysis of 53BP1 foci. Results Niraparib reduced colony formation in two of the four cell lines tested (P < .05), enhanced radiosensitivity in all four cell lines, delayed DDR (P < .05), and increased proton vs photon RBE. Conclusion Niraparib enhanced the sensitivity of four HNSCC cell lines to both photons and protons and increased the RBE of protons, possibly by inhibiting DDR. Niraparib may enhance the effectiveness of both photon and proton radiotherapy for patients with HNSCC.

show abstract

Novel DNA targeted therapies for head and neck cancers: clinical potential and biomarkers

Abstract: ABSTRACT

Cited by 52 publications

References 99 publications

Patterns of protein expression in human head and neck cancer cell lines differ after proton vs photon radiotherapy

Patterns of protein expression in human head and neck cancer cell lines differ after proton vs photon radiotherapy

Lessons learned from SMAD4 loss in squamous cell carcinomas

Proton and photon radiosensitization effects of niraparib, a PARP‐1/‐2 inhibitor, on human head and neck cancer cells

Contact Info

Product

Resources

About