Poly(ADP-Ribose)Polymerase (PARP) Inhibitors and Radiation Therapy

Jannetti, Stephen A.; Zeglis, Brian M.; Zalutsky, Michael R.; Reiner, Thomas

doi:10.3389/fphar.2020.00170

Cited by 65 publications

(46 citation statements)

References 138 publications

(187 reference statements)

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“…This suggests that patients usually treated with this chemoradiotherapy could benefit from the addition of NBTXR3 in their treatment. These results also open up interesting new perspectives concerning the combination of NBTXR3 with other chemoradiotherapies, such as, g, poly(ADP-ribose)polymerase inhibitors (PARPi) 25 or tyrosine kinase inhibitors (TKI). 26 NBTXR3 activated by RT may also be valuable in combinations with other therapies, such as immune checkpoint inhibitors like anti-PD-1.…”

Section: Discussionmentioning

confidence: 92%

NBTXR3 Radiotherapy-Activated Functionalized Hafnium Oxide Nanoparticles Show Efficient Antitumor Effects Across a Large Panel of Human Cancer Models

Zhang

Marill

Darmon

et al. 2021

IJN

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Purpose The side effects of radiotherapy induced on healthy tissue limit its use. To overcome this issue and fully exploit the potential of radiotherapy to treat cancers, the first-in-class radioenhancer NBTXR3 (functionalized hafnium oxide nanoparticles) has been designed to amplify the effects of radiotherapy. Patients and Methods Thanks to its physical mode of action, NBTXR3 has the potential to be used to treat any type of solid tumor. Here we demonstrate that NBTXR3 can be used to treat a wide variety of solid cancers. For this, we evaluated different parameters on a large panel of human cancer models, such as nanoparticle endocytosis, in vitro cell death induction, dispersion, and retention of NBTXR3 in the tumor tissue and tumor growth control. Results Whatever the model considered, we show that NBTXR3 was internalized by cancer cells and persisted within the tumors throughout radiotherapy treatment. NBTXR3 activated by radiotherapy was also more effective in destroying cancer cells and in controlling tumor growth than radiotherapy alone. Beyond the effects of NBTXR3 as single agent, we show that the antitumor efficacy of cisplatin-based chemoradiotherapy treatment was improved when combined with NBTXR3. Conclusion These data support that NBTXR3 could be universally used to treat solid cancers when radiotherapy is indicated, opening promising new therapeutic perspectives of treatment for the benefit of many patients.

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Section: Discussionmentioning

confidence: 92%

NBTXR3 Radiotherapy-Activated Functionalized Hafnium Oxide Nanoparticles Show Efficient Antitumor Effects Across a Large Panel of Human Cancer Models

Zhang

Marill

Darmon

et al. 2021

IJN

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“…Several clinical trials are ongoing to approve these drugs for several cancer types such as colorectal, melanoma, and prostate cancers (NCT00535353, NCT00804908, NCT03732820) and to assess efficacy of new inhibitors in combination with DNA damaging agents (NCT01127178, NCT01311713). Combinatorial treatments with these drugs and classic treatments have been explored with almost any chemotherapeutic agents and with radiotherapy [192], recently prompting the development of inhibitors labeled with therapeutic isotopes, that have proven to be particularly effective in brain tumor models [193,194]. Moreover, discovering that PARP inhibitors present antiangiogenic activity promoted development of targeted therapies combining PARP inhibition with anti-angiogenic agents to improve treatment of ovarian cancer [195,196].…”

Section: Parp1 Inhibition Gave the Most Important Results In The Syntmentioning

confidence: 99%

Inhibition of DNA Repair in Cancer Therapy: Toward a Multi-Target Approach

Lodovichi

Cervelli

Pellicioli

et al. 2020

IJMS

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Alterations in DNA repair pathways are one of the main drivers of cancer insurgence. Nevertheless, cancer cells are more susceptible to DNA damage than normal cells and they rely on specific functional repair pathways to survive. Thanks to advances in genome sequencing, we now have a better idea of which genes are mutated in specific cancers and this prompted the development of inhibitors targeting DNA repair players involved in pathways essential for cancer cells survival. Currently, the pivotal concept is that combining the inhibition of mechanisms on which cancer cells viability depends is the most promising way to treat tumorigenesis. Numerous inhibitors have been developed and for many of them, efficacy has been demonstrated either alone or in combination with chemo or radiotherapy. In this review, we will analyze the principal pathways involved in cell cycle checkpoint and DNA repair focusing on how their alterations could predispose to cancer, then we will explore the inhibitors developed or in development specifically targeting different proteins involved in each pathway, underscoring the rationale behind their usage and how their combination and/or exploitation as adjuvants to classic therapies could help in patients clinical outcome.

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“…Therefore, recent years have seen a surge of interest in the combination of PARPi with other therapies which may revert resistant phenotypes, expanding the indication of these drugs beyond HRR deficient tumors [ 96 , 97 ]. Currently, a number of ongoing clinical trials are assessing, amongst other schemes, the effects of the combination of olaparib and IR on a wide range of tumors, from breast and ovarian to glioblastoma and lung cancers [ 98 , 99 , 100 , 101 , 102 ]. This combination would entail a lower systemic toxicity than combining, for example, PARPi with chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Zebrafish Xenografts Unveil Sensitivity to Olaparib beyond BRCA Status

Varanda

Martins-Logrado

Ferreira

et al. 2020

Cancers

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Poly (ADP-ribose) polymerase (PARP) inhibition in BRCA-mutated cells results in an incapacity to repair DNA damage, leading to cell death caused by synthetic lethality. Within the treatment options for advanced triple negative breast cancer, the PARP inhibitor olaparib is only given to patients with BRCA1/2 mutations. However, these patients may show resistance to this drug and BRCA1/2 wild-type tumors can show a striking sensitivity, making BRCA status a poor biomarker for treatment choice. Aiming to investigate if the zebrafish model can discriminate sensitivities to olaparib, we developed zebrafish xenografts with different BRCA status and measured tumor response to treatment, as well as its impact on angiogenesis and metastasis. When challenged with olaparib, xenografts revealed sensitivity phenotypes independent of BRCA. Moreover, its combination with ionizing radiation increased the cytotoxic effects, showing potential as a combinatorial regimen. In conclusion, we show that the zebrafish xenograft model may be used as a sensitivity profiling platform for olaparib in monotherapy or in combinatorial regimens. Hence, this model presents as a promising option for the future establishment of patient-derived xenografts for personalized medicine approaches beyond BRCA status.

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Poly(ADP-Ribose)Polymerase (PARP) Inhibitors and Radiation Therapy

Cited by 65 publications

References 138 publications

NBTXR3 Radiotherapy-Activated Functionalized Hafnium Oxide Nanoparticles Show Efficient Antitumor Effects Across a Large Panel of Human Cancer Models

NBTXR3 Radiotherapy-Activated Functionalized Hafnium Oxide Nanoparticles Show Efficient Antitumor Effects Across a Large Panel of Human Cancer Models

Inhibition of DNA Repair in Cancer Therapy: Toward a Multi-Target Approach

Zebrafish Xenografts Unveil Sensitivity to Olaparib beyond BRCA Status

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