Clinical Use of PARP Inhibitors in Cancer – From Bench to Bedside and Back Again

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 42310

Special Issue Editor

Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
Interests: molecular oncology; cancer pharmacology; acute myeloid leukemia; targeted therapy; PARP1; PARP inhibitors; vitamin C

Special Issue Information

Dear Colleagues,

This Special Issue of Cancers will connect clinicians with laboratory-based researchers to improve knowledge on PARP inhibitors (PARPi) as anticancer agents and stimulate new research fronts.

Poly(ADP-ribose) polymerases (PARPs) are capable of mono- or poly-(ADP-ribosyl)ation (PARylation) of many target molecules and are involved in a large number of physiological processes. Discovered for their role in DNA damage repair, this family of proteins is known to have a broad spectrum of biological actions, as well as binding to undamaged chromatin and regulating gene expression. PARPi, designed to block PARylation, were initially used to enhance the cytotoxic effects of DNA-damaging chemotherapy. Preclinical and clinical studies based on the synthetic lethality principle have highlighted the efficacy of PARPi as monotherapy in mutated BRCAs ovarian cancers. Surprisingly, PARPi has also been shown to benefit patients without BRCA loss of function. This has prompted the investigation of other potential antitumor mechanisms of PARPi and led to significant advances in the comprehension of the multifaceted action of PARP inhibitors. Their use is now expanding to several other cancer types, alone or in combination withinnovative and low-toxicity anticancer drugs, including the immune checkpoint inhibitors.

Recently, structural studies of PARPi highlighted different allosteric mechanisms of inducing PARP1 trapping and stimulated the development of more specific (allosteric) PARPi that could help to address the emerging resistance to PARPi.

Authors are warmly invited to submit letters, review articles, and original research to explore novel PARPi, new therapeutic drug combination strategies, new predictive biomarkers of response, and any other clinical and research questions that may advance the huge potential of PARPi towards a personalized treatment approach.

Dr. Isabella Faraoni
Guest Editor

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Published Papers (12 papers)

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Research

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14 pages, 2467 KiB  
Article
Using Patient-Derived Xenograft (PDX) Models as a ‘Black Box’ to Identify More Applicable Patients for ADP-Ribose Polymerase Inhibitor (PARPi) Treatment in Ovarian Cancer: Searching for Novel Molecular and Clinical Biomarkers and Performing a Prospective Preclinical Trial
by Jiayu Chen, Yan Li, Haiyuan Wang, Ting Li, Yu Gu, Wei Wang, Ying Shan, Jie Yin, Yongxue Wang, Meng Qin, Siyi Li, Lingya Pan, Siying Peng and Ying Jin
Cancers 2022, 14(19), 4649; https://doi.org/10.3390/cancers14194649 - 24 Sep 2022
Cited by 1 | Viewed by 3517
Abstract
(1) The accuracy of patient-derived xenografts (PDXs) in predicting ADP-ribose polymerase inhibitor (PARPi) efficacy in ovarian cancer was tested, novel biomarkers were investigated, and whether PARPis could replace platinum-based chemotherapy as a first-line therapy was explored. (2) PDXs were reconstructed for 40 patients [...] Read more.
(1) The accuracy of patient-derived xenografts (PDXs) in predicting ADP-ribose polymerase inhibitor (PARPi) efficacy in ovarian cancer was tested, novel biomarkers were investigated, and whether PARPis could replace platinum-based chemotherapy as a first-line therapy was explored. (2) PDXs were reconstructed for 40 patients with ovarian cancer, and niraparib, olaparib and paclitaxel, and carboplatin (TC) sensitivity tests were conducted. Whole exon sequencing and homologous recombination deficiency (HRD) scores were performed, and patient clinical information was collected. The molecular biomarkers were identified by reverse-transcription quantitative PCR and immunoblotting. (3) Niraparib and olaparib sensitivity were tested in 26 patients and showed high consistency. Approximately half of BRCA wild-type, HRD-negative, and platinum-resistant patients may benefit from PARPis. AKT1 enrichment indicated PARPi resistance; high KRAS expression indicated PARPi sensitivity. CA125 below 10 U/mL during chemotherapy has a sensitivity and specificity similar to platinum sensitivity in predicting PARPi efficacy. Niraparib and TC sensitivity tests were performed on 23 patients, and TC showed a better response in this preclinical trial. (4) PDX can indicate individualized PARPi efficacy. Decreased CA125 levels and KRAS and ATK1 expression levels may be novel biomarkers. The preclinical evidence does not support the implementation of PARPis as the first-line treatment in an unselected population. Full article
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20 pages, 4260 KiB  
Article
Overcoming Temozolomide Resistance in Glioblastoma via Enhanced NAD+ Bioavailability and Inhibition of Poly-ADP-Ribose Glycohydrolase
by Jianfeng Li, Christopher A. Koczor, Kate M. Saville, Faisal Hayat, Alison Beiser, Steven McClellan, Marie E. Migaud and Robert W. Sobol
Cancers 2022, 14(15), 3572; https://doi.org/10.3390/cancers14153572 - 22 Jul 2022
Cited by 3 | Viewed by 2582
Abstract
Glioblastoma multiforme (GBM) is an incurable brain cancer with an average survival of approximately 15 months. Temozolomide (TMZ) is a DNA alkylating agent for the treatment of GBM. However, at least 50% of the patients treated with TMZ show poor response, primarily due [...] Read more.
Glioblastoma multiforme (GBM) is an incurable brain cancer with an average survival of approximately 15 months. Temozolomide (TMZ) is a DNA alkylating agent for the treatment of GBM. However, at least 50% of the patients treated with TMZ show poor response, primarily due to elevated expression of the repair protein O6-methylguanine-DNA methyltransferase (MGMT) or due to defects in the mismatch repair (MMR) pathway. These resistance mechanisms are either somatic or arise in response to treatment, highlighting the need to uncover treatments to overcome resistance. We found that administration of the NAD+ precursor dihydronicotinamide riboside (NRH) to raise cellular NAD+ levels combined with PARG inhibition (PARGi) triggers hyperaccumulation of poly(ADP-ribose) (PAR), resulting from both DNA damage-induced and replication-stress-induced PARP1 activation. Here, we show that the NRH/PARGi combination enhances the cytotoxicity of TMZ. Specifically, NRH rapidly increases NAD+ levels in both TMZ-sensitive and TMZ-resistant GBM-derived cells and enhances the accumulation of PAR following TMZ treatment. Furthermore, NRH promotes hyperaccumulation of PAR in the presence of TMZ and PARGi. This combination strongly suppresses the cell growth of GBM cells depleted of MSH6 or cells expressing MGMT, suggesting that this regimen may improve the efficacy of TMZ to overcome treatment resistance in GBM. Full article
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19 pages, 2743 KiB  
Article
Poly(ADP)-Ribosylation Inhibition: A Promising Approach for Clear Cell Renal Cell Carcinoma Therapy
by Yaroslava Karpova, Danping Guo, Peter Makhov, Adam M. Haines, Dmitriy A. Markov, Vladimir Kolenko and Alexei V. Tulin
Cancers 2021, 13(19), 4973; https://doi.org/10.3390/cancers13194973 - 03 Oct 2021
Cited by 10 | Viewed by 2637
Abstract
Poly(ADP-ribose) polymerase 1 (PARP-1) and glycohydrolase (PARG) enzymes regulate chromatin structure, transcription activation, and DNA repair by modulating poly(ADP-ribose) (pADPr) level. Interest in PARP-1 inhibitors has soared recently with the recognition of their antitumor efficacy. We have shown that the development of clear [...] Read more.
Poly(ADP-ribose) polymerase 1 (PARP-1) and glycohydrolase (PARG) enzymes regulate chromatin structure, transcription activation, and DNA repair by modulating poly(ADP-ribose) (pADPr) level. Interest in PARP-1 inhibitors has soared recently with the recognition of their antitumor efficacy. We have shown that the development of clear cell renal cell carcinoma (ccRCC) is associated with extreme accumulation of pADPr caused by the enhanced expression of PARP-1 and decreased PARG levels. The most severe misregulation of pADPr turnover is found in ccRCC specimens from metastatic lesions. Both, classical NAD-like and non-NAD-like PARP-1 inhibitors reduced viability and clonogenic potential of ccRCC cell lines and suppressed growth of ccRCC xenograft tumors. However, classical NAD-like PARP-1 inhibitors affected viability of normal kidney epithelial cells at high concentrations, while novel non-NAD-like PARP-1 inhibitors exhibited activity against malignant cells only. We have also utilized different approaches to reduce the pADPr level in ccRCC cells by stably overexpressing PARG and demonstrated the prominent antitumor effect of this “back-to-normal” intervention. We also generated ccRCC cell lines with stable overexpression of PARG under doxycycline induction. This genetic approach demonstrated significantly affected malignancy of ccRCC cells. Transcriptome analysis linked observed phenotype with changes in gene expression levels for lipid metabolism, interferon signaling, and angiogenesis pathways along with the changes in expression of key cancer-related genes. Full article
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Review

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24 pages, 1360 KiB  
Review
Radiotherapy, PARP Inhibition, and Immune-Checkpoint Blockade: A Triad to Overcome the Double-Edged Effects of Each Single Player
by Maria Manuela Rosado and Claudio Pioli
Cancers 2023, 15(4), 1093; https://doi.org/10.3390/cancers15041093 - 08 Feb 2023
Cited by 3 | Viewed by 1656
Abstract
Radiotherapy and, more recently, PARP inhibitors (PARPis) and immune-checkpoint inhibitors represent effective tools in cancer therapy. Radiotherapy exerts its effects not only by damaging DNA and inducing tumor cell death, but also stimulating anti-tumor immune responses. PARPis are known to exert their therapeutic [...] Read more.
Radiotherapy and, more recently, PARP inhibitors (PARPis) and immune-checkpoint inhibitors represent effective tools in cancer therapy. Radiotherapy exerts its effects not only by damaging DNA and inducing tumor cell death, but also stimulating anti-tumor immune responses. PARPis are known to exert their therapeutic effects by inhibiting DNA repair, and they may be used in combination with radiotherapy. Both radiotherapy and PARPis modulate inflammatory signals and stimulate type I IFN (IFN-I)-dependent immune activation. However, they can also support the development of an immunosuppressive tumor environment and upregulate PD-L1 expression on tumor cells. When provided as monotherapy, immune-checkpoint inhibitors (mainly antibodies to CTLA-4 and the PD-1/PD-L1 axis) result particularly effective only in immunogenic tumors. Combinations of immunotherapy with therapies that favor priming of the immune response to tumor-associated antigens are, therefore, suitable strategies. The widely explored association of radiotherapy and immunotherapy has confirmed this benefit for several cancers. Association with PARPis has also been investigated in clinical trials. Immunotherapy counteracts the immunosuppressive effects of radiotherapy and/or PARPis and synergies with their immunological effects, promoting and unleashing immune responses toward primary and metastatic lesions (abscopal effect). Here, we discuss the beneficial and counterproductive effects of each therapy and how they can synergize to overcome single-therapy limitations. Full article
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16 pages, 1186 KiB  
Review
Epigenetic Insights on PARP-1 Activity in Cancer Therapy
by Giulia Pinton, Sara Boumya, Maria Rosa Ciriolo and Fabio Ciccarone
Cancers 2023, 15(1), 6; https://doi.org/10.3390/cancers15010006 - 20 Dec 2022
Cited by 1 | Viewed by 1770
Abstract
The regulation of chromatin state and histone protein eviction have been proven essential during transcription and DNA repair. Poly(ADP-ribose) (PAR) polymerase 1 (PARP-1) and poly(ADP-ribosyl)ation (PARylation) are crucial mediators of these processes by affecting DNA/histone epigenetic events. DNA methylation/hydroxymethylation patterns and histone modifications [...] Read more.
The regulation of chromatin state and histone protein eviction have been proven essential during transcription and DNA repair. Poly(ADP-ribose) (PAR) polymerase 1 (PARP-1) and poly(ADP-ribosyl)ation (PARylation) are crucial mediators of these processes by affecting DNA/histone epigenetic events. DNA methylation/hydroxymethylation patterns and histone modifications are established by mutual coordination between all epigenetic modifiers. This review will focus on histones and DNA/histone epigenetic machinery that are direct targets of PARP-1 activity by covalent and non-covalent PARylation. The effects of these modifications on the activity/recruitment of epigenetic enzymes at DNA damage sites or gene regulatory regions will be outlined. Furthermore, based on the achievements made to the present, we will discuss the potential application of epigenetic-based therapy as a novel strategy for boosting the success of PARP inhibitors, improving cell sensitivity or overcoming drug resistance. Full article
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25 pages, 584 KiB  
Review
Clinical Application of Poly(ADP-ribose) Polymerase (PARP) Inhibitors in Prostate Cancer
by Andrisha-Jade Inderjeeth, Monique Topp, Elaine Sanij, Elena Castro and Shahneen Sandhu
Cancers 2022, 14(23), 5922; https://doi.org/10.3390/cancers14235922 - 30 Nov 2022
Cited by 3 | Viewed by 2103
Abstract
Approximately a quarter of men with metastatic castrate resistant prostate cancer (mCRPC) have alterations in homologous recombination repair (HRR). These patients exhibit enhanced sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Leveraging the synthetic lethality between PARP inhibition and HRR deficiency, studies have established marked [...] Read more.
Approximately a quarter of men with metastatic castrate resistant prostate cancer (mCRPC) have alterations in homologous recombination repair (HRR). These patients exhibit enhanced sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Leveraging the synthetic lethality between PARP inhibition and HRR deficiency, studies have established marked clinical benefit and a survival advantage from PARP inhibitors (PARPi) in mCRPC, most notably in cancers with BRCA1/2 alterations. The role of PARPi is evolving beyond patients with HRR alterations, with studies increasingly focused on exploiting synergistic effects from combination therapeutics. Strategies combining PARP inhibitors with androgen receptor pathway inhibitors, radiation, radioligand therapy, chemotherapy and immunotherapy demonstrate potential additional benefits in mCRPC and these approaches are rapidly moving into the metastatic hormone sensitive treatment paradigm. In this review we summarise the development and expanding role of PARPi in prostate cancer including biomarkers of response, the relationship between the androgen receptor and PARP, evidence for combination therapeutics and the future directions of PARPi in precision medicine for prostate cancer. Full article
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38 pages, 1609 KiB  
Review
Role of PARP Inhibitors in Cancer Immunotherapy: Potential Friends to Immune Activating Molecules and Foes to Immune Checkpoints
by Ornella Franzese and Grazia Graziani
Cancers 2022, 14(22), 5633; https://doi.org/10.3390/cancers14225633 - 16 Nov 2022
Cited by 7 | Viewed by 3426
Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) induce cytotoxic effects as single agents in tumors characterized by defective repair of DNA double-strand breaks deriving from BRCA1/2 mutations or other abnormalities in genes associated with homologous recombination. Preclinical studies have shown that PARPi-induced DNA damage [...] Read more.
Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) induce cytotoxic effects as single agents in tumors characterized by defective repair of DNA double-strand breaks deriving from BRCA1/2 mutations or other abnormalities in genes associated with homologous recombination. Preclinical studies have shown that PARPi-induced DNA damage may affect the tumor immune microenvironment and immune-mediated anti-tumor response through several mechanisms. In particular, increased DNA damage has been shown to induce the activation of type I interferon pathway and up-regulation of PD-L1 expression in cancer cells, which can both enhance sensitivity to Immune Checkpoint Inhibitors (ICIs). Despite the recent approval of ICIs for a number of advanced cancer types based on their ability to reinvigorate T-cell-mediated antitumor immune responses, a consistent percentage of treated patients fail to respond, strongly encouraging the identification of combination therapies to overcome resistance. In the present review, we analyzed both established and unexplored mechanisms that may be elicited by PARPi, supporting immune reactivation and their potential synergism with currently used ICIs. This analysis may indicate novel and possibly patient-specific immune features that might represent new pharmacological targets of PARPi, potentially leading to the identification of predictive biomarkers of response to their combination with ICIs. Full article
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19 pages, 1045 KiB  
Review
BMN673 Is a PARP Inhibitor with Unique Radiosensitizing Properties: Mechanisms and Potential in Radiation Therapy
by Aashish Soni, Xixi Lin, Emil Mladenov, Veronika Mladenova, Martin Stuschke and George Iliakis
Cancers 2022, 14(22), 5619; https://doi.org/10.3390/cancers14225619 - 16 Nov 2022
Cited by 3 | Viewed by 2111
Abstract
BMN673 is a relatively new PARP inhibitor (PARPi) that exhibits superior efficacy in vitro compared to olaparib and other clinically relevant PARPi. BMN673, similar to most clinical PARPi, inhibits the catalytic activities of PARP-1 and PARP-2 and shows impressive anticancer potential as monotherapy [...] Read more.
BMN673 is a relatively new PARP inhibitor (PARPi) that exhibits superior efficacy in vitro compared to olaparib and other clinically relevant PARPi. BMN673, similar to most clinical PARPi, inhibits the catalytic activities of PARP-1 and PARP-2 and shows impressive anticancer potential as monotherapy in several pre-clinical and clinical studies. Tumor resistance to PARPi poses a significant challenge in the clinic. Thus, combining PARPi with other treatment modalities, such as radiotherapy (RT), is being actively pursued to overcome such resistance. However, the modest to intermediate radiosensitization exerted by olaparib, rucaparib, and veliparib, limits the rationale and the scope of such combinations. The recently reported strong radiosensitizing potential of BMN673 forecasts a paradigm shift on this front. Evidence accumulates that BMN673 may radiosensitize via unique mechanisms causing profound shifts in the balance among DNA double-strand break (DSB) repair pathways. According to one of the emerging models, BMN673 strongly inhibits classical non-homologous end-joining (c-NHEJ) and increases reciprocally and profoundly DSB end-resection, enhancing error-prone DSB processing that robustly potentiates cell killing. In this review, we outline and summarize the work that helped to formulate this model of BMN673 action on DSB repair, analyze the causes of radiosensitization and discuss its potential as a radiosensitizer in the clinic. Finally, we highlight strategies for combining BMN673 with other inhibitors of DNA damage response for further improvements. Full article
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15 pages, 1098 KiB  
Review
PARP Inhibitors Resistance: Mechanisms and Perspectives
by Elena Giudice, Marica Gentile, Vanda Salutari, Caterina Ricci, Lucia Musacchio, Maria Vittoria Carbone, Viola Ghizzoni, Floriana Camarda, Francesca Tronconi, Camilla Nero, Francesca Ciccarone, Giovanni Scambia and Domenica Lorusso
Cancers 2022, 14(6), 1420; https://doi.org/10.3390/cancers14061420 - 10 Mar 2022
Cited by 22 | Viewed by 5552
Abstract
PolyADP-ribose polymerase (PARP) inhibitors (PARPis) represent the first clinically approved drugs able to provoke “synthetic lethality” in patients with homologous recombination-deficient (HRD) tumors. Four PARPis have just received approval for the treatment of several types of cancer. Besides, another three additional PARPis underlying [...] Read more.
PolyADP-ribose polymerase (PARP) inhibitors (PARPis) represent the first clinically approved drugs able to provoke “synthetic lethality” in patients with homologous recombination-deficient (HRD) tumors. Four PARPis have just received approval for the treatment of several types of cancer. Besides, another three additional PARPis underlying the same mechanism of action are currently under investigation. Despite the success of these targeted agents, the increasing use of PARPis in clinical practice for the treatment of different tumors raised the issue of PARPis resistance, and the consequent disease relapse and dismal prognosis for patients. Several mechanisms of resistance have been investigated, and ongoing studies are currently focusing on strategies to address this challenge and overcome PARPis resistance. This review aims to analyze the mechanisms underlying PARPis resistance known today and discuss potential therapeutic strategies to overcome these processes of resistance in the future. Full article
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16 pages, 1034 KiB  
Review
PARP Inhibitors in Glioma: A Review of Therapeutic Opportunities
by Hao-Wen Sim, Evanthia Galanis and Mustafa Khasraw
Cancers 2022, 14(4), 1003; https://doi.org/10.3390/cancers14041003 - 16 Feb 2022
Cited by 16 | Viewed by 6408
Abstract
Gliomas are the most common malignant primary brain tumor in adults. Despite advances in multimodality therapy, incorporating surgery, radiotherapy, systemic therapy, tumor treating fields and supportive care, patient outcomes remain poor, especially in glioblastoma where median survival has remained static at around 15 [...] Read more.
Gliomas are the most common malignant primary brain tumor in adults. Despite advances in multimodality therapy, incorporating surgery, radiotherapy, systemic therapy, tumor treating fields and supportive care, patient outcomes remain poor, especially in glioblastoma where median survival has remained static at around 15 months, for decades. Low-grade gliomas typically harbor isocitrate dehydrogenase (IDH) mutations, grow more slowly and confer a better prognosis than glioblastoma. However, nearly all gliomas eventually recur and progress in a way similar to glioblastoma. One of the novel therapies being developed in this area are poly(ADP-Ribose) polymerase (PARP) inhibitors. PARP inhibitors belong to a class of drugs that target DNA damage repair pathways. This leads to synthetic lethality of cancer cells with coexisting homologous recombination deficiency. PARP inhibitors may also potentiate the cytotoxic effects of radiotherapy and chemotherapy, and prime the tumor microenvironment for immunotherapy. In this review, we examine the rationale and clinical evidence for PARP inhibitors in glioma and suggest therapeutic opportunities. Full article
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22 pages, 9452 KiB  
Review
PARP Inhibitors and Radiometabolic Approaches in Metastatic Castration-Resistant Prostate Cancer: What’s Now, What’s New, and What’s Coming?
by Andrea Marchetti, Matteo Rosellini, Giacomo Nuvola, Elisa Tassinari, Veronica Mollica, Alessandro Rizzo, Matteo Santoni, Alessia Cimadamore, Andrea Farolfi, Rodolfo Montironi, Stefano Fanti and Francesco Massari
Cancers 2022, 14(4), 907; https://doi.org/10.3390/cancers14040907 - 11 Feb 2022
Cited by 8 | Viewed by 3466
Abstract
In recent years, the advances in the knowledge on the molecular characteristics of prostate cancer is allowing to explore novel treatment scenarios. Furthermore, technological discoveries are widening diagnostic and treatment weapons at the clinician disposal. Among these, great relevance is being gained by [...] Read more.
In recent years, the advances in the knowledge on the molecular characteristics of prostate cancer is allowing to explore novel treatment scenarios. Furthermore, technological discoveries are widening diagnostic and treatment weapons at the clinician disposal. Among these, great relevance is being gained by PARP inhibitors and radiometabolic approaches. The result is that DNA repair genes need to be altered in a high percentage of patients with metastatic prostate cancer, making these patients optimal candidates for PARP inhibitors. These compounds have already been proved to be active in pretreated patients and are currently being investigated in other settings. Radiometabolic approaches combine specific prostate cancer cell ligands to radioactive particles, thus allowing to deliver cytotoxic radiations in cancer cells. Among these, radium-223 and lutetium-177 have shown promising activity in metastatic pretreated prostate cancer patients and further studies are ongoing to expand the applications of this therapeutic approach. In addition, nuclear medicine techniques also have an important diagnostic role in prostate cancer. Herein, we report the state of the art on the knowledge on PARP inhibitors and radiometabolic approaches in advanced prostate cancer and present ongoing clinical trials that will hopefully expand these two treatment fields. Full article
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34 pages, 3032 KiB  
Review
PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword
by Clifford M. Csizmar, Antoine N. Saliba, Elizabeth M. Swisher and Scott H. Kaufmann
Cancers 2021, 13(24), 6385; https://doi.org/10.3390/cancers13246385 - 20 Dec 2021
Cited by 17 | Viewed by 5295
Abstract
Despite recent discoveries and therapeutic advances in aggressive myeloid neoplasms, there remains a pressing need for improved therapies. For instance, in acute myeloid leukemia (AML), while most patients achieve a complete remission with conventional chemotherapy or the combination of a hypomethylating agent and [...] Read more.
Despite recent discoveries and therapeutic advances in aggressive myeloid neoplasms, there remains a pressing need for improved therapies. For instance, in acute myeloid leukemia (AML), while most patients achieve a complete remission with conventional chemotherapy or the combination of a hypomethylating agent and venetoclax, de novo or acquired drug resistance often presents an insurmountable challenge, especially in older patients. Poly(ADP-ribose) polymerase (PARP) enzymes, PARP1 and PARP2, are involved in detecting DNA damage and repairing it through multiple pathways, including base excision repair, single-strand break repair, and double-strand break repair. In the context of AML, PARP inhibitors (PARPi) could potentially exploit the frequently dysfunctional DNA repair pathways that, similar to deficiencies in homologous recombination in BRCA-mutant disease, set the stage for cell killing. PARPi appear to be especially effective in AML with certain gene rearrangements and molecular characteristics (RUNX1-RUNX1T1 and PML-RARA fusions, FLT3- and IDH1-mutated). In addition, PARPi can enhance the efficacy of other agents, particularly alkylating agents, TOP1 poisons, and hypomethylating agents, that induce lesions ordinarily repaired via PARP1-dependent mechanisms. Conversely, emerging reports suggest that long-term treatment with PARPi for solid tumors is associated with an increased incidence of myelodysplastic syndrome (MDS) and AML. Here, we (i) review the pre-clinical and clinical data on the role of PARPi, specifically olaparib, talazoparib, and veliparib, in aggressive myeloid neoplasms and (ii) discuss the reported risk of MDS/AML with PARPi, especially as the indications for PARPi use expand to include patients with potentially curable cancer. Full article
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