Positron Emission Tomography Imaging of Poly-(Adenosine Diphosphate-Ribose) Polymerase 1 Expression in Breast Cancer: A Nonrandomized Clinical Trial.
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ABSTRACT:
SUBMITTER: McDonald ES
PROVIDER: S-EPMC7163777 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Poly(ADP-ribose) polymerase (PARP) is involved in repair of DNA breaks and is over-expressed in a wide variety of tumors, making PARP an attractive biomarker for positron emission tomography (PET) and single photon emission computed tomography imaging. Consequently, over the past decade, there has been a drive to develop nuclear imaging agents targeting PARP. Here, we report the discovery of a PET tracer that is based on the potent PARP inhibitor olaparib (1). Our lead PET tracer candidate, [18F]20, was synthesized and evaluated as a potential PARP PET radiotracer in mice bearing subcutaneous glioblastoma xenografts using ex vivo biodistribution and PET-magnetic resonance imaging techniques. Results showed that [18F]20 could be produced in a good radioactivity yield and exhibited specific PARP binding allowing visualization of tumors over-expressing PARP. [18F]20 is therefore a potential candidate radiotracer for in vivo PARP PET imaging.
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Project description:Recently, the development of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors as a synthetic lethality approach has brought a major breakthrough in the treatment of breast cancer susceptibility gene (BRCA)-mutant cancers. Because sporadic cancers have also been found to commonly have other defects in DNA repair, PARP inhibitors are under active clinical investigation in combination with DNA-damaging therapeutics in a wide range of sporadic cancers. In this review, the authors discuss DNA repair mechanisms and PARP as a therapeutic target and summarize an update on clinical trials of available PARP inhibitors and predictive biomarkers for their efficacy.
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Project description:Pancreatic cancer is the third most common cause of cancer death in the United States and eleventh worldwide. The majority of patients present with advanced disease with five-year overall survival of less than 10%. Traditional chemotherapy has been the mainstay treatment for years, with limited improvement in survival. Relative success has been achieved with agents targeting the DNA damage repair (DDR) mechanisms with poly adenosine diphosphate-ribose polymerase (PARP) inhibitors. The initial benefit was observed in patients with germline breast cancer-associated (BRCA) mutations. Multiple trials are now underway exploring PARP inhibitors in other DDR mutations such as the ataxia-telangiectasia mutated (ATM) gene and the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene (familial atypical multiple mole and melanoma syndrome), mismatch repair genes (Lynch syndrome), and others. PARP inhibitors are being evaluated as a single agent or combination chemotherapy, immunotherapy, and maintenance after chemotherapy. Here, we review current clinical trials targeting various DDR mutations and treatment strategies.
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Project description:Ovarian cancer is one of the leading causes of death from gynecologic cancers. In this present era of cancer treatment, therapeutic options for patients with advanced or recurrent ovarian cancer are limited. The present standard of care treatment for advanced ovarian cancer is a platinum-based doublet chemotherapy (paclitaxel and carboplatin with or without bevacizumab) after a maximum attempt of surgical cytoreduction. However, there are no promising options for the management of patients with ovarian cancer refractory to the platinum-based chemotherapy. Therefore, newer, safe, and more effective treatment modalities are required for patients with advanced or recurrent ovarian cancer. Poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors have shown an impressive safety profile and anti-tumor efficacy in patients with breast cancer 1 and 2 (BRCA1 and BRCA2) gene-mutated ovarian cancer who were previously treated with the standard of care chemotherapy. We have done a detailed review of the literature to emphasize the role of PARP inhibitors in the treatment of advanced or relapsed ovarian cancer.
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Project description:Poly(ADP-ribose) polymerases are a family of DNA-dependent nuclear enzymes catalyzing the transfer of ADP-ribose moieties from cellular nicotinamide-adenine-dinucleotide to a variety of target proteins. Although they have been considered as resident nuclear elements of the DNA repair machinery, recent works revealed a more intricate physiologic role of poly(ADP-ribose) polymerases with numerous extranuclear activities. Indeed, poly(ADP-ribose) polymerases participate in fundamental cellular processes like chromatin remodelling, transcription or regulation of the cell-cycle. These new insight into the physiologic roles of poly(ADP-ribose) polymerases widens the range of human pathologies in which pharmacologic inhibition of these enzymes might have a therapeutic potential. Here, we overview our current knowledge on extranuclear functions of poly(ADP-ribose) polymerases with a particular focus on the mitochondrial ones and discuss potential fields of future clinical applications.
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Project description:1. The isolated nuclei of the slime mould Physarum polycephalum contain an enzyme that will incorporated [adenine-3H] NAD+ into an acid-insoluble product, which is shown to be poly(ADP-ribose). 2. This incorporation has an optimum pH of 8.2 and a temperature optimum below 10degreesC. 3. Optimum stimulation is given by 15 mM-Mg2+. 4. 2-Mercaptoethanol or dithiothreitol also stimulates the incorporation, the latter at an optimum concentration of about 1 mM. 5. Under optimum conditions the Km value for the reaction is 0.28 mM at 15degreesC. Nicotinamide inhibits the incorporation with a Ki of 5.7 muM. 6. Exogenous DNA stimulates the incorporation by about 100%. 7. Preincubation of the nuclei with deoxyribonuclease, but not with ribonuclease, almost completely inactivates the incorporation of NAD+. 8. The enzyme is unstable at both 0degrees and 15degreesC in the absence of dithiothreitol. The presence of dithiothreitol at a concentration of 1 mM stabilizes the enzyme at both these temperatures. 9. The activity of this enzyme per nucleus was shown in three separate experiments to fall by about one-half in early S phase and then to rise to its pre-mitotic value after about 3 h, that is in late S phase. 10. The possible physiological function of this enzyme system is discussed.
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Project description:BackgroundMore patients with ovarian cancer are being treated with poly(adenosine diphosphate-ribose) polymerase inhibitors because regulatory agencies have granted these drugs new approvals for a variety of treatment indications. However, poly(adenosine diphosphate-ribose) polymerase inhibitors are expensive. When administered as a maintenance therapy, these drugs may be administered for months or years. How much of this cost patients experience as out-of-pocket spending is unknown.ObjectiveThis study aimed to estimate the out-of-pocket spending that patients experience during poly(adenosine diphosphate-ribose) polymerase inhibitor treatment and to characterize which healthcare services account for that spending.Study designA retrospective cohort study was performed with a sample of patients with ovarian cancer treated between 2014 and 2017 with olaparib, niraparib, or rucaparib. Patients were identified using MarketScan, a health insurance claims database. All insurance claims during poly(adenosine diphosphate-ribose) polymerase inhibitor treatment were collected. The primary outcome variable was the patients' out-of-pocket spending (copayment, coinsurance, and deductibles) during poly(adenosine diphosphate-ribose) polymerase inhibitor treatment for the medication itself. Other outcomes of interest included out-of-pocket spending for other healthcare services, the types and frequency of other healthcare services used, health plan spending, the estimated proportion of patients' household income used each month for healthcare, and patients' out-of-pocket spending immediately before poly(adenosine diphosphate-ribose) polymerase inhibitor treatment.ResultsWe identified 503 patients with ovarian cancer with a median age of 55 years (interquartile range, 50-62 years); 83% of those had out-of-pocket spendings during poly(adenosine diphosphate-ribose) polymerase inhibitor treatment. The median treatment duration was 124 days (interquartile range, 66-240 days). The mean out-of-pocket spending for poly(adenosine diphosphate-ribose) polymerase inhibitors was $305 (standard deviation, $2275) per month. On average, this accounted for 44.8% (standard deviation, 34.8%) of the patients' overall monthly out-of-pocket spending. The mean out-of-pocket spending for other healthcare services was $165 (standard deviation, $769) per month. Health plans spent, on average, $12,661 (standard deviation, $15,668) per month for poly(adenosine diphosphate-ribose) polymerase inhibitors and $7108 (standard deviation, $15,254) per month for all other healthcare services. The cost sharing for office visits, laboratory tests, and imaging studies represented the majority of non-poly(adenosine diphosphate-ribose) polymerase inhibitor treatment out-of-pocket spending. The average amount patients paid for all healthcare services per month during poly(adenosine diphosphate-ribose) polymerase inhibitor treatment was $470 (standard deviation, $2407), which was estimated to be 8.7% of the patients' monthly household income. The mean out-of-pocket spending in the 12 months before poly(adenosine diphosphate-ribose) polymerase inhibitor treatment was $3110 (standard deviation, $6987).ConclusionPatients can face high out-of-pocket costs for poly(adenosine diphosphate-ribose) polymerase inhibitors, although the sum of cost sharing for other healthcare services used during poly(adenosine diphosphate-ribose) polymerase inhibitor treatment is often higher. The spending on healthcare costs consumes a large proportion of these patients' household income. Patients with ovarian cancer experience high out-of-pocket costs for healthcare, both before and during poly(adenosine diphosphate-ribose) polymerase inhibitor treatment.
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Project description:Imaging of poly (ADP-ribose) polymerase-1 (PARP-1) expression in vivo is a potentially powerful tool for developing PARP-1 inhibitors for drug discovery and patient care. We have synthesized several derivatives of benzimidazole carboxamide as PARP-1 inhibitors, which can be (18)F-labeled easily for positron emission tomographic (PET) imaging. Of the compounds synthesized, 12 had the highest inhibition potency for PARP-1 (IC50=6.3 nM). [(18)F]12 was synthesized under conventional conditions in high specific activity with 40-50% decay-corrected yield. MicroPET studies using [(18)F]12 in MDA-MB-436 tumor-bearing mice demonstrated accumulation of [(18)F]12 in the tumor that was blocked by olaparib, suggesting that the uptake of [(18)F]12 in the tumor is specific to PARP-1 expression.
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Project description:Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common cause of dementia among the elderly population. The good correlation between the density and neocortical spread of neurofibrillary tangles (NFTs) and the severity of cognitive impairment offers an opportunity to use a noninvasive imaging technique such as positron emission tomography (PET) for early diagnosis and staging of the disease. PET imaging of NFTs holds promise not only as a diagnostic tool but also because it may enable the development of disease-modifying therapeutics for AD. In this review, we focus on the structural diversity of tau PET tracers, the challenges related to identifying high-affinity and highly selective NFT ligands, and recent progress in the clinical development of tau PET radioligands.
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Project description:Granzyme A (GzmA) in killer cells induces caspase-independent programmed cell death. In this study, we show that GzmA cleaves the DNA damage sensor poly(adenosine 5'-diphosphate-ribose) polymerase-1 (PARP-1) after Lys(498) in its automodification domain, separating the DNA binding domain from the catalytic domain, which interferes with repair of GzmA-induced DNA damage and enhances susceptibility to GzmA-mediated death. Overexpressing K498A PARP-1 reduces GzmA-mediated death and drives dying cells to necrosis rather than apoptosis. Conversely, inhibiting or genetically disrupting PARP-1 enhances cell vulnerability. The N-terminal GzmA cleavage fragment of PARP-1 acts as a PARP-1 dominant negative, binding to DNA and blocking DNA repair. Disrupting PARP-1, which is also a caspase target, is therefore required for efficient apoptosis by both caspase-independent and caspase-dependent pathways.
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