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Email: Gar med. Email: sekerem ccf. Email: ggarciam mdanderson. The most promising thus far is PRIMA-1, which is a small molecule therapy that entered its second phase of clinical trials in Aprea, This therefore causes reactivation of the p53 protein that should subsequently regain its ability to induce apoptosis.
There has been a range of papers investigating the therapeutic possibilities of PRIMA-1 in a number of different cancers.
One seminal paper is the study by Bykov et al. Human tumour cell lines were used to find growth inhibition profiles for PRIMA-1 and 44 other commonly used cancer therapies, p53 expression levels and population doubling time as a measure of the size of the tumour. The study however only analysed cell lines with mutant protein levels exceeding 1 unit, determined by western blotting. As a result, no conclusion can be drawn about the efficacy of PRIMA-1 in cell lines where p53 expression had reached very low levels or stopped completely, and the authors suggested that the efficacy would depend on the levels of mutant p53 in the cell.
This was contested by Zandi et al. A further problem of using selected cell lines for the studies of PRIMA-1 is a lack of evidence of the effects of the drug in vivo and in human subjects. Lambert et al. An animal model study by Watanabe et al. With this said, the results of this study did not show a significant decrease in tumour size of 1. The main implications of the deficiency of in vivo analysis are that potential side effects could go unnoticed before the drug is administered to humans.
Mouse models may identify some potential problem areas; however, as shown in the TGN study, mouse models cannot be entirely relied on to highlight any potential complications Suntharalingam et al.
Furthermore, a lack of identification of severe side effects would undermine the purpose of this novel targeted drug. In addition, the identification needs to be undertaken over a long period of time to observe complications that may arise further down the line of treatment. Rao et al. In this trial, however, other effects of the drug were not monitored and the trial took place in a mouse model Rao et al. The study involved mixing the p53 modulators with food and measuring the tumour size on the lungs after both 20 and 32 weeks.
Photographs of the lungs are shown in the study by Rao et al. From these, it is clear to see that both the p53 modulators decreased the size of the tumours and also that CP may in fact be the more effective option, despite it being less well researched at present Rao et al. With this shortage of availability of in vivo evidence, a model investigating drug selectivity could be used to get an insight into the likelihood of complications occurring.
The expectation is then that the higher the selectivity of the drug, the less side effects it will cause as a result of acting on healthy cells. This was tested by Bykov et al. PRIMA-1 had a target selectivity that was higher than the current cancer therapies in colon cancer, NSCLC and melanomas with selective advantages over certain therapies in other cancers. A P -value of 0. It should however be noted that a P -value of 0. The high selectivity of the drug may also have positive repercussions with respect to drug resistance, which is becoming an ever-increasing problem in all aspects of medicine.
An inevitable increase in resistance to cancer chemotherapy drugs as their prescription is increasing is another motivation for developing novel cancer therapies. More research would have to be done into the potential effect of these resistance mechanisms on the suitability of the drug as a cancer therapy.
Data would need to be collected to investigate the effect of these mechanisms in vivo and whether the level of resistance would affect its therapeutic potential or whether further actions could be taken to prevent these mechanisms affecting the efficacy of PRIMA A cluster analysis was performed by Bykov et al. Clustering was performed according to Ward's method, and a dendogram was generated showing 44 therapies and their relation to PRIMA-1 Bykov et al.
As can be seen from the figure, PRIMA-1 clusters away from many other commonly used therapies, only showing similarities to the purine analogues. This could be a potential benefit with respect to multi-drug resistance mechanisms, as tumour cells would have to evolve different resistance mechanisms to PRIMA-1 than conventional cancer therapies to avoid being affected by the novel drug.
As well as potential issues concerning resistance, the Lambert et al. At 15 min, a sample of the solution containing PRIMA-1 and its degradation products was analysed using mass spectrometry and nuclear magnetic resonance. This showed the mixture to contain three compounds, methylene quinuclidinone and two unknown compounds. For their structures, see Lambert et al. It would therefore be imperative that the effects of these unknown compounds were investigated fully, as well as those of the PRIMA itself, to ensure that the drug will be suitable for clinical use.
Formaldehyde has been classified as a known human carcinogen by the International Agency for Research on Cancer National Cancer Institute, a ; however, the potential implications of this have not yet been assessed in a PRIMA-1 study.
In conclusion, cancer is a disease that is hugely prevalent, with cases increasing year on year. Treatment has progressed in recent years, with chemotherapy now available to treat most cancers with an increasing success rate.
Despite this improvement, the afflicting associated side effects with chemotherapy leave many opportunities for innovation. Drug targeting is proving to offer many potential alternatives, with targeting the apoptosis pathway being one of the most explored.
PRIMA-1 exploits the high occurrence of a mutated p53 protein in cancers and acts to restore the mutated protein to its wild-type state. The restored p53 can then resume its role inducing apoptosis to prevent superfluous cell proliferation. There have been a number of studies investigating the possibility of PRIMA-1, and other pmodulating drugs such as CP, as novel cancer therapies to replace chemotherapy.
Combining the results of these studies provides an overall positive outlook on the potential of these therapies with just a few obstacles being presented before the therapy can be put into clinical use.
It is therefore suggested that further investigations are made into the in vivo effects of the drug, especially in the long term, with a focus of identifying other possible effects of the drugs. This article has been cited by other articles in PMC. Abstract Poly ADP-ribose polymerase PARP inhibitor maintenance therapy is the latest breakthrough in the management of newly diagnosed advanced ovarian cancer.
Keywords: PARP inhibitors, advanced ovarian cancer. Introduction For women with newly diagnosed advanced ovarian cancer AOC , first-line therapy with a combination of debulking surgery and platinum-based chemotherapy has been the standard of care for decades. Open in a separate window. Selecting patients for first-line maintenance PARP inhibitor therapy Following the results from first-line PARP inhibitor trials and regulatory approvals, the oncology community is reviewing best practice in first-line treatment of patients with newly diagnosed AOC and discussing which patients should be offered a maintenance PARP inhibitor.
Outstanding questions that need to be addressed include the following: What is the role of traditional clinical factors, that is, primary debulking surgery PDS or interval debulking surgery IDS and residual tumour, in the decision-making process?
Key message on monitoring There are no data showing a survival benefit by close and intensive follow-up compared with less intensive follow-up. Duration of first-line PARP inhibitor maintenance therapy In patients with AOC, most recurrences occur during the first 3 years after completion of first-line chemotherapy.
Managing toxicities of PARP inhibitors during maintenance therapy Clinicians, nurses and patients need to be aware of class-specific and drug-specific toxicities and how to manage them. Treatment of patients in recurrence following maintenance PARP inhibitor therapy With current approvals for PARP inhibitors in the recurrent disease setting, excluding women who previously received a PARP inhibitor, 33 other postprogression approaches need to be considered for patients in recurrence following maintenance PARP inhibitor therapy.
Next steps for clinical trials Ongoing and planned trials are addressing the possibility of reintroducing PARP inhibitors in the treatment strategy of patients who have previously received a PARP inhibitor.
Footnotes Contributors: All authors have written parts of and have reviewed the whole manuscript. References 1. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med ; ;— A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med ; — Cancer ; — Ledermann JA. Parp inhibitors in ovarian cancer.
Ann Oncol ; 27 :i40—4. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. Niraparib in patients with newly diagnosed advanced ovarian cancer. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. Lynparza FDA label for olaparib. The forefront of ovarian cancer therapy: update on PARP inhibitors. Ann Oncol ; 31 — Ann Oncol ; 31 :S Gyn oncol Clin Cancer Res ; 24 — Is postoperative computed tomography evaluation a prognostic indicator in patients with optimally debulked advanced ovarian cancer?
Oncology ; 87 —9. SGO Annual Meeting, Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma ARIEL3 : post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial. Lancet Oncol ; 21 — Science ; :eaax A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for niraparib efficacy in preclinical tumor models.
Oncotarget ; 9 — J Clin Oncol Hollis RL, Gourley C. Genetic and molecular changes in ovarian cancer. Cancer Biol Med ; 13 — Comparison of genomic instability test scores used for predicting PARP activity in ovarian cancer.
ESMO recommendations on predictive biomarker testing for homologous recombination deficiency and PARP inhibitor benefit in ovarian cancer. J Clin Oncol. JCO ; 38 Lancet Oncol ; 18 — Safety and dose modification for patients receiving niraparib. Ann Oncol ; 30 Emerging drugs for the treatment of ovarian cancer: a focused review of PARP inhibitors. Expert Opin Emerg Drugs ; 25 — Bevacizumab and platinum-based combinations for recurrent ovarian cancer: a randomised, open-label, phase 3 trial.
Parp inhibitors in ovarian cancer: sensitivity prediction and resistance mechanisms. J Cell Mol Med ; 23 — OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol ; 30 — Ann Oncol ; 31 :S— Clin Cancer Res ; 19 — Olaparib as maintenance therapy in patients with BRCA mutated recurrent platinum sensitive ovarian cancer: real world data and post progression outcome.
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