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    The different types and the overwhelming number of cancer cases across the globe have prompted scholars to pursue more effective therapies than traditional treatment

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    PARP (Poly (ADP)-Ribose Polymerase) Inhibitors – Application of Synthetic Lethality Concepts in Cancer Treatments

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    The different types and the overwhelming number of cancer cases across the globe have prompted scholars to pursue more effective therapies than traditional treatment

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    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
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    19 views2 pages

    PARP (Poly (ADP) - Ribose Polymerase) Inhibitors - Application of Synthetic Lethality Concepts in Cancer Treatments

    Uploaded by

    International Journal of Innovative Science and Research Technology
    The different types and the overwhelming number of cancer cases across the globe have prompted scholars to pursue more effective therapies than traditional treatment

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
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    of 2

    Volume 6, Issue 2, February – 2021 International Journal of Innovative Science and Research Technology

    ISSN No:-2456-2165

    PARP (poly (ADP)-ribose polymerase) Inhibitors –


    Application of Synthetic Lethality Concepts in
    Cancer Treatments
    Michael Halim* 1
    1
    University of Salford, MSc Biomedical Science, Greater Manchester, United Kingdom

    Abstract:- The different types and the overwhelming cancer treatment, researchers observed a lower response rate
    number of cancer cases across the globe have prompted in patients who had previous exposure with conventional
    scholars to pursue more effective therapies than therapy based on platinum (Litton, et al., 2018). Patients
    traditional treatments. One approach that has from the EMBRACA clinical trials indicate higher QoL,
    demonstrated considerable progress is related to the use PFS and OS after the intervention in comparison to those
    of PARP inhibitors. Essentially, PARP inhibitors such as receiving standard platinum therapy (Shen, et al.,
    Talazoparib, Olaparib and Rucaparib use a concept of 2013).Specifically, interim analysis from the EMRACA
    synthetic lethality to kill tumour cells. According to clinical trials recorded an Overall Survival of 22.3 months in
    Sebastian (2011) synthetic lethality occurs when a comparison to 19.5 months from standard chemotherapy
    deficiency in one gene expression does not cause cell (Exman, et al., 2019). The Overall Survival Rate is yet to be
    death while a collection of two or more deficiencies in determined from ongoing research since Talazoparib is a
    gene expression leads to cell death. PARP inhibitors relatively novel drug only approved in 16th October, 2018
    exploit this concept to eradicate tumour cells. (Exman, et al., 2019). Side effects of Talazoparib include
    nausea, fatigue and anaemia (Litton, et al., 2018).
    Keywords:- PARP Inhibitors, Talazoparib, Olaparib,
    Rucaparib.  Olaparib
    Olaparib has been studied in different types of cancer.
    I. INTRODUCTION Well known clinical trials generating knowledge on the drug
    are the NRG Oncology trial and the PAOLA-1 trials (Oza,
    In detail, normal and cancer cells undergo constant et al., 2015). The drug is effective at treating refractory
    DNA damage due to environmental hazards and other ovarian cancer, breast cancer and Oviduct cancer (Institute
    molecular toxics. Normal cells repair DNA damage through of Cancer Research, 2019). In contrast to Talazoparib,
    two pathways; (1)PARP which is primed for repairing single Olaparib can be used efficiently in conjunction with other
    strands and ; (2) BRCA1/2 that repairs double strands cancer therapies (Washington, et al., 2019). Research
    (Sebastian, 2011; Litton, et al., 2018). By contrast, a cancer indicates that Olaparib is effective at eliminating targeted
    cell with deficiencies in BRCA1 and BRCA2 gene tumour cells; however, cancer may relapse after a while
    expression only has the PARP pathway to repair DNA usually less than three years (Institute of Cancer Research,
    damage (Sebastian, 2011). Therefore, introducing PARP 2019). Olaparib has had successful outcomes as a
    inhibitors such Talazoparib, Olaparib and Rucaparib make it maintenance drug for patients suffering from Ovarian
    impossible to repair DNA damage in tumour cells thus, cancer. As of 2016 and with 79% maturity data, Olaparib
    leading to further damage ending in cell death (Sebastian, recorded an Overall Survival Rate of 75% (European
    2011; Litton, et al., 2018). PARP inhibitors do not kill Society For Medical Oncology, 2018). Even so Olaparib is
    normal cells as they still have the BRCA1/2 pathways to relatively ineffective in other scenarios for instance,
    repair DNA (Litton, et al., 2018). Robson, et al.(2019) observed that there was no
    improvement in the Overall Survival rate for patients with
    II. RESULTS AND DISCUSSION metastatic breast cancer. Patients who undergo treatment
    with Olaparib experience side effects such as nausea,
     Talazoparib fatigue, heartburn and constipation (European Society For
    One of the most common cancer therapies based on Medical Oncology, 2018).
    PARP inhibitors is Talazoparib which is used to treat breast
    cancer (Exman, et al., 2019; Litton, et al., 2018). From the  Rucaparib
    EMBRACA clinical trials, Talazoparib is a more potent Rucaparib is a PARP inhibitor used to treat advanced
    treatment than conventional cancer therapy based on ovarian cancer and endometrial cancer (Shirley, 2019). In
    platinum (Litton, et al., 2018). Notably, Talazoparib, the ARIEL-2 trial, researchers emphasized the role of
    Olaparib and Rucaparib work solely in patients with Rucaparib as maintenance therapy (Yvette Drew, et al.,
    mutations in BRCA1/2 which impedes homologous 2019). Specifically, Rucaparib is an approved therapy for
    recombination (Exman, et al., 2019). Even though women with ovarian cancer who have undergone more than
    Talazoparib is considered more effective than standard two chemotherapies (Molin, et al., 2018). From studies, the

    IJISRT21FEB502 www.ijisrt.com 734


    Volume 6, Issue 2, February – 2021 International Journal of Innovative Science and Research Technology
    ISSN No:-2456-2165
    drug has different degrees of outcomes depending on the [7]. Robson, M. E. et al., 2019. OlympiAD final overall
    presence of LOH (loss of heterozygosity) which is the survival and tolerability results: Olaparib versus
    subsequent loss of a gene and the chromosomal region [8]. chemotherapy treatment of physician’s choice in
    surrounding the gene or the existence BRCA gene mutations patients with a germline BRCA mutation and HER2-
    (Molin, et al., 2018). Data on the efficacy of Rucaparib is negative metastatic breast cancer. Annals of Oncology,
    still being collected and is not mature to be used in the 30(4).
    calculation of the overall survival rate (Molin, et al., [9]. Sebastian, N., 2011. "Synthetic Lethality: General
    2018).Nevertheless, the overall rate of response (ORR) of principles, utility and detection using genetic screens
    Rucaparib in ARIEL 3 patients with BRCA1/2 mutations is in human cells". FEBS Lett, 3 Jan, Volume 585 (1), p.
    38% which is significantly higher than placebo at 9%. 1–6.
    Notably, clinical trials indicate that the Rucaparib may [10]. Shen, Y. et al., 2013. BMN 673, a novel and highly
    display “off-target effects” when interacting with PARP1 potent PARP1/2 inhibitor for the treatment of human
    and PARP2 (Molin, et al., 2018) The most common side- cancers with DNA repair deficiency. Clin Cancer Res,
    effects after treatment with the drug are fatigue (69%), 19 (18), p. 5003–5015.
    nausea (75%), constipation and vomiting (Molin, et al., [11]. Shirley, M., 2019. Rucaparib: A Review in Ovarian
    2018; Yvette Drew, et al., 2019). Cancer. Targeted Oncology, 14(2), pp. 237-246.
    [12]. Washington, C., Richardson, D. & Moore, K., 2019.
    III. CONCLUSION Olaparib in the treatment of ovarian cancer. Future
    Medicine, 15(30).
    PARP inhibitors are generally effective in treating [13]. Yvette Drew, et al., 2019. Real‐World Delivery of
    cancers, nonetheless, more clinical trials and research have Rucaparib to Patients with Ovarian Cancer:
    to be conducted in order to increase its overall efficacy, Recommendations Based on an Integrated Safety
    improve the overall survival rate of cancer patients, and Analysis of ARIEL2 and Study 10. The Official
    reduce the associated side effects. Furthermore, it is worth Journal of the Society of Transitional Oncology.
    considering that PARP inhibitors should be combined with
    other medications to create stronger drug cocktails capable
    of delivering more efficacious results accompanied by lesser
    adverse outcomes. Overall, PARP inhibitors demonstrate
    high potential in cancer treatments, and might become an
    ideal drug, not only restricted to cancer treatments, but also
    in other domains of medicine and biomedical science, such
    as metabolic pathway disorders and genetic defects, in time
    to come.

    REFERENCES

    [1]. European Society for Medical Oncology, 2018.


    ESMO18: Olaparib maintenance improves
    progression-free survival in advanced ovarian cancer
    by 3 years. Oncology Central, 22 October.
    [2]. Exman, P., Barroso-Sousa, R. & Tolaney, S. M., 2019.
    Evidence to date: talazoparib in the treatment of breast
    cancer. Onco Targets and Therapy, Volume 12, p.
    5177–5187.
    [3]. Institute of Cancer Research, 2019. Olaparib becomes
    first gene-targeted medicine to show benefits in
    prostate cancer. The Lancet Oncology.
    [4]. Litton, J. K. et al., 2018. Talazoparib in patients with
    advanced breast cancer and a germline BRCA
    mutation. The New England Journal of Medicine, 23
    August, 379(8), p. 753–763.
    [5]. Molin, G. D., Omatsu, K., Sood, A. K. & Coleman, R.,
    2018. Rucaparib in ovarian cancer: an update on
    safety, efficacy and place in therapy. Ther Adv Med
    Oncol, Volume 10.
    [6]. Oza, A. M. et al., 2015. Olaparib combined with
    chemotherapy for recurrent platinum-sensitive ovarian
    cancer: a randomised phase 2 trial. The Lancet
    Oncology, 16(1), pp. 87-97.

    IJISRT21FEB502 www.ijisrt.com 735

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