PARP inhibitors as single agents and in combination therapy: the most promising treatment strategies in clinical trials for BRCA-mutant ovarian and triple-negative breast cancers

Luo, Linjie; Keyomarsi, Khandan

doi:10.1080/13543784.2022.2067527

Cited by 35 publications

(33 citation statements)

References 154 publications

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“…Entretanto, é válido destacar também que é comum o desenvolvimento de resistência na maioria dos pacientes que recebem PARPi, sendo imprescindível a identificação de outros alvos extras para contornar esse problema (Luo & Keyomarsi, 2022).…”

Section: Discussionunclassified

Evolução e desenvolvimento do tratamento farmacológico relativo ao câncer de mama triplo negativo: revisão integrativa

Vasconcelos

Freitas²,

Loureiro³

et al. 2023

RSD

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Este artigo tem como objetivo analisar e criticar as experiências existentes de terapia farmacológica para tratamento do câncer de mama triplo negativo (TNBC), visando compreender a possibilidade de avanços significativos na área. O TNBC, em especial, gera intensa preocupação em profissionais de saúde, pacientes e familiares pela alta frequência do prognóstico desfavorável e sua incidência em pacientes jovens. Assim, optou-se pela realização do modelo de revisão integrativa de literatura, utilizando como arcabouço bibliográfico artigos presentes nas bases de dados eletrônicas: PUBMED (Publisher Medline) e BVS (Biblioteca Virtual em Saúde). Portanto, foram escolhidas aquelas publicações que relacionassem corretamente as palavras-chave e passassem pelos filtros de seleção, isto é, as que contivessem informações pertinentes e capazes de agregar substancialmente à discussão. Então, foram colhidas referências acerca do desempenho de diversos fármacos no tratamento dos 6 diferentes tipos de TNBC, entre eles a ciclofosfamida, os taxanos, as platinas, entre outros. Ademais, também foram encontrados resultados positivos para combinação de diferentes medicamentos, e a aliança a métodos mais tradicionais como a quimioterapia, estabelecendo a quimioterapia neoadjuvante. Somando-se à melhora das taxas de sobrevida oriundas de experimentos realizados com remédios inibidores de checkpoint e, até mesmo a aprovação de alguns desses por órgãos federativos de saúde, é possível inferir que os tratamentos farmacológicos existentes denotam um resultado adequado, mas, que representa, contudo, uma parcela minoritária do grande potencial a ser explorado por intermédio do desenvolvimento de novos trâmites terapêuticos com fármacos sabidamente já eficazes, e com novos que ainda hão de ser testados.

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Section: Discussionunclassified

Evolução e desenvolvimento do tratamento farmacológico relativo ao câncer de mama triplo negativo: revisão integrativa

Vasconcelos

Freitas²,

Loureiro³

et al. 2023

RSD

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“…In OC involving BRCA mutations, inhibition of PARP causes chromosomal instability [ 125 ], due to the activation of other error-prone DNA-repair pathways and, ultimately, leads to cell death [ 126 ]. Luo and Keyomarsi present the four main PARP inhibitors that are currently approved for use [ 127 ]. Unfortunately, however, there is evidence that many patients who are treated with PARP-inhibitors confer resistance to the treatment, presenting a challenge to its clinical use [ 128 ].…”

Section: Parp Inhibitorsmentioning

confidence: 99%

Applications of Proteomics in Ovarian Cancer: Dawn of a New Era

et al. 2022

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The ability to identify ovarian cancer (OC) at its earliest stages remains a challenge. The patients present an advanced stage at diagnosis. This heterogeneous disease has distinguishable etiology and molecular biology. Next-generation sequencing changed clinical diagnostic testing, allowing assessment of multiple genes, simultaneously, in a faster and cheaper manner than sequential single gene analysis. Technologies of proteomics, such as mass spectrometry (MS) and protein array analysis, have advanced the dissection of the underlying molecular signaling events and the proteomic characterization of OC. Proteomics analysis of OC, as well as their adaptive responses to therapy, can uncover new therapeutic choices, which can reduce the emergence of drug resistance and potentially improve patient outcomes. There is an urgent need to better understand how the genomic and epigenomic heterogeneity intrinsic to OC is reflected at the protein level, and how this information could potentially lead to prolonged survival.

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“…In 2020 the FDA approved two PARP1i, olaparib and rucaparib to treat metastatic castration-resistant prostate cancer, and it approved olaparib to treat eligible patients with pancreatic cancer. Because PARP1 plays many roles in DNA repair, replication stress responses, and chromatin remodeling, additional uses for PARP1i in cancer monotherapy, combination therapy, and maintenance therapy continue to be explored ( Table 1 ) [ 157 , 158 , 159 , 160 , 161 , 162 , 163 ].…”

Section: Targeting Replication Stress Signaling and Fork Repair/resta...mentioning

confidence: 99%

“…For PARP1i, only completed Phase II/III trials with peer-reviewed publications since 2015 are listed: data from . Several recent reviews provide additional information about the numerous PARP1i clinical trials [ 157 , 158 , 159 , 160 , 161 , 162 , 163 ]. ** CNS, central nervous system; TNBC, triple negative breast cancer; OS, osteosarcoma.…”

Section: Figurementioning

confidence: 99%

Targeting Replication Stress Response Pathways to Enhance Genotoxic Chemo- and Radiotherapy

Nickoloff

2022

Molecules

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Proliferating cells regularly experience replication stress caused by spontaneous DNA damage that results from endogenous reactive oxygen species (ROS), DNA sequences that can assume secondary and tertiary structures, and collisions between opposing transcription and replication machineries. Cancer cells face additional replication stress, including oncogenic stress that results from the dysregulation of fork progression and origin firing, and from DNA damage induced by radiotherapy and most cancer chemotherapeutic agents. Cells respond to such stress by activating a complex network of sensor, signaling and effector pathways that protect genome integrity. These responses include slowing or stopping active replication forks, protecting stalled replication forks from collapse, preventing late origin replication firing, stimulating DNA repair pathways that promote the repair and restart of stalled or collapsed replication forks, and activating dormant origins to rescue adjacent stressed forks. Currently, most cancer patients are treated with genotoxic chemotherapeutics and/or ionizing radiation, and cancer cells can gain resistance to the resulting replication stress by activating pro-survival replication stress pathways. Thus, there has been substantial effort to develop small molecule inhibitors of key replication stress proteins to enhance tumor cell killing by these agents. Replication stress targets include ATR, the master kinase that regulates both normal replication and replication stress responses; the downstream signaling kinase Chk1; nucleases that process stressed replication forks (MUS81, EEPD1, Metnase); the homologous recombination catalyst RAD51; and other factors including ATM, DNA-PKcs, and PARP1. This review provides an overview of replication stress response pathways and discusses recent pre-clinical studies and clinical trials aimed at improving cancer therapy by targeting replication stress response factors.

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PARP inhibitors as single agents and in combination therapy: the most promising treatment strategies in clinical trials for BRCA-mutant ovarian and triple-negative breast cancers

Cited by 35 publications

References 154 publications

Evolução e desenvolvimento do tratamento farmacológico relativo ao câncer de mama triplo negativo: revisão integrativa

Evolução e desenvolvimento do tratamento farmacológico relativo ao câncer de mama triplo negativo: revisão integrativa

Applications of Proteomics in Ovarian Cancer: Dawn of a New Era

Targeting Replication Stress Response Pathways to Enhance Genotoxic Chemo- and Radiotherapy

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