Combined PARP inhibitors and small molecular inhibitors in solid tumor treatment (Review)

Jin, Ning; Xia, Yu; Gao, Qinglei

doi:10.3892/ijo.2023.5476

Cited by 8 publications

(4 citation statements)

References 185 publications

(179 reference statements)

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“…In addition, STAT target genes can affect DNA repair mechanisms, suggesting that combinations of STAT inhibitors with PARP inhibitors or telomerase inhibitors may show enhanced efficacy [229].…”

Section: Discussionmentioning

confidence: 99%

Oncogenic STAT Transcription Factors as Targets for Cancer Therapy: Innovative Strategies and Clinical Translation

Wang,

Lopez McDonald,

Hariprasad

et al. 2024

Cancers

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Despite advances in our understanding of molecular aspects of oncogenesis, cancer remains a leading cause of death. The malignant behavior of a cancer cell is driven by the inappropriate activation of transcription factors. In particular, signal transducers and activators of transcription (STATs), which regulate many critical cellular processes such as proliferation, apoptosis, and differentiation, are frequently activated inappropriately in a wide spectrum of human cancers. Multiple signaling pathways converge on the STATs, highlighting their importance in the development and progression of oncogenic diseases. STAT3 and STAT5 are two members of the STAT protein family that are the most frequently activated in cancers and can drive cancer pathogenesis directly. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations in the last decade, although effective treatment options remain limited. In this review, we investigate the specific roles of STAT3 and STAT5 in normal physiology and cancer biology, discuss the opportunities and challenges in pharmacologically targeting STAT proteins and their upstream activators, and offer insights into novel therapeutic strategies to identify STAT inhibitors as cancer therapeutics.

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Section: Discussionmentioning

confidence: 99%

Oncogenic STAT Transcription Factors as Targets for Cancer Therapy: Innovative Strategies and Clinical Translation

Wang,

Lopez McDonald,

Hariprasad

et al. 2024

Cancers

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“…Several proteins are involved in the HR repair pathway, and their alteration may render tumor cells more susceptible to PARPi monotherapy when HR repair is impaired [153]. In settings in which PARPi monotherapy has shown limited efficacy, combined strategies with PARPis can be devised to optimize efficacy and extend PARPi-based therapy to more tumor types with different molecular profiles [164].…”

Section: Current Therapeutic Strategies Targeting Ddr Proteins In Gcmentioning

confidence: 99%

Histone and DNA Methylation as Epigenetic Regulators of DNA Damage Repair in Gastric Cancer and Emerging Therapeutic Opportunities

De Marco,

Sanese,

Simone

et al. 2023

Cancers

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Gastric cancer (GC), one of the most common malignancies worldwide, is a heterogeneous disease developing from the accumulation of genetic and epigenetic changes. One of the most critical epigenetic alterations in GC is DNA and histone methylation, which affects multiple processes in the cell nucleus, including gene expression and DNA damage repair (DDR). Indeed, the aberrant expression of histone methyltransferases and demethylases influences chromatin accessibility to the DNA repair machinery; moreover, overexpression of DNA methyltransferases results in promoter hypermethylation, which can suppress the transcription of genes involved in DNA repair. Several DDR mechanisms have been recognized so far, with homologous recombination (HR) being the main pathway involved in the repair of double-strand breaks. An increasing number of defective HR genes are emerging in GC, resulting in the identification of important determinants of therapeutic response to DDR inhibitors. This review describes how both histone and DNA methylation affect DDR in the context of GC and discusses how alterations in DDR can help identify new molecular targets to devise more effective therapeutic strategies for GC, with a particular focus on HR-deficient tumors.

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“… 7 – 10 Several ongoing clinical trials are investigating the benefit of PARP inhibitors in this clinical setting. 11 , 12 Despite these successes, many patients do not show long-term responses to PARP inhibitor monotherapy or in combination with chemotherapy. Most patients who initially responded to single-agent PARP inhibitor or ICI therapy eventually develop resistance and experience clinical progression.…”

Section: Introductionmentioning

confidence: 99%

Exceptional synergistic response of PARP inhibitor and immune checkpoint inhibitor in esophageal adenocarcinoma with a germline BRCA2 mutation: a case report

Mahadevia,

Ponvilawan,

Al-Obaidi

et al. 2024

Ther Adv Med Oncol

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Immune checkpoint inhibitors (ICIs) and poly (ADP-ribose) polymerase (PARP) inhibitors have shown efficacy in various tumors. A significant therapeutic challenge with either ICIs or PARP inhibitors as monotherapy is treatment failure from intrinsic primary resistance or the development of secondarily acquired resistance after a period of responsiveness. The combination of PARP inhibitors and ICIs could mitigate this by potentiating treatment response. We describe an 83-year-old male patient who initially presented with abdominal pain, and weight loss along with alternating constipation and diarrhea. Imaging and biopsy revealed metastatic esophageal adenocarcinoma. Genomic testing revealed germline BRCA2 mutation. The patient initially underwent a few cycles of chemoimmunotherapy. However, due to intolerance to chemotherapy, the patient’s case was discussed at a multidisciplinary molecular tumor board. He was switched to PARP inhibitor olaparib and ICI nivolumab. This combination led to a durable complete response. A combination of poly-ADP ribose polymerase inhibitor (PARPi) plus ICI may work in synergy through various mechanisms including enhanced neoantigen expression, release of immune-activating cytokines, and increased programmed death-ligand 1 expression. This may culminate in accentuated efficacy outcomes with a manageable safety profile. This exceptional response with ICI and PARPi in our case is consistent with the synergistic value of this combination, and prospective studies are warranted to definitively characterize clinical utility.

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Combined PARP inhibitors and small molecular inhibitors in solid tumor treatment (Review)

Cited by 8 publications

References 185 publications

Oncogenic STAT Transcription Factors as Targets for Cancer Therapy: Innovative Strategies and Clinical Translation

Oncogenic STAT Transcription Factors as Targets for Cancer Therapy: Innovative Strategies and Clinical Translation

Histone and DNA Methylation as Epigenetic Regulators of DNA Damage Repair in Gastric Cancer and Emerging Therapeutic Opportunities

Exceptional synergistic response of PARP inhibitor and immune checkpoint inhibitor in esophageal adenocarcinoma with a germline BRCA2 mutation: a case report

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