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Open research questions in PARP inhibition in cancer therapy

30 unresolved questions extracted from the limitations and future-work sections of 127 PARP inhibition in cancer therapy papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • ConclusionsOur findings establish that NFV synergizes with CDDP in killing Pt-resistant ovarian cancer cells by promoting a caspase-8-dependent apoptotic-to-secondary pyroptotic response, supporting further investigation of NFV as a potential drug to be repurposed to increase the efficacy of Pt-based therapy.

    The combination of nelfinavir and cisplatin drives lytic cell death through a caspase-8/caspase-3/GSDME axis in platinum-resistant ovarian cancer cells · 2026 · DOI

  • Abstract Schlafen 5 (SLFN5) is an important regulator of Type I interferon (IFN-I) signaling and tumorigenesis, yet the structural basis for its biologic activity remains unclear.

    SLFN5 restrains type I interferon responses and promotes glioblastoma via its N-terminal Schlafen core domain · 2026 · DOI

  • However, further investigation is warranted to confirm (a) whether PARP1 can be specifically and effec- tively targeted across ARDs, with therapeutic benefit; and (b) whether other PARP family members have overlapping roles with PARP1 in inflammation and immunity.

    PARP1 as a novel therapeutic and diagnostic tool in autoimmune rheumatic diseases: a systematic literature review · 2026 · DOI

  • As the first SLR to consider the role of PARP1 and PARPs more broadly in ARDs, our review substantially adds to the literature on novel therapeutic strategies and diagnostic tools for people with ARDs, while synthesising the existing evidence. The broad search strategy employed in this SLR ensured capture of all relevant articles. Inclusion of both human and animal studies facilitated a thorough review of existing and potential future applications of the role of PARP1 in ARDs. However, our SLR has several limitations. Firstly, there was a high degree of heterogeneity with respect to study design, model systems, and outcomes assessed. As described in the Cochrane Handbook [27], variability in study populations, interventions, outcomes, and method- ological approaches represents important sources of clinical and methodological heterogeneity that may limit compara- bility across studies. This methodological diversity also pre- cluded quantitative synthesis. Consequently, a quantitative meta-analysis was not considered appropriate and findings were synthesised narratively. Although the review followed established systematic review principles, formal risk-of- bias tools were not uniformly applicable because of the Page 9 of 13 138 broad inclusion of mechanistic, translational and preclini- cal studies. Secondly, much of the evidence was derived from preclinical or mechanistic studies rather than clinical investigations, so conclusions regarding the translational relevance and therapeutic efficacy in people with ARDs are limited and may warrant further investigation. Many experi- mental studies also employed different dosing strategies and outcome measures, further making it difficult to determine class effects or establish consistent mechanistic pathways. Thirdly, sample sizes in human studies were small and often focused on specific populations or ethnic cohorts, limit- ing generalisability. Genetic association findings were also inconsistent across populations, reflecting the complex and multifactorial genetic architecture of ARDs. Finally, the topic under study is at risk of publication bias, since posi- tive mechanistic findings are more likely to be published than negative or neutral results.

    PARP1 as a novel therapeutic and diagnostic tool in autoimmune rheumatic diseases: a systematic literature review · 2026 · DOI

  • The advancement of chemotherapy in breast cancer is moving toward personalization rather than abandonment. Chemotherapy will likely remain essential for many patients, but its delivery is becoming more selective, adaptive, and biologically integrated. Future progress will depend on refining predictive markers, especially through multimodal approaches that combine genomic alterations, immune contexture, molecular subtyping, and dynamic biomarkers such as ctDNA. Better identification of true chemosensitive disease could minimize toxicity in low-benefit populations while enabling rational escalation in high-risk groups. At the same time, overcoming resistance will require moving beyond single-marker thinking. Resistance is rarely explained by one pathway alone; instead, it reflects evolving tumor ecosystems. Integrative profiling before, during, and after treatment may allow clinicians to identify emerging resistant clones and modify therapy accordingly. The neoadjuvant setting remains ideal for this research because it offers serial tissue access and direct assessment of response. Finally, future therapeutic strategies will likely blend chemotargeted agents, and posttherapy with immunotherapy, neoadjuvant residual disease–directed interventions.

    Breast cancer chemotherapy in transition: predictive markers, resistance mechanisms, and new treatment approaches · 2026 · DOI

  • The analysis does not examine biomarker-treatment interactions for Olaparib monotherapy versus combination therapy beyond BRCA and TP53 mutations. Prospective studies should evaluate whether estrogen receptor status, Ki67 proliferation index, and P16 expression modify the therapeutic benefit of Bevacizumab addition to Olaparib in primary HGSOC.

    Comparison of survival outcomes of Olaparib or Olaparib combine with Bevacizumab in patients with primary high-grade serous ovarian carcinoma · 2026 · DOI

  • The real-world setting comparison lacks stratification by platinum-free interval and prior platinum sensitivity status, which are critical determinants of maintenance therapy efficacy in primary HGSOC. Future comparative effectiveness studies should investigate whether the OS advantage of Olaparib plus Bevacizumab persists across platinum-sensitive versus platinum-resistant subgroups.

    Comparison of survival outcomes of Olaparib or Olaparib combine with Bevacizumab in patients with primary high-grade serous ovarian carcinoma · 2026 · DOI

  • The study identifies imbalances in key predictors of PARP inhibition response (such as HRD status and BRCA/TP53 mutation patterns) but does not establish how residual confounding from these imbalances affects the validity of OS and PFS comparisons between treatment arms in the unselected HGSOC population.

    Comparison of survival outcomes of Olaparib or Olaparib combine with Bevacizumab in patients with primary high-grade serous ovarian carcinoma · 2026 · DOI

  • The high proportion of unknown adverse event data in Table 3 (up to 26.67% for thrombocytopenia in the combination group) introduces confounding in safety comparisons between Olaparib monotherapy and Olaparib plus Bevacizumab. Future prospective studies should implement systematic adverse event classification protocols with complete ascertainment for hematologic and hepatotoxic outcomes.

    Comparison of survival outcomes of Olaparib or Olaparib combine with Bevacizumab in patients with primary high-grade serous ovarian carcinoma · 2026 · DOI

  • The multivariate Cox regression analysis was constrained by limited cohort size, which may reduce the robustness of adjustments for confounding variables in the BRCA-mutated and TP53-mutated patient subgroups. The study needs larger, well-annotated cohorts with comprehensive biomarker profiling to validate the observed OS advantages of Olaparib plus Bevacizumab in BRCA-positive patients.

    Comparison of survival outcomes of Olaparib or Olaparib combine with Bevacizumab in patients with primary high-grade serous ovarian carcinoma · 2026 · DOI

  • The ADP-ribosylhydrolase assay used NUDT5 as a background control for AMP generation, but the potential cross-reactivity or non-specific hydrolysis of ADPr-Ub conjugates by contaminating hydrolases in the recombinant protein preparations (S2A Fig) has not been addressed, potentially affecting specificity measurements.

    Specificity and recognition of the ADP-ribosyl-ubiquitin modification in the DNA damage response · 2026 · DOI

  • The DUB (deubiquitinase) panel testing in S2E Fig is mentioned but not detailed in the main text methods; the identity and activity of specific DUBs that can remove ubiquitin from ADP-ribosyl-ubiquitin modifications versus standard polyubiquitin chains needs systematic characterization to understand ADPr-Ub turnover in vivo.

    Specificity and recognition of the ADP-ribosyl-ubiquitin modification in the DNA damage response · 2026 · DOI

  • While RNF114, RNF125, RNF138, and RNF166 recruitment was measured via live-cell imaging at 240s post-irradiation, the temporal dynamics and stoichiometry of ADPr-Ub formation on endogenous chromatin substrates (beyond peptides) throughout the DNA damage response timeline remain unexplored.

    Specificity and recognition of the ADP-ribosyl-ubiquitin modification in the DNA damage response · 2026 · DOI

  • The DNA damage response experiments used only H2O2 (2 mM, 10 min) and olaparib treatments; the ADPr-Ub modification dynamics have not been characterized across other DNA damage types (ionizing radiation, UV, bleomycin) or PARP inhibitor doses to establish the generalizability of DTX2/DTX3L recruitment patterns.

    Specificity and recognition of the ADP-ribosyl-ubiquitin modification in the DNA damage response · 2026 · DOI

  • The study identified DTX2 and DTX3L as ubiquitin ligases that modify ADP-ribosylated peptides in vitro, but the specificity determinants distinguishing ADP-ribosyl-ubiquitin (ADPr-Ub) modification from standard ubiquitination on non-ADP-ribosylated substrates have not been systematically characterized using the RING-DTC domain variants.

    Specificity and recognition of the ADP-ribosyl-ubiquitin modification in the DNA damage response · 2026 · DOI

  • The hydrolytic assays for ADP-ribosylhydrolases were conducted using only 10 µM ADP-ribosylated substrates and 500 nM hydrolase concentrations; substrate concentration-dependent kinetics and enzyme saturation behavior for mono-ARHs proteins (TARG1, ARH1, PARP14 MD1) across physiologically relevant concentration ranges remain unmeasured.

    Specificity and recognition of the ADP-ribosyl-ubiquitin modification in the DNA damage response · 2026 · DOI

  • Chemotherapy remains the standard of care, yet acquired resistance is a critical barrier and the programs that establish and stabilize it are still poorly defined.

    Cisplatin-Induced Plasticity Drives Cross-Resistance to CDK4/6 Inhibitors and Reveals Targetable Vulnerabilities Through HDAC Inhibition in Esophageal Squamous Cell Carcinoma. · 2026 · DOI

  • Of the 235 tumors, 188 were classi- fied by CHORD as either HRD or HRP, while 47 tumors (20%) could not be determined.

    Comprehensive comparison of homologous recombination deficiency predictors in early-stage triple-negative breast cancer · 2026 · DOI

  • Although dose reduction is recommended for patients with moderate renal impairment in Western guidelines, standardized criteria have not been established in Japan, and real-world evidence on predictors of severe anemia is limited.

    Severe anemia as a risk factor in Japanese patients with ovarian cancer receiving olaparib: a retrospective study · 2026 · DOI

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30 open questions have been extracted from the limitations and future-work passages of 127 PARP inhibition in cancer therapy papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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