Combination Of PARP Inhibitors Research Articles

In Vivo Efficacy Testing of Peptide Receptor Radionuclide Therapy Radiosensitization Using Olaparib.

Peptide receptor radionuclide therapy (PRRT), a form of internal targeted radiation treatment using [177Lu]Lu [DOTA0-Tyr3]octreotate, is used to treat patients with metastasized neuroendocrine tumors (NETs). Even though PRRT is now the second line of treatment for patients with metastasized NETs, the majority of patients will not be cured by the treatment. PRRT functions by inducing DNA damage upon radioactive decay and inhibition of DNA damage repair proteins could therefore be used as a strategy to potentiate PRRT. Previous work has shown promising results on the combination of PRRT with the PARP inhibitor olaparib in cell lines and mice and we have been taken the next step for further in vivo validation using two different xenografted mouse models. We observed that this combination therapy resulted in increased therapeutic efficacy only in one model and not the other. Overall, our findings indicate a tumor-type dependent anti-tumor response to the combination of PRRT and olaparib. These data emphasize the unmet need for the molecular stratification of tumors to predetermine the potential clinical value of combining PARP inhibition with PRRT.

Pharmacological effects of Niraparib and its combination with angiogenic inhibitor in ovarian cancer.

Background: Ovarian cancer (OC) represents the seventh most lethal female tumors worldwide. The combination of PARP inhibitor (PARPi) and angiogenic inhibitor has been shown to be effective as a first-line or second-line maintenance regimen to synergistically exert antitumor effects, which prompts us to further evaluate the therapeutic effect of the combination of PARP inhibitor Niraparib and anti-angiogenic Brivanib on OC. Method:3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay were applied to evaluate the anti-proliferative effect of Niraparib, Brivanib, or the combination treatment on OC cells. The Annexin V-FITC/PI apoptotic assay was adopted to detect cell apoptosis. Tumor xenograft experiment and immunohistochemical (IHC) analysis were performed to evaluate the effect of single or combination treatment on the tumorigenicity of OC in vivo. Results: Our current findings revealed that OC cells harboring BRAC1/2 mutations were more sensitive to Niraparib treatment compared to those with BRAC wild-type, and the addition of Brivanib enhanced programmed cell death (PCD) to sensitize OC cells with BRAC mutations to Niraparib treatment in vitro and in vivo. Conclusion: Our work illustrates that the combination regimen of PARPi and angiogenic inhibitor treatment should be beneficial for the OC patients with BRAC mutations, at least partially owing to the induction of multiple forms of programmed cell death (PCD).

Combining Poly (ADP-Ribose) Polymerase (PARP) Inhibitors with Chemotherapeutic Agents: Promise and Challenges.

Better understanding of molecular drivers and dysregulated pathways has furthered the concept of precision oncology and rational drug development. The role of DNA damage response (DDR) pathways has been extensively studied in carcinogenesis and as potential therapeutic targets to improve response to chemotherapy or overcome resistance. Treatment with small molecule inhibitors of PARP has resulted in clinical response and conferred survival benefit to patients with ovarian cancer, BRCA-mutant breast cancer, HRD-deficient prostate cancer and BRCA-mutant pancreatic cancer, leading to US Food and Drug Administration (FDA) approvals. However, the observed clinical benefit with single agent PARP inhibitors is limited to few tumor types within the relevant genetic context. Since DDR pathways are essential for repair of damage caused by cytotoxic agents, PARP inhibitors have been evaluated in combination with various chemotherapeutic agents to broaden the therapeutic application of this class of drugs. In this chapter, we discuss the combination of PARP inhibitors with different chemotherapeutics agents, clinical experience to date, lessons learnt, and future directions for this approach.

Combining PARP Inhibition and Immunotherapy in BRCA-Associated Cancers.

Poly (ADP-ribose) polymerase (PARP) inhibitors have significantly improved treatment outcomes of homologous recombination (HR) repair-deficient cancers. While the activity of these agents is largely linked to multiple mechanisms underlying the synthetic lethality of PARP inhibition and HR deficiency, emerging data suggest that their efficacy is also tied to their effects on the immune microenvironment and dependent upon cytotoxic T-cell activation. Effects observed in preclinical models are currently being validated in on-treatment biopsy samples procured from patients enrolled in clinical trials. Although this work has stimulated the development of combinations of PARP inhibitors with immunomodulatory agents, results to date have not demonstrated the superiority of combined PARP inhibition and immune checkpoint blockade compared with PARP inhibition alone. These results have stimulated a more comprehensive assessment of the immunosuppressive components of the tumor microenvironment that must be addressed so that the efficacy of PARP inhibitor agents can be maximized.

The role of PARP inhibitor combination therapy in ovarian cancer.

The use of PARP inhibitors (PARPi) has transformed the care of advanced high-grade serous/endometrioid ovarian cancer. PARPi are now available to patients in both the first-line and recurrent platinum-sensitive disease settings; therefore, most patients will receive PARPi at some point in their treatment pathway. The majority of this expanding population of patients eventually acquire resistance to PARPi, in addition to those with primary PARPi resistance. We discuss the rationale behind developing combination therapies, to work synergistically with PARPi and overcome mechanisms of resistance to restore drug sensitivity, and clinical evidence of their efficacy to date.

Natural phytochemicals prevent side effects in BRCA-mutated ovarian cancer and PARP inhibitor treatment.

Ovarian cancer is among the most common malignant tumors in gynecology and is characterized by insidious onset, poor differentiation, high malignancy, and a high recurrence rate. Numerous studies have shown that poly ADP-ribose polymerase (PARP) inhibitors can improve progression-free survival (PFS) in patients with BRCA-mutated ovarian cancer. With the widespread use of BRCA mutation and PARP inhibitor (PARPi) combination therapy, the side effects associated with BRCA mutation and PARPi have garnered attention worldwide. Mutations in the BRCA gene increase KEAP1-NRF2 ubiquitination and reduce Nrf2 content and cellular antioxidant capacity, which subsequently produces side effects such as cardiovascular endothelial damage and atherosclerosis. PARPi has hematologic toxicity, producing thrombocytopenia, fatigue, nausea, and vomiting. These side effects not only reduce patients' quality of life, but also affect their survival. Studies have shown that natural phytochemicals, a class of compounds with antitumor potential, can effectively prevent and treat the side effects of chemotherapy. Herein, we reviewed the role of natural phytochemicals in disease prevention and treatment in recent years, including sulforaphane, lycopene, catechin, and curcumin, and found that these phytochemicals have significant alleviating effects on atherosclerosis, nausea, and vomiting. Moreover, these mechanisms of action significantly correlated with the side-effect-producing mechanisms of BRCA mutations and PARPi. In conclusion, natural phytochemicals may be effective in alleviating the side effects of BRCA mutant ovarian cancer cells and PARP inhibitors.

Abstract B030: Combined inhibition of BET proteins and PARP promotes impaired DNA damage repair response and cell cycle dysregulation in preclinical models of bladder cancer

Abstract Background: Bladder cancer (BC) remains a common and deadly malignancy, with a projected 81,180 new diagnoses and 17,100 deaths in the United States in 2022. According to the MSK/TCGA Bladder Cancer dataset, mutations in DNA damage response (DDR) genes that are part of the homologous recombination (HR) pathway occurred in up to 55% of patients, representing a potential therapeutic target in BC. In previous work, we used UNC’s EpiG Diamond compound library to show that, as a class, inhibition of the methyl-lysine reader bromodomain and extra-terminal domain (BET) proteins potently abrogate BC cell line viability. Here, we evaluated mechanisms related to HR inhibition that could explain pan-BET inhibitor OTX-015’s potency in BC. Methods: 5637 and J82 BC cells were treated with 1 µM OTX-015 or 0.1% DMSO control for 48-hours, total RNA was extracted, and then bulk RNA-sequencing (RNA-seq) was performed on an Illumina NovaSeq 6000 (Novogene, Sacramento, CA). Expression data was analyzed using Geneious Prime v2022.2.1 (Biomatters, San Diego, CA). Cells were then treated with 1 μM OTX-015, 5 μM of the PARP inhibitor olaparib, or combination for gene and protein expression analysis. Gene expression changes in BRCA1, BRCA2, PALB2, and RAD51, as well as MYC as a positive control, were confirmed by RT-PCR in biological triplicates after 48-hour incubation, normalized to an SDHA housekeeper and compared to a 0.1% DMSO control. Western blotting evaluated OTX-015 and olaparib effects on BRCA1, BRCA2, c-MYC, PALB2, and RAD51 protein expression after 72-hour incubation, using a GAPDH loading control and compared to a 0.1% DMSO control. Last, cells were treated with the same treatment schema for 24-72 hours, fixed with methanol, stained with propidium iodide (25 μg/mL), and flow cytometry evaluated effects on cell cycle using a ThermoFisher Attune NxT and FlowJo v10.8.1 (BD Life Sciences, Ashland, OR). Results: Bulk RNA-seq analyses revealed significantly altered expression of HR pathway genes in 5637 and J82 cells treated with OTX-015±olaparib. In 5637 cells, OTX-015 alone significantly reduced BRCA1, BRCA2, PALB2 and RAD51 expression, (n=3; P<0.001 for all), but only PALB2 and RAD51 expression was significantly reduced after combination treatment (n=3; P<0.001 for both). In J82 cells, OTX-015 alone and combination treatment significantly reduced BRCA1, PALB2 and RAD51 expression, (n=3; P<0.001 for all). Similarly, both OTX-015 and combination treatment resulted in reduced BRCA1, c-MYC, PALB2 and RAD51 protein expression in both cell lines. In both cell lines, combination treatment resulted in a substantially increased G2/M fraction at 48 hours compared to 0.1% DMSO (5637 cells: 62.9% vs 12.6% G2/M; J82 cells: 28.2% vs 17.8% G2/M). Conclusions: These data indicate that OTX-015-mediated inhibition of RAD51 and PALB2 could be responsible for impaired HR. Cell cycle data revealed a G2/M stall, rather than an S phase stall, suggesting mechanisms independent from impaired HR could be responsible for cell cycle dysregulation. Citation Format: Ryan M. Kemper, Manfred Meng, Daniel J. Crona. Combined inhibition of BET proteins and PARP promotes impaired DNA damage repair response and cell cycle dysregulation in preclinical models of bladder cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B030.

Clinical Application of Poly(ADP-ribose) Polymerase (PARP) Inhibitors in Prostate Cancer.

Approximately a quarter of men with metastatic castrate resistant prostate cancer (mCRPC) have alterations in homologous recombination repair (HRR). These patients exhibit enhanced sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Leveraging the synthetic lethality between PARP inhibition and HRR deficiency, studies have established marked clinical benefit and a survival advantage from PARP inhibitors (PARPi) in mCRPC, most notably in cancers with BRCA1/2 alterations. The role of PARPi is evolving beyond patients with HRR alterations, with studies increasingly focused on exploiting synergistic effects from combination therapeutics. Strategies combining PARP inhibitors with androgen receptor pathway inhibitors, radiation, radioligand therapy, chemotherapy and immunotherapy demonstrate potential additional benefits in mCRPC and these approaches are rapidly moving into the metastatic hormone sensitive treatment paradigm. In this review we summarise the development and expanding role of PARPi in prostate cancer including biomarkers of response, the relationship between the androgen receptor and PARP, evidence for combination therapeutics and the future directions of PARPi in precision medicine for prostate cancer.

TALASUR trial: a single arm phase II trial assessing efficacy and safety of TALazoparib and Avelumab as maintenance therapy in platinum-Sensitive metastatic or locally advanced URothelial carcinoma

BackgroundUrothelial carcinoma (UC) is the ninth most commonly diagnosed cancer worldwide, with a 3.8/1 male to female ratio. Platinum-based chemotherapy is the first line standard of care for fit patients with advanced UC. However, despite a response rate (RR) for approximately half of patients receiving standard chemotherapy, durable responses are rare (median progression-free progression (PFS) around 8 months). Recently, immune checkpoint inhibitors (ICI) have emerged as new therapeutic options. Among them, Avelumab, an anti-PD-L1 antibody, was assessed in maintenance treatment, demonstrating an overall survival improvement in the JAVELIN Bladder-100 phase III trial. These findings led to its approval as first line maintenance therapy for patients with locally advanced or metastatic UC who have not progressed on prior platinum-containing chemotherapy. However, disease progression as best response was noticed for 37% of patients under Avelumab as maintenance treatment.UC has targetable genomic alterations, including DNA damage repair (DDR) alterations. DDR deficiency is known to major sensitivity to both platinum-based chemotherapy and PD-1/PD-L1 blockade and the combination of ICI and PARP inhibitors showed promising results. It therefore warrants to assess the interest of combining ICI plus PARP inhibitors as maintenance treatment in UC patients.MethodsThe TALASUR trial is a single-arm multicenter phase 2 study aiming to assess the antitumor activity of the combination of Avelumab with Talazoparib among patients with locally advanced/metastatic UC in maintenance therapy after platinum-based chemotherapy.The primary objective is to determine the efficacy of the combination, assessed through PFS. Secondary objectives are as follows: safety profile of the association, objective response, duration of tumoral response, disease control rate, time to subsequent therapy, quality of life. A blood and tumor collections will be also constituted.Patient will receive the combination therapy of daily oral Talazoparib (1 mg/day) and intra-venous Avelumab 800 mg on days 1 and 15, in a 28-day cycle. Fifty patients will be enrolled.DiscussionTalazoparib with Avelumab combination may have additive activity when administrated jointly. We hypothesize that combination will increase the antitumor activity in UC first line maintenance setting with an acceptable safety profile.Trial registrationNCT04678362, registered December 21, 2020. Protocol version: Version 1.3 dated from 2020 09 11.

TRAIL Receptor Targeting Agents Potentiate PARP Inhibitor Efficacy in Pancreatic Cancer Independently of BRCA2 Mutation Status.

Chemotherapy, the standard treatment for pancreatic ductal adenocarcinoma (PDAC), has only a modest effect on the outcome of patients with late-stage disease. Investigations of the genetic features of PDAC have demonstrated a frequent occurrence of mutations in genes involved in homologous recombination (HR), especially in the breast cancer susceptibility gene 2 (BRCA2). Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved as a maintenance treatment for patients with advanced PDAC with germline BRCA1/2 mutations following a platinum-containing first-line regimen. Limitations to the use of PARP inhibitors are represented by the relatively small proportion of patients with mutations in BRCA1/2 genes and the modest capability of these substances of inducing objective response. We have previously shown that pancreatic cancer with BRCA2 mutations exhibits a remarkably enhanced sensitivity towards tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) receptor-stimulating agents. We thus aimed to investigate the effect of combined treatment with PARP inhibitors and TRAIL receptor-stimulating agents in pancreatic cancer and its dependency on the BRCA2 gene status. The respective effects of TRAIL-targeting agents and the PARP inhibitor olaparib or of their combination were assessed in pancreatic cancer cell lines and patient-derived organoids. In addition, BRCA2-knockout and -complementation models were investigated. The effects of these agents on apoptosis, DNA damage, cell cycle, and receptor surface expression were assessed by immunofluorescence, Western blot, and flow cytometry. PARP inhibition and TRAIL synergized to cause cell death in pancreatic cancer cell lines and PDAC organoids. This effect proved independent of BRCA2 gene status in three independent models. Olaparib and TRAIL in combination caused a detectable increase in DNA damage and a concentration-dependent cell cycle arrest in the G2/M and S cell cycle phases. Olaparib also significantly increased the proportion of membrane-bound death receptor 5. Our results provide a preclinical rationale for the combination of PARP inhibitors and TRAIL receptor agonists for the treatment of pancreatic cancer and suggest that the use of PARP inhibitors could be extended to patients without BRCA2 mutations if used in combination with TRAIL agonists.

Combined inhibition of PARP and EZH2 for cancer treatment: Current status, opportunities, and challenges

Tumors with BRCA1/2 mutations or homologous recombination repair defects are sensitive to PARP inhibitors through the mechanism of synthetic lethality. Several PARP inhibitors are currently approved for ovarian, breast and pancreatic cancer in clinical practice. However, more than 40% of patients with BRCA1/2 mutations are insensitive to PARP inhibitors, which has aroused attention to the mechanism of PARP resistance and sensitization schemes. PARP inhibitor resistance is related to homologous recombination repair, stability of DNA replication forks, PARylation and epigenetic modification. Studies on epigenetics have become the hotspots of research on PARP inhibitor resistance. As an important epigenetic regulator of transcription mediated by histone methylation, EZH2 interacts with PARP through DNA homologous recombination, DNA replication, posttranslational modification, tumor immunity and other aspects. EZH2 inhibitors have been just shifting from the bench to the bedside, but the combination scheme in cancer therapy has not been fully explored yet. Recently, a revolutionary drug design combining PARP inhibitors and EZH2 inhibitors based on PROTAC techniques has shed light on the resolution of PARP inhibitor resistance. This review summarizes the interactions between EZH2 and PARP, suggests the potential PARP inhibitor sensitization effect of EZH2 inhibitors, and further discusses the potential populations that benefit from the combination of EZH2 inhibitors and PARP inhibitors.

151 (PB031) - Combination therapy with decitabine and olaparib in poly(ADP-ribose) polymerase inhibitor (PARPi) resistant high grade serous ovarian cancer

Background: Recurrent high grade serous ovarian cancer (HGSOC) is incurable and lethal. Therefore, novel drug combinations are critically needed for this patient population. DNA methyltransferase inhibitors (DNMTi) can cause DNA damage, which activates poly(ADP-ribose) polymerase (PARP) and leads to PARP trapping. Additionally, DNMTi are incorporated into replicating DNA, which causes DNMT-DNA adducts that are then degraded. Therefore, the novel drug combination of DNMTi decitabine and PARP inhibitor (PARPi) olaparib were tested in preclinical HGSOC models.

Recent advances in cancer therapy using PARP inhibitors.

When DNA repair is inadequate it increases the chances of the genome becoming unstable and it undergoes a malignant mutation. The deficiency of DNA repair PARP proteins may be leveraged for cancer therapy by increasing genomic instability and causing massive DNA damage in cancer cells. DNA repair components are under increased demand in cancer cells because of the continuous replication of DNA. The oncogenic loss of BRCA and an inefficient DNA repair led to cancer cells being dependent on particular DNA repair pathways, like the Poly (ADP-ribose) polymerase pathway. Breast cancer gene 1 and 2 plays a crucial role in DNA repair and genome integrity explaining how BRCA1 and BRCA2 mutations raise the menace of cancer. PARP inhibitors inhibit the base exclusion repair pathway, resulting in the buildup of unrepaired single strand breaks, which cause inflated replication forks in the S phase and subsequently the development of damaging double stranded breaks. Cells having BRCA mutations are unable to repair DNA breaks, leading to apoptosis and eventually death of cancer cells. Numerous indicators, such as a lack of homologous recombination and a high degree of replication pressure, indicate that this therapy will be very effective. Combining PARP inhibitors with chemotherapy, an immune checkpoint inhibitor, and a targeted drug is an effective strategy for combating PARP inhibitors resistance. Several PARP-based combination approaches are in preclinical and clinical development. Various clinical trials are successfully completed and some are undergoing to evaluate the efficacy of these molecules. This review will describe the current views and clinical updates on PARP inhibitors.

METTL16 antagonizes MRE11-mediated DNA end resection and confers synthetic lethality to PARP inhibition in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Characterization of genetic alterations will improve our understanding and therapies for this disease. Here, we report that PDAC with elevated expression of METTL16, one of the 'writers' of RNA N6-methyladenosine modification, may benefit from poly-(ADP-ribose)-polymerase inhibitor (PARPi) treatment. Mechanistically, METTL16 interacts with MRE11 through RNA and this interaction inhibits MRE11's exonuclease activity in a methyltransferase-independent manner, thereby repressing DNA end resection. Upon DNA damage, ATM phosphorylates METTL16 resulting in a conformational change and autoinhibition of its RNA binding. This dissociates the METTL16-RNA-MRE11 complex and releases inhibition of MRE11. Concordantly, PDAC cells with high METTL16 expression show increased sensitivity to PARPi, especially when combined with gemcitabine. Thus, our findings reveal a role for METTL16 in homologous recombination repair and suggest that a combination of PARPi with gemcitabine could be an effective treatment strategy for PDAC with elevated METTL16 expression.

Targeting Krebs-cycle-deficient renal cell carcinoma with Poly ADP-ribose polymerase inhibitors and low-dose alkylating chemotherapy.

Loss-of-function mutations in genes encoding the Krebs cycle enzymes Fumarate Hydratase (FH) and Succinate Dehydrogenase (SDH) induce accumulation of fumarate and succinate, respectively and predispose patients to hereditary cancer syndromes including the development of aggressive renal cell carcinoma (RCC). Fumarate and succinate competitively inhibit αKG-dependent dioxygenases, including Lysine-specific demethylase 4A/B (KDM4A/B), leading to suppression of the homologous recombination (HR) DNA repair pathway. In this study, we have developed new syngeneic Fh1- and Sdhb-deficient murine models of RCC, which demonstrate the expected accumulation of fumarate and succinate, alterations in the transcriptomic and methylation profile, and an increase in unresolved DNA double-strand breaks (DSBs). The efficacy of poly ADP-ribose polymerase inhibitors (PARPis) and temozolomide (TMZ), alone and in combination, was evaluated both in vitro and in vivo. Combination treatment with PARPi and TMZ results in marked in vitro cytotoxicity in Fh1- and Sdhb-deficient cells. In vivo, treatment with standard dosing of the PARP inhibitor BGB-290 and low-dose TMZ significantly inhibits tumor growth without a significant increase in toxicity. These findings provide the basis for a novel therapeutic strategy exploiting HR deficiency in FH and SDH-deficient RCC with combined PARP inhibition and low-dose alkylating chemotherapy.

1672P Tumor and immune cell dynamics at single-cell resolution on combined PARP inhibition and anti-PD-L1 therapy

Poly (ADP-ribose) polymerase inhibitors (PARPi) have immunomodulatory properties, which may enhance anti-PD-(L)1 therapy efficacy. However, the exact immunomodulatory mechanism is still debated. To explore this, we performed single-cell RNA and T cell receptor sequencing (scRNA + scTCR-seq) on sequential tumor biopsies collected at three timepoints in the ARIANES academic phase II basket trial, associating the PARPi rucaparib (R) to the anti-PD-L1 atezolizumab (A), in patients (pts) with DNA repair-deficient tumors.

Antiproliferative Effects of EGFR inhibitor Cetuximab and PARP Inhibitor Combination on Non-Small Cell Lung Cancer Cell Line A549 and Cervical Cancer Cell Line HeLa.

In this study, the efficacy of Cetuximab and Parp inhibitor (Parp 1 inhibitor) used in targeted therapies, alone or in combination, on non-small cell lung cancer cell line A549 and cervical cancer cell line HeLa cells were evaluated. For this purpose different cell kinetic parameters were used. Cell viability, mitotic index, BrdU labelling index and apoptotic index were evaluated in experiments. In single applications Cetuximab at concentrations ranging from 1 mg/ml to 10 mg/ml and Parp inhibitor at concentrations 5 µM -7 µM - 10 µM were applied. IC50 concentration of Cetuximab for A549 was 1 mg/ml, the IC50 concentration of Cetuximab for HeLa was 2 mg/ml, the IC50 concentration of Parp inhibitor for A549 was 5 µM, and the IC50 concentration of Parp inhibitor for HeLa was 7 µM. In both single and combinations, there was a significant decrease in cell viability, mitotic index, BrdU labelling index and there was a significant increase in apoptotic index. A comparison of cetuximab, PARPi and combination applications showed the superiority of combined applications over single applications in all cell kinetic parameters used.

PARP inhibitor resistance in breast and gynecological cancer: Resistance mechanisms and combination therapy strategies.

Breast cancer and gynecological tumors seriously endanger women’s physical and mental health, fertility, and quality of life. Due to standardized surgical treatment, chemotherapy, and radiotherapy, the prognosis and overall survival of cancer patients have improved compared to earlier, but the management of advanced disease still faces great challenges. Recently, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) have been clinically approved for breast and gynecological cancer patients, significantly improving their quality of life, especially of patients with BRCA1/2 mutations. However, drug resistance faced by PARPi therapy has hindered its clinical promotion. Therefore, developing new drug strategies to resensitize cancers affecting women to PARPi therapy is the direction of our future research. Currently, the effects of PARPi in combination with other drugs to overcome drug resistance are being studied. In this article, we review the mechanisms of PARPi resistance and summarize the current combination of clinical trials that can improve its resistance, with a view to identify the best clinical treatment to save the lives of patients.

Emerging Role of PARP Inhibitors in Metastatic Prostate Cancer.

We highlight the clinical development of Poly (ADP-Ribose) polymerase (PARP) inhibitors in prostate cancer. Approximately 10 to 30% of metastatic prostate cancer patients carry germline or somatic mutations in DNA repair pathways. BRCA2 is the most commonly mutated gene in DNA damage repair pathways. Because of its critical function in homologous recombination repair (HRR) machinery, deleterious BRCA2 mutation enables synthetic lethality to a PARP inhibitor. Olaparib demonstrated clinical benefit in patients with deleterious mutations in HRR-related genes and most clearly in patients with BRCA2 mutations. Olaparib received the US FDA approval or mCRPC patients with a qualifying HRR gene mutation in May 2020. Rucaparib received an accelerated FDA approval for patients with BRCA1- or BRCA2-mutated mCRPC based on 43% objective response rate in a phase II study. To expand the application of a PARP inhibitor, several trials have evaluated various combination strategies with an androgen receptor signaling inhibitor, immunotherapy, radium-223, and others. While no PARP inhibitor combination regimen has been approved, promising data from a PARP inhibitor and an ASI combination have been reported. PARP inhibitor represents a standard treatment for patient with mCRPC with germline or somatic mutations in BRCA2 and other HRR pathway genes.

Combined inhibition of BADSer99 phosphorylation and PARP ablates models of recurrent ovarian carcinoma

BackgroundPoly (ADP-ribose) polymerase inhibitors (PARPis) have been approved for the treatment of recurrent epithelial ovarian cancer (EOC), regardless of BRCA status or homologous recombination repair deficiency. However, the low response of platinum-resistant EOC, the emergence of resistance in BRCA-deficient cancer, and therapy-associated toxicities in patients limit the clinical utility of PARPis in recurrent EOC.MethodsThe association of phosphorylated (p) BADS99 with clinicopathological parameters and survival outcomes in an EOC cohort was assessed by immunohistochemistry. The therapeutic synergy, and mechanisms thereof, between a pBADS99 inhibitor and PARPis in EOC was determined in vitro and in vivo using cell line and patient-derived models.ResultsA positive correlation between pBADS99 in EOC with higher disease stage and poorer survival is observed. Increased pBADS99 in EOC cells is significantly associated with BRCA-deficiency and decreased Cisplatin or Olaparib sensitivity. Pharmacological inhibition of pBADS99 synergizes with PARPis to enhance PARPi IC50 and decreases survival, foci formation, and growth in ex vivo culture of EOC cells and patient-derived organoids (PDOs). Combined inhibition of pBADS99 and PARP in EOC cells or PDOs enhances DNA damage but impairs PARPi stimulated DNA repair with a consequent increase in apoptosis. Inhibition of BADS99 phosphorylation synergizes with Olaparib to suppress the xenograft growth of platinum-sensitive and resistant EOC. Combined pBADS99-PARP inhibition produces a complete response in a PDX derived from a patient with metastatic and chemoresistant EOC.ConclusionsA rational and efficacious combination strategy involving combined inhibition of pBADS99 and PARP for the treatment of recurrent EOC is presented.