RBN-2397, a PARP7 Inhibitor, Synergizes with Paclitaxel to Inhibit Proliferation and Migration of Ovarian Cancer Cells.

Objectives: Mono(ADP-ribosyl)ation (MARylation), a post translational modification of proteins, is emerging as an important regulator of the biology of cancer cells. PARP7 (TiPARP), a mono (ADP-ribosyl) transferase (MART), MARylates its substrate α-tubulin in ovarian cancer cells, promoting destabilization of microtubules, cell growth, and migration. Recent development of RBN-2397, a potent inhibitor that selectively acts on PARP7, has provided a new tool for exploring the role of PARP7 catalytic activity in biological processes. In this study, we investigated the role of PARP7 catalytic activity in the regulation of ovarian cancer cell biology via MARylation of α-tubulin. Methods: Ovarian cancer cell lines (OVCAR4, OVCAR3) were treated with RBN-2397 and paclitaxel, both separately and in combination. Western blotting and immunoprecipitation confirmed the effects of RBN-2397 on α-tubulin MARylation and stabilization. Cell proliferation and migration were assessed, and α-tubulin stabilization was quantified using immunofluorescent imaging. RNA-sequencing was performed to assess the effects on gene expression changes. Results: RBN-2397 inhibited PARP7 activity, decreasing α-tubulin MARylation, leading to its stabilization, and reducing cancer cell proliferation and migration. The addition of paclitaxel further enhanced these effects, highlighting a synergistic interaction between the two drugs. Mutating the site of PARP7-mediated MARylation on α-tubulin similarly resulted in microtubule stabilization and decreased cell migration in the presence of paclitaxel. Conclusions: This study demonstrates that targeting PARP7 with RBN-2397, particularly in combination with paclitaxel, offers an effective strategy for inhibiting aggressive ovarian cancer cell phenotypes. Our findings underscore the potential of combining PARP7 inhibitors with established chemotherapeutics to enhance treatment efficacy in ovarian cancer.

Predicting VTE and utility of thromboprophylaxis in metastatic and recurrent cervical cancer.

OBJECTIVE: Patients with cervical cancer who are diagnosed with venous thromboembolism (VTE) have worse outcomes compared to those not affected. There has yet to be a reliable method to predict or prevent VTE in cervical cancer patients. Our objective is to describe the incidence of VTE in patients with recurrent and metastatic (r/mCC) and determine risk factors that may predict VTE in this setting. METHODS: We performed an observational cohort study of 386 patients with r/mCC who received at least one line of systemic chemotherapy. We collected demographic, clinical, histologic data and Khorana scores for all patients. Inclusion and exclusion criteria were applied before analysis. Statistical analysis was performed using Pearson chi-square, Student's t-test, and Wilcoxon rank-sum. RESULTS: 232 patients were included for evaluation. Mean age was 49 years (range 20-83). The majority (167, 72%) of patients had squamous cell histology. 169 (72.8%) patients received treatment for recurrent disease and 63 (27.2%) for metastatic, stage IVB disease. 180 (78%) patients received prior radiation and 134 (58%) received bevacizumab. VTE was diagnosed in 89 (38%) patients. There were no statistically significant differences amongst clinical and pathologic characteristics between patients who developed VTE and those who did not. There was no significant association between BMI, Khorana score, radiation, bevacizumab, or immunotherapy and the development of VTE. CONCLUSION: Approximately 40% of patients with r/mCC experienced a new VTE. There were no independent risk factors that could predict VTE in this population. Due to the overwhelmingly high incidence of VTE, prophylactic anticoagulation could be strongly considered in patients with r/mCC.

Pembrolizumab plus lenvatinib combination therapy for advanced endometrial carcinoma.

INTRODUCTION: Advanced and recurrent endometrial carcinoma remains a difficult diagnosis to treat due to the limited and ineffective available treatment options following platinum and taxane chemotherapy. Patients who are microsatellite stable (MSS) or mismatch repair proficient (pMMR) have even poorer outcomes with fewer effective therapies. Fortunately, recent Phase Ib/II and Phase III trials have demonstrated that combination pembrolizumab and lenvatinib resulted in improved ORR, PFS, and OS than currently used therapies in this setting. AREAS COVERED: In this article, we review the history and notable clinical trials responsible for the advancement and status of treatment options available for advanced endometrial cancer. Most importantly, we review the recently published data on the efficacy, safety, and tolerability of the combination pembrolizumab and lenvatinib in advanced and recurrent endometrial cancer. EXPERT OPINION: The combination pembrolizumab and lenvatinib is an effective treatment regimen for patients with advanced and recurrent endometrial cancer who are MSS or pMMR who have failed prior platinum-based treatment. This combination should be routinely offered to patients following progression or recurrence of systemic platinum and taxane chemotherapy. Although this regimen is safe and effective, clinicians should be aware of the known toxicities and assess patients regularly to determine if dose modifications or interruptions are indicated.