Wei Bao

Cisplatin-induced PANDAR-Chemo-EVs contribute to a more aggressive and chemoresistant ovarian cancer phenotype through the SRSF9-SIRT4/SIRT6 axis

We previously elucidated that long non-coding RNA Promoter of CDKN1A Antisense DNA damage Activated RNA (PANDAR) as a p53-dependent oncogene to promote cisplatin resistance in ovarian cancer (OC). Intriguingly, high level of p53-independent PANDAR was found in cisplatin-resistant patients with p53 mutation. Here, our study probed the new roles and the underlying mechanisms of PANDAR in p53-mutant OC cisplatin-resistance. A2780 and A2780-DDP cells were served as OC cisplatin-sensitive and cisplatin-resistant cells. HO-8910PM cells were subjected to construct chemotherapy-induced extracellular vesicles (Chemo-EVs). Transmission electron microscopy (TEM) and nanoparticle tracking analysis were employed to evaluate Chemo-EVs. Cell viability was assessed using cell counting kit-8 and colony formation assays. Cell apoptosis was assessed using Annexin V and propidium iodide staining. The relationships between PANDAR, serine and arginine-rich pre-mRNA splicing factor 9 (SRSF9) were verified by RNA immunoprecipitation and fluorescence in situ hybridization. Tumor xenograft experiment was employed to evaluate the effects of PANDAR-Chemo-EVs on OC cisplatin-resistance in vivo. Immunofluorescent staining and immunohistochemistry were performed in tumor tissue. PANDAR level increased in OC patients with p53-mutation. PANDAR efflux enacted via exosomes under cisplatin conditions. Additionally, exosomes from OC cell lines carried PANDAR, which significantly increased cell survival and chemoresistance in vitro and tumor progression and metastasis in vivo. During cisplatin-induced stress, SRSF9 was recruited to nuclear bodies by increased PANDAR and muted apoptosis in response to cisplatin. Besides, SRSF9 significantly increased the ratio of SIRT4/SIRT6 mRNA in OC. Cisplatin-induced exosomes transfer PANDAR and lead to a rapid adaptation of OC cell survival through accumulating SRSF9 following cisplatin stress exposure.

A phase II trial of cytoreductive surgery combined with niraparib maintenance in platinum-sensitive, secondary recurrent ovarian cancer: SGOG SOC-3 study

In China, secondary cytoreductive surgery (SCR) has been widely used in ovarian cancer (OC) over the past two decades. Although Gynecologic Oncology Group-0213 trial did not show its overall survival benefit in first relapsed patients, the questions on patient selection and effect of subsequent targeting therapy are still open. The preliminary data from our pre-SOC1 phase II study showed that selected patients with second relapse who never received SCR at recurrence may still benefit from surgery. Moreover, poly(ADP-ribose) polymerase inhibitors (PARPi) maintenance now has been a standard care for platinum sensitive relapsed OC. To our knowledge, no published or ongoing trial is trying to answer the question if patient can benefit from a potentially complete resection combined with PARPi maintenance in OC patients with secondary recurrence. SOC-3 is a multi-center, open, randomized, controlled, phase II trial of SCR followed by chemotherapy and niraparib maintenance vs chemotherapy and niraparib maintenance in patients with platinum-sensitive second relapsed OC who never received SCR at recurrence. To guarantee surgical quality, if the sites had no experience of participating in any OC-related surgical trials, the number of recurrent lesions evaluated by central-reviewed positron emission tomography-computed tomography image shouldn't be more than 3. Eligible patients are randomly assigned in a 1:1 ratio to receive either SCR followed by 6 cycles of platinum-based chemotherapy and niraparib maintenance or 6 cycles of platinum-based chemotherapy and niraparib maintenance alone. Patients who undergo at least 4 cycles of chemotherapy and must be, in the opinion of the investigator, without disease progression, will be assigned niraparib maintenance. Major inclusion criteria are secondary relapsed OC with a platinum-free interval of no less than 6 months and a possibly complete resection. Major exclusion criteria are borderline tumors and non-epithelial ovarian malignancies, received debulking surgery at recurrence and impossible to complete resection. The sample size is 96 patients. Primary endpoint is 12-month non-progression rate. ClinicalTrials.gov Identifier: NCT03983226.

PCL-PEtOx-based Crystalline-core Micelles for the Targeted Delivery of Paclitaxel and Trabectedin in Ovarian Cancer Therapy.

Ovarian cancer (OC), which primarily metastasizes through ascites, is both invasive and fatal. Despite its toxicity and drug resistance, the platinum-based chemotherapy Taxol®+Carboplatin has been the first-line standard treatment for decades. Trabectedin (TBD) is a recently developed, highly effective antitumor drug that is also capable of regulating tumor-associated macrophages (TAMs), however, its severe side-effects hinder further clinical application. Here, we developed safe and efficient pH-responsive crystalline-core micelles for the combined treatment of OCs, exploiting parallel delivery of paclitaxel (PTX) and TBD. PCL-PEtOx-COOH was selected as the optimal carrier to encapsulate PTX or TBD, which self-assemble into micelles with internal crystalline cores. The carboxyl group exposed on the surface of the micelles was utilized to react with the amines of Herceptin and hyaluronic acid cross-linked polymer (Herceptin-HA) to form PTX(Target). Similarly, TBD(Target) was formed by reaction with the CD206-targeted peptide mUNO. The low critical micelle concentrations of PTX(Target) and TBD(Target) stabilize the micelles in the bloodstream and normal tissues to prevent drug release. In an acidic microenvironment, the tertiary amide group on PEtOx chain of micelles ionizes, causing disassembly and pH-responsive release. Compared with Taxol®+Carboplatin, the combination therapy displayed dramatically improved safety and efficacy, as evidenced by the elimination of peritoneal tumor spheroids and reduced expression of NOX4, a gene that is overexpressed in most OC tissues. Furthermore, in human tissues, the ROS-response gene NOX4 is linked to the development of M2-type TAMs. Collectively, this study provides a safe and effective non-platinum-based chemotherapy for OC, offering an alternative to traditional Taxol®+Carboplatin. STATEMENT OF SIGNIFICANCE: (1) Significance: This work reports a new approach for ovarian cancer (OC) treatment. We utilized trabectedin (TBD) which a recently developed, highly effective antitumor drug that is also capable of regulating tumor associated macrophages (TAMs) combined with paclitaxel (PTX) to replace platinum-based chemotherapy Taxol®+Carboplatin (TC regimen). Compared to the clinical formulations, Yondelis® and Taxol®, pH-responsive PCL-PEtOx-based crystalline-core micelles were utilized for targeted independent delivery of TBD and PTX to TAMs and tumor cells, which maintained safe and efficient transport, overcoming the challenges posed by TAMs and carboplatin resistance. The system capabilities have also been confirmed in organoid and PDX models. (2) This is the first report demonstrating that this approach simultaneously overcomes the abdominal metastasis and carboplatin resistance of OC.

Surgery and Niraparib in Secondary Recurrent Ovarian Cancer (SOC-3 Trial)

This is a Phase II, open-label, multicenter, randomized umbrella study to evaluate the efficacy of cytoreductive surgery and Niraparib maintenance in participants with platinum-sensitive secondary recurrent ovarian cancer. Cohort 1 will focus on participants without prior use of PARP inhibitor, and without prior secondary cytoreduction (SCR) when first recurrence. Cohort 2 will focus on participants with prior use of PARP inhibitor, but without prior SCR when first recurrence. Cohort 3 will focus on participants with SCR when first recurrence, but without prior use of PARP inhibitor.