Jinsong Liu

Crizotinib Enhances PARP Inhibitor Efficacy in Ovarian Cancer Cells and Xenograft Models by Inducing Autophagy

Abstract Poly (ADP-ribose) polymerase inhibitors (PARPi) can encounter resistance through various mechanisms, limiting their effectiveness. Our recent research showed that PARPi alone can induce drug resistance by promoting autophagy. Moreover, our studies have revealed that anaplastic lymphoma kinase (ALK) plays a role in regulating the survival of ovarian cancer cells undergoing autophagy. Here, we explored whether the ALK-inhibitor crizotinib could enhance the efficacy of PARPi by targeting drug-induced autophagic ovarian cancer cell and xenograft models. Our investigation demonstrates that crizotinib enhances the anti-tumor activity of PARPi across multiple ovarian cancer cells. Combination therapy with crizotinib and olaparib reduced cell viability and clonogenic growth in two-olaparib resistant cell lines. More importantly, this effect was consistently observed in patient-derived organoids. Furthermore, combined treatment with crizotinib and olaparib led to tumor regression in human ovarian xenograft models. Mechanistically, the combination resulted in increased levels of reactive oxygen species (ROS), induced DNA damage, and decreased the phosphorylation of AKT, mTOR, and ULK-1, contributing to increased olaparib-induced autophagy and apoptosis. Notably, pharmacologic, or genetic inhibition or autophagy reduced the sensitivity of ovarian cancer cell lines to olaparib and crizotinib treatment, underscoring the role of autophagy in cell death. Blocking ROS mitigated olaparib/crizotinib-induced autophagy and cell death while restoring levels of phosphorylated AKT, mTOR and ULK-1. These findings suggest that crizotinib can improve the therapeutic efficacy of olaparib by enhancing autophagy. Implications: The combination of crizotinib and PARPi presents a promising strategy, that could provide a novel approach to enhance outcomes for patients with ovarian cancer.

EGFR, HLA-G, CD70, c-MET, and NY-ESO1 as potential biomarkers in high grade epithelial ovarian carcinoma

High grade epithelial ovarian carcinoma is an aggressive tumor. Treatment includes platinum therapy, however it recurs in most patients due to therapy resistance. In this project, we study the immunohistochemical (IHC) expression of five potential biomarkers/prognostic markers in high grade epithelial ovarian carcinoma: EGFR, HLA-G, CD70, c-MET, and NY-ESO1. A cohort of 274 patients is used. We compare the IHC expression with age, stage, ascites status, family history of cancer, disease free survival (DFS) and overall survival (OS). EGFR expression is significantly correlated with family history and worse OS. HLA-G is associated with worse OS. To confirm the results of EGFR and HLA-G, a second separated cohort of 248 patients is used. Positive EGFR expression again shows worse OS, while HLA-G expression has worse prognostic trend. CD70 has a worse OS trend. C-MET and NY-ESO1 do not have any clinical correlations. EGFR can potentially serve as target in future clinical immune therapy trials.

IMGN853 Induces Autophagic Cell Death in Combination Therapy for Ovarian Cancer

Abstract Antibodies targeting folate receptor 1 (FOLR1) induce autophagic cell death in addition to antibody-dependent cytotoxicity, but the biological relevance of anti-FOLR1 antibody–induced autophagy for clinical applications remains unclear. In this study, we investigated the role of autophagic cell death triggered by IMGN853 (mirvetuximab soravtansine), an FOLR1-targeted antibody–drug conjugate, and explored potential combinations of IMGN853 with chemotherapeutic drugs used for ovarian cancer treatment. We discovered that FOLR1 was predominantly expressed in epithelial ovarian cancer cells, with similar expression levels observed in both primary ovarian tumors and metastatic omental tumors from patients with high-grade serous ovarian cancer (HGSC). Treatment with IMGN853 improved survival in mice bearing patient-derived xenografts of HGSC, enhanced autophagic flux, and induced cell death in HGSC cells. Additionally, it increased expression of the autophagy-related marker LC3B-II and cell death as marked by cleaved caspase-3, in a manner dependent on beclin-1, in HGSC models. Notably, combinations of IMGN853 with topotecan or the anti–VEGF-A antibody (B20) significantly reduced tumor growth compared with IMGN853 alone, whereas no significant effect was observed with olaparib. Our findings indicate that IMGN853 induces autophagic cell death, which contributes to its tumor-inhibiting effects. The identification of these effective combination therapies and the mechanisms behind FOLR1-mediated autophagic cell death could facilitate further clinical development of IMGN853. Significance: FOLR1 is heterogeneously overexpressed in epithelial ovarian cancer. We examined the combined effects of the anti-FOLR1 antibody–drug conjugate (IMGN853) with other drugs, including topotecan, anti–VEGF-A antibody, and olaparib. These findings could contribute to the continued development of IMGN853 in the treatment of ovarian cancer.

Targeting polyploid giant cancer cells potentiates a therapeutic response and overcomes resistance to PARP inhibitors in ovarian cancer

To understand the mechanism of acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib, we induced the formation of polyploid giant cancer cells (PGCCs) in ovarian and breast cancer cell lines, high-grade serous cancer (HGSC)–derived organoids, and patient-derived xenografts (PDXs). Time-lapse tracking of ovarian cancer cells revealed that PGCCs primarily developed from endoreplication after exposure to sublethal concentrations of olaparib. PGCCs exhibited features of senescent cells but, after olaparib withdrawal, can escape senescence via restitutional multipolar endomitosis and other noncanonical modes of cell division to generate mitotically competent resistant daughter cells. The contraceptive drug mifepristone blocked PGCC formation and daughter cell formation. Mifepristone/olaparib combination therapy substantially reduced tumor growth in PDX models without previous olaparib exposure, while mifepristone alone decreased tumor growth in PDX models with acquired olaparib resistance. Thus, targeting PGCCs may represent a promising approach to potentiate the therapeutic response to PARPi and overcome PARPi-induced resistance.

Expression of B7–H4 and IDO1 is associated with drug resistance and poor prognosis in high-grade serous ovarian carcinomas

High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy. While immune checkpoint inhibitors against PD-L1 and CTLA-4 have shown significant effects in multiple tumor types, the response rate to single-agent immune checkpoint inhibitors is low in HGSC. Alternative biomarkers and targets must be identified to guide patient selection and new therapeutic strategies in HGSC. Here, we aim to investigate the clinical significance of novel immune modulators, including B7-H4, IDO1, Tim3, IL6, and IL-8, in patients with HGSC. A total of 48 patients with HGSCs, comprising 24 cases that were sensitive and 24 that were resistant to standard paclitaxel and carboplatin chemotherapy, were selected for our initial analysis. A NanoString assay including 33 immune-related genes was used to compare the expression of different immune regulatory molecules in the sensitive and resistant groups. Differentially expressed proteins were verified using multiplex immunohistochemical staining on tissue arrays of 202 patients with HGSCs who underwent primary surgery at MDACC. We analyzed the expression levels of immune checkpoints and compared expression profiles with clinicopathologic features including response, progression-free survival, and overall survival. HGSC tumors resistant to therapy expressed higher levels of B7-H4 (69.3%), IDO1 (71.8%), Tim3 (89.1%), and inflammatory factors IL-6 and IL-8, and expressed higher Tim3 in stromal components. High expression of B7-H4 and IDO1 was associated with significantly lower overall survival and progression-free survival. B7-H4 and IDO1 were co-expressed in 49.1% of studied cases. A panel of immunomodulatory proteins including B7-H4, IDO1, Tim3, IL-6, and IL-8 are expressed at high levels in HGSCs. These modulators represent novel targets to enhance immunotherapy in patients with HGSCs.

PPP2R1A mutations portend improved survival after cancer immunotherapy

Immune checkpoint blockade (ICB) therapy is effective against many cancers, although resistance remains a major issue and new strategies are needed to improve clinical outcomes

Normal Risk Ovarian Screening Study: 21-Year Update

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. PURPOSE The Normal Risk Ovarian Screening Study (NROSS) tested a two-stage screening strategy in postmenopausal women at conventional hereditary risk where significantly rising cancer antigen (CA)-125 prompted transvaginal sonography (TVS) and abnormal TVS prompted surgery to detect ovarian cancer. METHODS A total of 7,856 healthy postmenopausal women were screened annually for a total of 50,596 woman-years in a single-arm study (ClinicalTrials.gov identifier: NCT00539162 ). Serum CA125 was analyzed with the Risk of Ovarian Cancer Algorithm (ROCA) each year. If risk was unchanged and <1:2,000, women returned in a year. If risk increased above 1:500, TVS was undertaken immediately, and if risk was intermediate, CA125 was repeated in 3 months with a further increase in risk above 1:500 prompting referral for TVS. An average of 2% of participants were referred to TVS annually. RESULTS Thirty-four patients were referred for operations detecting 15 ovarian cancers and two borderline tumors with 12 in early stage (I-II). In addition, seven endometrial cancers were detected with six in stage I. As four ovarian cancers and two borderline tumors were diagnosed with a normal ROCA, the sensitivity for detecting ovarian and borderline cancer was 74% (17 of 23), and 70% of ROCA-detected cases (12 of 17) were in stage I-II. NROSS screening reduced late-stage (III-IV) disease by 34% compared with UKCTOCS controls and by 30% compared with US SEER values. The positive predictive value (PPV) was 50% (17 of 34) for detecting ovarian cancer and 74% (25 of 34) for any cancer, far exceeding the minimum acceptable study end point of 10% PPV. CONCLUSION While the NROSS trial was not powered to detect reduced mortality, the high specificity, PPV, and marked stage shift support further development of this strategy.

Combination Therapy with Copanlisib and Niraparib in Patients with Recurrent Endometrial and Ovarian Cancer (COPANIRA): Efficacy, Toxicity, and Translational Insights

Abstract Purpose: Patients with recurrent endometrial or ovarian cancer have poor survival outcomes. We evaluated the clinical efficacy and toxicity of copanlisib [a phosphatidylinositol 3-kinase (PI3K) inhibitor] and niraparib [a poly (ADP-ribose) polymerase inhibitor (PARPi)] in this patient population with translational insights. Patients and Methods: This was a phase Ib trial. Copanlisib was administered intravenously on days 1, 8, and 15 of a 28-day cycle, and niraparib was given orally once daily. Four dose levels were explored over a dose-limiting toxicity (DLT) window of 28 days. The primary objective was to determine the recommended phase II dose (RP2D) of this combination. Secondary objectives included safety, objective response rate (ORR), and pharmacokinetics. Tumor biopsies were analyzed using reverse phase protein array (RPPA) to identify molecular correlates of response. Results: Thirty patients were enrolled. An RP2D was not established due to DLTs, most commonly a grade 3 maculopapular rash attributed to copanlisib. The ORR was 12.5% (95% confidence interval, 2.8%–33.6%). RPPA was performed on tumors from eight patients. PI3K pathway activity did not correlate with PI3K mutational status. Nineteen proteins were differentially expressed between patients with stable disease and those with progressive disease; many were substrates of Akt (protein kinase B), implicating downstream PI3K signaling in response. Conclusions: The combination of copanlisib and niraparib demonstrated limited tolerability, and the ORR was modest. However, functional proteomic analyses identified candidate biomarkers—particularly Akt pathway substrates—which may inform future strategies to optimize PI3K and PARPi combinations.