Investigator
Mayo Clinic
Dual FAK and EPHA2 targeting by brigatinib tackles PARP inhibitor adaptive survival response in high-grade serous ovarian cancer
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are an important therapy for high-grade serous ovarian cancer (HGSOC). However, PARPi resistance frequently emerges, necessitating previously unrecognized approaches to improve HGSOC responses. Here, we showed that the anaplastic lymphoma kinase (ALK) inhibitor brigatinib enhances PARPi activity in HGSOC cells by disrupting an adaptive survival mechanism orchestrated by Fos-related antigen 1 (FRA1) in response to PARPi. This effect of brigatinib occurred through an ALK-independent pathway, wherein brigatinib induced a dual blockade of focal adhesion kinase (FAK) and EPH receptor A2 (EPHA2) tyrosine kinases, leading to the suppression of protein kinase B (Akt) and extracellular-regulated kinase (ERK) signaling accompanied by disruption of a phosphorylation event crucial for FRA1 protein stability. Moreover, in HGSOC patient-derived xenograft (PDX) models, brigatinib and PARPi combination therapy induced tumor regression and improved overall survival compared with PARPi alone, particularly in models with high FAK and EPHA2. These findings support dual targeting of FAK and EPHA2 as a strategy to achieve effective and durable PARPi responses and identify a promising biomarker-based combinatorial approach using brigatinib and PARPi for HGSOC, particularly the subset characterized by high FAK and EPHA2.
Investigation of selective glucocorticoid receptor modulation in high-grade serous ovarian cancer PDX models
In ovarian cancer (OvCa), tumor cell high glucocorticoid receptor (GR) has been associated with poor patient prognosis. In vitro, GR activation inhibits chemotherapy-induced OvCa cell death in association with transcriptional upregulation of genes encoding anti-apoptotic proteins. A recent randomized phase II study demonstrated improvement in progression-free survival (PFS) for heavily pre-treated OvCa patients randomized to receive therapy with a selective GR modulator (SGRM) plus chemotherapy compared to chemotherapy alone. We hypothesized that SGRM therapy would improve carboplatin response in OvCa patient-derived xenograft (PDX). Six high-grade serous (HGS) OvCa PDX models expressing GR mRNA ( One of the 6 GR-positive PDX models showed a significant improvement in PFS with the addition of a SGRM. Interestingly, the single model with an improved PFS was least carboplatin sensitive. Possible explanations for the modest SGRM activity include the high carboplatin sensitivity of 5 of the PDX tumors and the potential that SGRMs activate the tumor invasive immune cells in patients (absent from immunocompromised mice). The level of tumor GR protein expression alone appears insufficient for predicting SGRM response. The significant improvement in PFS shown in 1 of the 6 models after treatment with a SGRM plus chemotherapy underscores the need to determine predictive biomarkers for SGRM therapy in HGS OvCa and to better identify patient subgroups that are most likely to benefit from adding GR modulation to chemotherapy.
A Phase I Trial of Nab-Paclitaxel/Bevacizumab (AB160) Nano-Immunoconjugate Therapy for Gynecologic Malignancies
Abstract Purpose: AB160 is a 160-nm nano-immunoconjugate consisting of nab-paclitaxel (ABX) nanoparticles noncovalently coated with bevacizumab (BEV) for targeted delivery into tissues expressing high levels of VEGF. Preclinical data showed that AB160 resulted in greater tumor targeting and tumor inhibition compared with sequential treatment with ABX then BEV. Given individual drug activity, we investigated the safety and toxicity of AB160 in patients with gynecologic cancers. Patients and Methods: A 3+3 phase I trial was conducted with three potential dose levels in patients with previously treated endometrial, cervical, and platinum-resistant ovarian cancer to ascertain the recommended phase II dose (RP2D). AB160 was administered intravenously on days 1, 8, and 15 of a 28-day cycle (ABX 75–175 mg/m2, BEV 30–70 mg/m2). Pharmacokinetic analyses were performed. Results: No dose-limiting toxicities (DLT) were seen among the three dose levels tested. Grade 3/4 toxicities included neutropenia, thromboembolic events, and leukopenia. DL2 (ABX 150 mg/m2, BEV 60 mg/m2) was chosen as the RP2D. Seven of the 19 patients with measurable disease (36.8%) had confirmed partial responses (95% confidence interval, 16.3%–61.6%). Pharmacokinetic analyses demonstrated that AB160 allowed 50% higher paclitaxel dosing and that paclitaxel clearance mirrored that of therapeutic antibodies. Conclusions: The safety profile and clinical activity of AB160 supports further clinical testing in patients with gynecologic cancers; the RP2D is DL2 (ABX 150 mg/m2, BEV 60 mg/m2).
Epithelial-to-Mesenchymal Transition Supports Ovarian Carcinosarcoma Tumorigenesis and Confers Sensitivity to Microtubule Targeting with Eribulin
Abstract Ovarian carcinosarcoma (OCS) is an aggressive and rare tumor type with limited treatment options. OCS is hypothesized to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analyzed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated that the carcinoma components were more mesenchymal when compared with pure epithelial ovarian carcinomas, supporting the conversion theory and suggesting that EMT is important in the formation of these tumors. Preclinical OCS models were used to test the efficacy of microtubule-targeting drugs, including eribulin, which has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas. Vinorelbine and eribulin more effectively inhibited OCS growth than standard-of-care platinum-based chemotherapy, and treatment with eribulin reduced mesenchymal characteristics and N-MYC expression in OCS patient-derived xenografts. Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a downregulation of the mevalonate pathway and prevented further cholesterol biosynthesis. Finally, eribulin increased expression of genes related to immune activation and increased the intratumoral accumulation of CD8+ T cells, supporting exploration of immunotherapy combinations in the clinic. Together, these data indicate that EMT plays a key role in OCS tumorigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes. Significance: Genomic analyses and preclinical models of ovarian carcinosarcoma support the conversion theory for disease development and indicate that microtubule inhibitors could be used to suppress EMT and stimulate antitumor immunity.
Prognostic value of perioperative circulating tumor DNA (ctDNA) in endometrial cancer with high-risk features: a prospective observational study.
Although circulating tumor DNA (ctDNA) has emerged as a promising prognostic tool in various malignancies, evidence in endometrial cancer at high risk of recurrence is limited. This study evaluated the association of pre- and post-surgical ctDNA with advanced-stage disease, disease-free and overall survival in endometrial cancer with high-risk features. This prospective observational study was conducted at Mayo Clinic (7/2016-6/2021). Patients with endometrial cancer at preoperative biopsy, confirmed by final pathology, were included. Blood samples were collected before and 10 weeks after surgery. Tumor-specific junctions identified in pathology specimens and blood samples were used to detect ctDNA. Associations between pre- and post-surgical ctDNA and advanced-stage disease, recurrence, and death were evaluated using logistic regression [odds ratio (OR) and 95 % confidence interval] and Cox proportional hazards [hazard ratio (HR) and 95 % confidence interval]. Thirty-six patients were included: 6 (16.7 %) intermediate risk, 1 (2.8 %) high-intermediate risk, 28 (77.8 %) high risk, and 1 (2.8 %) advanced metastatic. Detection of pre- or post-surgical ctDNA was not significantly associated with advanced disease (pre-surgical OR 5.69 [0.88-66.02]; post-surgical OR 5.86 [0.83-72.68]). Pre-surgical ctDNA did not significantly predict recurrence (HR 0.99 [0.30-3.23]) or death (HR 3.23 [0.40-25.91]). In contrast, post-surgical ctDNA was associated with increased risk of recurrence (HR 3.32 [1.05-10.51]) and death (HR 5.97 [1.11-36.08]). Post-surgical ctDNA detection was associated with poor outcomes in patients with endometrial cancer. These findings support the potential of ctDNA as a biomarker to personalize surveillance and guide post-surgical treatment strategies.
