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Marrow adipocytes reprogrammed by myeloma cells induce bone lesions.

e17039 Background: Treatment strategies are needed for platinum-resistant recurrent ovarian cancer. Glucocorticoid receptor (GR) is associated with poor prognosis in ovarian cancer. GR signaling inhibits chemotherapy-induced cell death via transcriptional regulation of anti-apoptotic proteins. Non-selective (mifepristone) and selective GR antagonists (Relacorilant, Corcept Therapeutics) are under clinical development (eg. NCT02046421, NCT03776812). We hypothesized that GR antagonism would improve chemotherapy sensitivity in ovarian cancer patient-derived xenograft (PDX) models. Methods: Five PDX models were selected based on GR expression above median RNA seq levels. Tissues were transplanted into 300 female SCID-Bg mice at the Mayo Clinic. Once tumor diameter reached 0.2 cm, mice were randomized into treatment arms (2-25 mice per arm) and treated intraperitoneal (i.p): control (9% saline, CTL) on day 0 (D0), 1, 7, 8, 14, 15, 21, 22; mifepristone (MIF), 15 mg/kg D0, 1, 7, 8, 14, 15, 21, 22; relacorilant (134), 20 mg/kg D0, 1, 7, 8, 14, 15, 21, 22; carboplatin (CBDCA) at the MTD, 51 mg/kg D1, 8, 15, 22; CBDCA + MIF; CBDCA + 134. Tumor area was measured by ultrasound weekly (D0-D28), and the ratio calculated relative to D0. Tumor growth curves were compared between arms for each PDX via a linear mixed effects regression test of coincident curves. Time to progression was also evaluated and will be presented. Results: In 1/5 models (PH160), CBDCA + MIF significantly suppressed tumor growth compared to CBDCA alone (p < 0.05, Table 1). Addition of 134 to CBDCA did not suppress tumor growth compared to CBDCA alone in any model. In the 2 models with no difference of CBDCA versus CTL (PH160, PH454), addition of a GR antagonist to CBDCA suppressed tumor growth versus CTL. Conclusions: Addition of GR antagonists can improve response to chemotherapy. Work is ongoing to identify the GR transcriptional network, tumor, and host characteristics which predict responses to GR antagonists. [Table: see text]

e17038 Background: Carcinosarcomas (CS) are aggressive gynecologic malignancies defined by a biphasic tumor histology of carcinomatous and sarcomatous components. High expression of glucocorticoid receptor (GR) is associated with aggressive tumor biology in triple-negative breast, ovarian, and endometrial cancers. GR activation results in transcriptional regulation of epithelial-mesenchymal transition (EMT) genes. Therefore, we hypothesized that the sarcomatous component of Müllerian CS may be associated with relatively higher GR expression compared to the carcinomatous portion. Methods: Müllerian CSs from the University of Chicago tissue bank diagnosed from 5/19/2009 – 8/25/2014 were identified and pathology confirmed (RL). In addition, we evaluated GR expression in a mouse PDX CS model. Immunohistochemical expression of nuclear estrogen (ER), progesterone (PR), androgen (AR), and GR was quantified using the H-score. Scores between the sarcomatous and carcinomatous components were compared using a paired t-test. Results: Mean GR H-score was relatively higher in the sarcomatous vs carcinomatous component, overall (144.44 vs 38.89, P = 0.0014). Mean H-score also differed between sarcomatous and carcinomatous components for ER (3.06 vs 63.06, P = 0.016), PR (1.67 vs 47.22, P = 0.004), and AR (0 vs 2.78, P = 0.056). The significantly higher sarcomatous GR expression was replicated in IHC evaluation of the mouse PDX model. Conclusions: GR expression is significantly higher in the sarcomatous than the carcinomatous component of Müllerian CS, while ER, PR, and AR expression is significantly lower. Recent data suggest that an EMT gene signature is more prominently expressed in the sarcomatous versus carcinomatous component. We hypothesize that GR expression and activity may mediate EMT gene expression and represent a therapeutic target for CS. [Table: see text]

Abstract In lung adenocarcinoma, gene fusion involving the anaplastic lymphoma kinase (ALK) gene leads to overexpression of its tyrosine kinase domain, which serves as the oncogenic driver in lung tumors carrying such a molecular alteration. Similar fusions involving ROS1, RET and NTRK are also found in lung cancer and tumors with oncogenic fusions often respond well to targeted therapy. However, these tumors do develop resistance to the targeting drug and patients eventually relapse while on treatment. Although newer drugs have been developed, it remains a challenge to effectively control cancer recurrence after targeted therapy. In vivo tumor models carrying these fusions, particularly those that have progressed while on targeted treatment, will help to facilitate further drug evaluations prior to their administration to the patient as well as offer an opportunity to better understand the molecular mechanisms driving disease onset, progression, and drug resistance in tumors carrying the fusion of interest. Here, we describe the first patient-derived tumor xenograft (PDX) carrying an STRN-ALK fusion. The patient was diagnosed with stage IV lung adenocarcinoma in 2011. She was initially treated with crizotinib and remained stable until 2015. At the time of disease progression, a biopsy was taken with patient consent under CT guidance from a chest wall mass using an 18-gauge needle and then implanted into two SCID-beige mice subcutaneously and into the fat pad of the kidney. Palpable tumor was observed in both mice at about 28 weeks post implantation and passaged at 36 weeks. They have been passaged two successive times and viably frozen. Pathologic analysis of the PDX showed that both tumors have the same mucinous morphology as observed in the original biopsy sample. RNA-seq and matepair analysis revealed that the tumors carry a rare fusion involving the first three exons of STRN and exon 20 to 3’ end of the ALK gene. The patient has been on ceritinib since January 2016 and remains stable as of last follow up. Several unique features contributed to the success of this study. 1) The metastatic chest wall lesion used for the PDX developed was easily accessible on the chest wall using a relative large 18-gauge needle for CT-guided biopsies. 2) The slow growth of the tumor biopsy mirrors the clinical course of the disease observed in the patient. 3) The patient remains clinically stable and continues to respond to TKi. The availability of a viable PDX tumor model for this rare STRN-ALK fusion offers a unique opportunity to identify the most appropriate drug for the patient at the time of disease progression as well as the opportunity to examine the unique molecular features associated with this rare ALK fusion. This work was supported in part by the National Foundation for Cancer Research Hillsberg Lung Cancer Translational Research Grant and by the Biomarker Discovery Program at the Mayo Clinic Center for Individualized Medicine. Citation Format: HongZheng Res, XiaoNan Hou, Karlyn E. Pierson, Patric Eiken, Asha Nair, PingYang Yang, Joanne Eunhee Yi, Aaron S. Mansfield, Jin Jen. Establishment of a unique patient-derived tumor model positive for STRN-ALK fusion from a patient with stage IV lung adenocarcinoma [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A17.

Ovarian cancer is the most lethal gynecologic malignancy. About 75% of ovarian cancer patients relapse and/or develop chemo‐resistant disease after initial response to standard‐of‐care treatment with platinum‐based therapies. HER2 amplifications and overexpression in ovarian cancer are reported to vary, and responses to HER2 inhibitors have been poor. Next generation sequencing technologies in conjunction with testing using patient‐derived xenografts (PDX) allow validation of personalized treatments. Using a whole‐genome mate‐pair next generation sequencing (MPseq) protocol, we identified several high grade serous ovarian cancers (HGS‐OC) with DNA alterations in genes encoding members of the ERBB2 pathway. The efficiency of anti‐HER2 therapy was tested in three different PDX lines with the identified alterations and high levels of HER2 protein expression. Treatment responses to pertuzumab or pertuzumab/trastuzumab were compared in each PDX line WITH standard carboplatin and paclitaxel combination treatment. In all three PDX models, HER2‐targeted therapy resulted in significant inhibition of tumor growth compared with untreated controls. However, the responses in each case were inferior to those to chemotherapy, even for chemo‐resistant lines. When chemotherapy and HER2‐targeted therapy were administered together, a significant regression of tumor was observed after 6 weeks of treatment compared with chemotherapy alone. Post‐treatment analysis of these tissues revealed that inhibition of the ERBB2 pathway occurred at the level of phosphorylation and expression of downstream targets. In conclusion, while targeting of presumably activated ERBB2 pathway alone in HGS‐OC results in a modest treatment benefit, a combination therapy including both chemotherapy drugs and HER2 inhibitors provides a far better response. Further studies are needed to address development of recurrence and sensitivity of recurrent disease to HER2‐targeted therapy.