Search

BackgroundCombining poly (ADP-ribose) polymerase (PARP) with phosphatidylinositol-3-kinase (PI3K) pathway inhibitors is supported by strong preclinical rationale. We sought to assess safety and determine a recommended phase 2 dose (RP2D) for PARP inhibitor olaparib combined with the AKT inhibitor, capivasertib, and evaluate molecular markers of response and resistance.MethodsAs part of a larger phase 1b trial, we performed a safety lead in of olaparib and capivasertib followed by expansion (n=24) in endometrial, triple negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300mg orally twice daily and capivasertib orally twice daily on a four day on three day off schedule was evaluated. Two dose levels (DL) were planned: capivasertib 400mg (DL1); capivasertib 320mg (DL-1). Patients underwent biopsies at baseline and after 28 days.Findings38 patients were enrolled. 7 (18%) patients had known germlineBRCA1/2mutations. The first two patients on DL1 experienced dose limiting toxicities (DLTs) of diarrhea and vomiting in absence of maximum supportive care. No DLTs were observed on DL-1 (n=6), therefore, DL1 was re-explored (n=6) with no DLTs, confirming this as RP2D. Most common treatment-related grade 3 or 4 adverse events were anemia (23.7%) and leukopenia (10.5%).Of 32 subjects evaluable for response, 6 (19%) had partial response (PR) with a PR rate of 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlation between response and immune activity, as well as alterations in cell cycle and DNA damage response genes. Therapy resistance was associated with receptor tyrosine kinase (RTK) and RAS-MAPK pathway activity, as well as metabolism and epigenetics.InterpretationThe combination of olaparib and capivasertib is well tolerated and demonstrates evidence of durable activity in women’s cancers, with particularly promising response in endometrial cancer. Importantly, tumor samples acquired pre and on-therapy can help predict patient benefit.FundingAstraZeneca, MDACC Moonshots Program, MDACC Support Grant CA016672 NCI SPOREs in Ovarian (CA217685) and Uterine (CA098258) Cancer and a kind gift from the Miriam and Sheldon Medical Research Foundation. AZD5363 was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited).

(1) Background: Biomarkers might play a significant role in predicting the clinical outcomes of patients with ovarian cancer. By analyzing lipid metabolism genes, future perspectives may be uncovered, (2) Methods: RNA-seq data for serous ovarian cancer were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. The non-negative matrix factorization package in programming language R was used to classify molecular subtypes of lipid metabolism genes and the limma package in R was performed for functional enrichment analysis. Through lasso regression, we constructed a multi-gene prognosis model, (3) Results: Two molecular subtypes were obtained and an 11-gene signature was constructed (PI3, RGS, ADORA3, CH25H, CCDC80, PTGER3, MATK, KLRB1, CCL19, CXCL9 and CXCL10). Our prognostic model shows a good independent prognostic ability in ovarian cancer. In a nomogram, the predictive efficiency was notably superior to that of traditional clinical features. Related to known models in ovarian cancer with a comparable amount of genes, ours has the highest concordance index, (4) Conclusions: We propose an 11-gene signature prognosis prediction model based on lipid metabolism genes in serous ovarian cancer.

Here, we examined the role of EP-100 [luteinizing hormone-releasing hormone (LHRH) ligand joined to a lytic peptide], improving the efficacy of immune checkpoint blockade. LHRH-R–positive murine ovarian cancer cells (ID8, IG10, IF5, and 2C12) were sensitive to EP-100 and were specifically killed at low micromolar levels through LHRH-R. EP-100 increased PD-L1 levels on murine ovarian cancer cells. In vivo syngeneic mouse models (ID8 and IG10) demonstrated that single-agent EP-100 reduced tumor volume, tumor weight, and ascites volume. The greatest reductions in tumor and ascites volume were observed with the combination of EP-100 with an anti–PD-L1 antibody. Immune profiling analysis showed that the population of CD8+ T cells, natural killer cells, dendritic cells, and macrophages were significantly increased in tumor and ascitic fluid samples treated with anti–PD-L1, EP-100, and the combination. However, monocytic myeloid suppressor cells, B cells, and regulatory T cells were decreased in tumors treated with anti–PD-L1, EP-100, or the combination. In vitro cytokine arrays revealed that EP-100 induced IL1α, IL33, CCL20, VEGF, and Low-density lipoprotein receptor (LDLR) secretion. Of these, we validated increasing IL33 levels following EP-100 treatment in vitro and in vivo; we determined the specific biological role of CD8+ T-cell activation with IL33 gene silencing using siRNA and Cas9-CRISPR approaches. In addition, we found that CD8+ T cells expressed very low level of LHRH-R and were not affected by EP-100. Taken together, EP-100 treatment had a substantial antitumor efficacy, particularly in combination with an anti–PD-L1 antibody. These results warrant further clinical development of this combination.

IntroductionOverexpression of the epidermal growth factor receptor (EGFR) found in common subtypes of endometrial cancer has been associated with advanced stage disease and a poor prognosis. The purpose of this phase 2 study was to evaluate the efficacy and safety of cetuximab in patients with recurrent endometrial cancer.MethodsThe study was an open-label phase 2 clinical trial conducted at two institutions. Patients with recurrent or progressive endometrial cancer of any histologic type with the exception of uterine sarcoma received cetuximab at an initial dose of 400 mg/m2 IV followed by weekly doses of 250 mg/m2. One cycle was considered 4 weeks of treatment. The primary efficacy endpoint was clinical benefit response, defined as a complete or partial response or prolonged stable disease (>8 weeks) by RECIST 1.0 criteria.ResultsA total of 30 patients were enrolled with a median age of 64 years (range 42–83). Of the 20 evaluable patients, three (15%) had clinical benefit response (one complete response, two stable disease). The patient with a clinical benefit response received a total of 27 cycles and the two patients with stable disease were taken off the study due to progression after four and six cycles, respectively. Of the 10 inevaluable patients, nine received ≤1 cycle due to clinical deterioration and one had an anaphylactic reaction. One patient had a grade 3 rash which resolved after a delay in treatment. No dose reduction was reported.ConclusionsIn this cohort, single agent therapy with cetuximab was well tolerated and had a 15% clinical benefit response. Further studies are required to better identify patients who may respond to this treatment.

The clinical development of poly-(ADP)-ribose polymerase inhibitors (PARPi) began with the treatment of ovarian cancer patients harboring BRCA1/2 mutations and continues to be expanded to other gynecological cancers. Furthermore, The Cancer Genome Atlas (TCGA) analysis of endometrial and cervical cancers offered rationale that PARPi may be an option for treatment based on the molecular profiles of these cancer types. This review summarizes the current indications of PARPi, such as its role in the treatment and maintenance of recurrent ovarian cancer and for first-line maintenance therapy in advanced ovarian cancer. We also outline new concepts for PARPi therapy in other gynecological cancers such as endometrial and cervical cancers based on recent clinical data. Finally, we present potential future directions to continue exploring the world of PARPi resistance and combining PARPi with other therapies.

The discovery of cancer-causing BRCA1/2 mutations and the emergence of genetic testing have brought precision in patient selection for poly-(ADP)-ribose polymerase inhibitor (PARPi) treatment. Interestingly, patients who are carriers of BRCA1/2 mutations have a higher risk for developing cancer, but respond better to DNA-damaging cytotoxic therapy, such as platinum-based chemotherapy. The distinctive biology of ovarian cancer involves high genomic instability consisting of gene amplification, gene deletion, oncogene hypomethylation, loss of heterozygosity, and tumor suppressor gene promoter hypermethylation in many of the DNA damage response (DDR) genes, including BRCA1/2. Several of these genetic abnormalities can impair high fidelity DNA damage repair increasing the therapeutic audience for PARPi's. This is especially important given the clinical development over the last decade of this group of agents and the dramatic increase in progression free survival among ovarian cancer patients who received PARPi, both in treatment or maintenance setting. In this review, we summarize our current understanding of the role of BRCA1/2 mutations in ovarian cancer and present relevant clinical trials in which BRCA1/2 was investigated as biomarker for therapy. We also outline the role of homologous recombination (HR) deficiency as biomarker by presenting the recent clinical development and recent approvals PARPi for firstline maintenance in ovarian cancer.

Adaptive resistance to vascular endothelial growth factor (VEGF)–targeted therapies occurs frequently among cancer patients. To investigate the underlying mechanisms, we established an array of orthotopic mouse models of ovarian cancer with adaptive resistance to anti-VEGF antibodies (AVAs). Genomic profiling showed an important role of endothelial p130cas in AVA resistant tumors. AVA treatment induced internalization of a p130cas/VEGFR2/TNKS1BP1 (a tankyrase-1–binding protein) complex in endothelial cells and initiated cell death and autophagy; knockdown of LC3B or caspase-10 reversed cells’ resistance to AVA treatment. Targeting host p130cas reduced the growth of AVA-resistant orthotopic ovarian tumors. Genomic ablation of vascular p130cas in p130casflox/floxTie2Cre mice significantly prolonged survival of mice carrying syngeneic ovarian tumors with adaptive resistance to AVA therapy. In ovarian cancer patients, higher p130cas expression in tumor-associated vasculature was associated with higher mortality. Collectively, these findings have important implications to guide future therapeutic strategies to overcome resistance to anti-angiogenic therapy.

Implantation consists of a complex process based on coordinated crosstalk between the endometrium and trophoblast. Furthermore, it is known that the microenvironment of this fetal–maternal interface plays an important role in the development of extravillous trophoblast cells. This is mainly due to the fact that tissues mediate embryonic signaling biologicals, among other molecules, prostaglandins. Prostaglandins influence tissue through several cell processes including differentiation, proliferation, and promotion of maternal immune tolerance. The aim of this study is to investigate the potential pathological mechanism of the prostaglandin E2 receptor 4 (EP4) in modulating extravillous trophoblast cells (EVTs) in unexplained recurrent marriage (uRM). Our results indicated that the expression of EP4 in EVTs was decreased in women experiencing uRM. Furthermore, silencing of EP4 showed an inhibition of the proliferation and induced apoptosis in vitro. In addition, our results demonstrated reductions in β- human chorionic gonadotropin (hCG), progesterone, and interleukin (IL)-6, which is likely a result from the activation of the cyclic adenosine monophosphate (cAMP)- cAMP-dependent protein kinase A (PKA)-phosphorylating CREB (pCREB) pathway. Our data might provide insight into the mechanisms of EP4 linked to trophoblast function. These findings help build a more comprehensive understanding of the effects of EP4 on the trophoblast at the fetal–maternal interface in the first trimester of pregnancy.

Trace amine-associated receptor 1 (TAAR1) is a Gαs- protein coupled receptor that plays an important role in the regulation of the immune system and neurotransmission in the CNS. In ovarian cancer cell lines, stimulation of TAAR1 via 3-iodothyronamine (T1AM) reduces cell viability and induces cell death and DNA damage. Aim of this study was to evaluate the prognostic value of TAAR1 on overall survival of ovarian carcinoma patients and the correlation of TAAR1 expression with clinical parameters. Ovarian cancer tissue of n = 156 patients who were diagnosed with epithelial ovarian cancer (serous, n = 110 (high-grade, n = 80, low-grade, n = 24, unknown, n = 6), clear cell, n = 12, endometrioid, n = 21, mucinous, n = 13), and who underwent surgery at the Department of Obstetrics and Gynecology, University Hospital of the Ludwig-Maximilians University Munich, Germany between 1990 and 2002, were analyzed. The tissue was stained immunohistochemically with anti-TAAR1 and evaluated with the semiquantitative immunoreactive score (IRS). TAAR1 expression was correlated with grading, FIGO and TNM-classification, and analyzed via the Spearman’s rank correlation coefficient. Further statistical analysis was obtained using nonparametric Kruskal-Wallis rank-sum test and Mann-Whitney-U-test. This study shows that high TAAR1 expression is a positive prognosticator for overall survival in ovarian cancer patients and is significantly enhanced in low-grade serous carcinomas compared to high-grade serous carcinomas. The influence of TAAR1 as a positive prognosticator on overall survival indicates a potential prognostic relevance of signal transduction of thyroid hormone derivatives in epithelial ovarian cancer. Further studies are required to evaluate TAAR1 and its role in the development of ovarian cancer.

Angiogenesis is known to play an important role in normal ovarian physiology as well as in growth and progression of ovarian cancer. The first FDA approval of bevacizumab in 2004 was for metastatic colorectal cancer in combination with chemotherapy; this was a key point for several subsequent approvals of antiangiogenic drugs. The efficacy of bevacizumab treatment is modest, however, and most ovarian cancer patients eventually develop acquired resistance, which highlights the need for new targeted therapies and/or combination strategies. Understanding the multitude of variables in response to antiangiogenic therapy would offer potential strategies for selecting patients most likely to benefit from such therapy.

Simple Summary Since the Kirsten rat sarcoma viral oncogene homolog (KRAS) is mutated in about 25% of all human cancers and is at the center of pathways involved in tumorigenesis, it is necessary to compile and highlight the novel therapeutic strategies behind targeting this oncoprotein in cancer. Over the years, many have studied various methods to directly target KRAS with no success. Fortunately, there has been more success in targeting other proteins along the RAS pathway to yield a therapeutic response. However, some recent findings show promising results indicating that we are one step closer to developing an effective inhibitor that directly targets KRAS. The review presented here summarizes these recent findings and emphasizes the need to continue the search for the most optimal KRAS inhibitor that can be used to treat and potentially even cure certain tumor types. Abstract The Kirsten rat sarcoma viral oncogene homolog (KRAS) is mutated in approximately 25% of all human cancers and is known to be a major player promoting and maintaining tumorigenesis through the RAS/MAPK pathway. Over the years, a large number of studies have identified strategies at different regulatory levels to tackle this ‘difficult-to-target’ oncoprotein. Yet, the most ideal strategy to overcome KRAS and its downstream effects has yet to be uncovered. This review summarizes the role of KRAS activating mutations in multiple cancer types as well as the key findings for potential strategies inhibiting its oncogenic behavior. A comprehensive analysis of the different pathways and mechanisms associated with KRAS activity in tumors will ultimately pave the way for promising future work that will identify optimum therapeutic strategies.

Introduction: EphB4 is frequently overexpressed in ovarian and other solid tumors and involved in interactions between tumor cells and tumor microenvironment, contributing to metastasis. EphB4 and its membrane-bound ligand ephrin B2 (EFNB2) mediates bi-directional signaling. Currently, no small-molecule-based, peptides with dual functional binding to EphB4 are available. Therefore, we developed an EphB4 agonist that is capable of activating the forward EphB4 signaling and interfering with the reverse EFNB2 signaling. Methods: A high-affinity bi-directional ephrin agonist peptide (BIDEN-AP) that selectively activated EphB4 was discovered through structural modifications to the known EphB4 antagonist TNYLFSPNGPIARAW (TNYL-RAW) by surface plasma resonance and cell based assays. To improve pharmacokinetics and enhance peptide stability, BINDEN-AP peptide was conjugated to Core-Crosslinked Polymeric Micelles (CCPM). Anti-tumor and anti-angiogenic effects of BINDEN-AP peptide and its conjugate with CCPM were evaluated using orthotopic human A2789cp20-Luc ovarian cancer xenograft model, and PDX model of high grade serous ovarian carcinoma (HGSC). Results: We found that BIDEN-AP was selectively internalized via receptor-mediated endocytosis, mediated phosphorylation of EphB4 and its downstream adaptor protein Crk1 (MAPK14), and suppressed invasion and epithelial-to-mesenchymal transition in ovarian cancer cells. BIDEN-AP also inhibited endothelial migration and tube formation by 50% (p Conclusion: Given the robust anti-tumor effects of BIDEN-AP, these data could have direct relevance for further therapeutic development. Citation Format: Chiyi Xiong, Yunfei Wen, Jun Zhao, Dengke Yin, Lingyun Xu, Anca Chelariu-Raicu, Cody Yao, Xiaohong Leng, Jinsong Liu, Rajan R Chaudhari, Shuxing Zhang, Anil K Sood, Chun Li. Targeting forward and reverse EphB4/EFNB2 signaling by a peptide with dual functions [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 122.

Objective: Autophagic cell death is an important mechanism induced by blocking folate receptor (FRα) in inhibiting tumor growth. Here, our objective is to examine the biological effects of IMGN853 (mirvetuximab soravtansine) in preclinical models of ovarian cancer and to identify potential combination therapies. Methods: In vitro, immunoblotting, assays for cell viability, proliferation and cell cycle by fluorescence-activated cell sorting (FACS) were performed in an array of high grade serous carcinoma (HGSC) cell lines. Autophagy flux and activities of autophagy factors were also determined. In vivo, metastasis mouse models were used for testing the therapeutic efficacy of IMGN853 monotherapy or in combination with olaparib or cisplatin. Potential synergy with these drugs was assessed using in vitro assays. The resulting tumors were subjected to immunohistochemistry and reverse phase protein arrays (RPPA). Results: Data from the Cancer Genome Atlas Data (TCGA) revealed that FRα copy-number alterations was significantly correlated with shorter disease-free survival in patients with HGSC. Autophagy marker LC3 was upregulated following monotherapy with IMGN853 as well as in combination of IMGN853 with olaparib or cisplatin in HGSC cell lines such as OVCA8 and OVCA432, which express high-level of FRα. Experiments using metastatic HGSC models showed that IMGN853 monotherapy reduced tumor growth (30% change); the combination of IMGN853 and olaparib was superior to olaparib monotherapy (24% change; p 0.0033). Integrated analysis on RPPA revealed increased expression of ABL1 and PEA15 in the groups treated with IMGN853 monotherapy or in combination with olaparib. We further found reduced FRα expression and increased caspase 3 expression in IMGN853 groups compared with control. Conclusion: Our results point to sustained autophagy in FRα positive cells as a mechanism of effect of IMGN853. These findings could have implications for clinical development of anti-FRα therapies, especially in combination with other drugs such as olaparib. Citation Format: Anca Chelariu-Raicu, Elaine Stur, Cristina Ivan, Robert L. Coleman, Anil K. Sood, Wen Yunfei. Biological effects of a FRα-targeting antibody-drug conjugate, IMGN853 (mirvetuximab soravtansine) in high-grade serous ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1237.

6059 Background: The epidermal growth factor receptor (EGFR) is expressed in many types of cancer. Fifty to 70% of epithelial ovarian can overexpress EGFR, and its expression has been correlated with poor prognosis features in many cases. While these tumors are chemosensitive to platinum-based therapy, chemoresistance often develops. We conducted a phase I/II trial to examine the efficacy, safety, and toxicity of gefitinib, a tyrosine kinase inhibitor, combined with topotecan in women with recurrent ovarian cancer with EGFR receptor positivity (1+ or greater). Methods: Patients with measurable, recurrent or persistent cancer after treatment with a platinum and paclitaxel-containing regimen were eligible for this study (n = 19). We first used “run-in” dose escalation, in which a conventional 3+3 algorithm was used. Initial treatment was gefitinib 250 mg oral dose daily and topotecan at a dose of 2.0 mg/m2 on days 1, 8, and 15, with cycles repeated every 28 days. Dose escalations were planned for topotecan (Dose Levels 1–3: 2, 3, 4 mg/m2) until the MTD was reached. Next, an additional 10 patients with refractory or progressive ovarian cancer were enrolled in the phase II study. Results: 19 patients received a total of 61 cycles. Median age was 60 years. Histological types of treated patients included 73% serous (n = 14), 12.5% mixed (n = 2), 12.5% transitional (n = 2) and 6.3% clear cell (n = 1). There were 3 patients treated at dose level 1, 3 patients at dose level 2, and 3 patients treated at dose level 3. The maximum tolerated dose was topotecan 4.0mg/m2 IV days 1, 8 and 15, and gefitinib 250mg p.o. QD x28 days. Therefore, dose level 3 was used for the Phase II portion of the trial. Of the 19 patients included in the phase I/II, 3 patients were inevaluable for response to therapy due to toxicity, missed therapy or decline in performance status. Of the 16 patients, 81% patients (n = 13) had progressive disease, 12.5% stable disease (n = 2), and 6% partial response (n = 1). We assessed all 19 patients for adverse events; 60% had treatment-related grade 3 events, primarily blood disorders such as anemia (n = 3, 16%), neutrophil count decrease (n = 4, 21%). Conclusions: This prospective phase I/II clinical trial failed to show sufficient clinical activity of topotecan in combination with gefitinib in patients with EGFR-positive recurrent ovarian, fallopian tube, or peritoneal cancers. The drug combination was relatively well-tolerated in this cohort. As such, the study did not proceed to the next accrual goal secondary to the lack of response. Clinical trial information: NCT00317772.

Objective To study the expression and function of syndecan-4 in endometriosis. Design Histopathological investigation of eutopic endometrium and experimental laboratory study on a cell line derived from epithelial endometriotic cells (12Z). Setting University hospital laboratory. Patient(s) One hundred six women (62 controls/44 endometriosis) from the IVF center of Munster University Hospital aged 23–44 undergoing Pipelle biopsy and diagnostic exploratory laparoscopy. Intervention(s) Eutopic endometrial tissue was investigated by immunohistochemistry for the expression of syndecan-4. The human endometriotic cell line 12Z was transiently transfected with syndecan-4 small interfering RNA and investigated for changes in cell behavior. Main Outcome Measure(s) Syndecan-4 expression in eutopic endometrium was evaluated immunohistochemically in endometrial glands and stroma. Scoring results were correlated with the stages of the menstrual cycle and presence or absence of endometriosis. Quantitative polymerase chain reaction was used to measure syndecan-4-dependent expression changes of MMP2, MMP3, MMP9, Rac1, and ATF2. Altered cell behavior was monitored by matrigel invasion assays and cell viability assays. Result(s) Syndecan-4 expression was significantly higher in the glands and stroma of patients with endometriosis compared with controls, whereas no menstrual cycle–dependent expression was observed. In 12Z cells, syndecan-4 depletion did not affect cell viability but resulted in a significantly reduced matrigel invasiveness and reduced expression of the small GTPase Rac1, the transcription factor ATF-2, and MMP3. Conclusion(s) The upregulation of syndecan-4 in the eutopic endometrium of endometriosis patients may facilitate the pathogenetic process by promoting invasive cell growth via Rac1, MMP3, and ATF-2.