High throughput screening identifies dasatinib as synergistic with trametinib in low grade serous ovarian carcinoma.

BACKGROUND: Low grade serous ovarian carcinoma (LGSOC) is a distinct histotype of ovarian cancer characterised high levels of intrinsic chemoresistance, highlighting the urgent need for new treatments. High throughput screening in clinically-informative cell-based models represents an attractive strategy for identifying candidate treatment options for prioritisation in clinical studies. METHODS: We performed a high throughput drug screen of 1610 agents across a panel of 6 LGSOC cell lines (3 RAS/RAF-mutant, 3 RAS/RAF-wildtype) to identify novel candidate therapeutic approaches. Validation comprised dose-response analysis across 9 LGSOC models and 5 high grade serous comparator lines. RESULTS: 16 hits of 1610 screened compounds were prioritised for validation based on >50% reduction in nuclei counts in over half of screened cell lines at 1000 nM concentration. 11 compounds passed validation, and the four agents of greatest interest (dasatinib, tyrosine kinase inhibitor; disulfiram, aldehyde dehydrogenase inhibitor; carfilzomib, proteasome inhibitor; romidepsin, histone deacetylase inhibitor) underwent synergy profiling with the recently approved MEK inhibitor trametinib. Disulfiram demonstrated excellent selectivity for LGSOC versus high grade serous ovarian carcinoma comparator lines (P = 0.003 for IC50 comparison), while the tyrosine kinase inhibitor dasatinib demonstrated favourable synergy with trametinib across multiple LGSOC models (maximum zero interaction potency synergy score 46.9). The novel, highly selective Src family kinase (SFK) inhibitor NXP900 demonstrated a similar trametinib synergy profile to dasatinib, suggesting that SFK inhibition is the likely driver of synergy. CONCLUSION: Dasatinib and other SFK inhibitors represent novel candidate treatments for LGSOC and demonstrate synergy with trametinib. Disulfiram represents an additional treatment strategy worthy of investigation.

Compartment-specific multiomic profiling identifies SRC and GNAS as candidate drivers of epithelial-to-mesenchymal transition in ovarian carcinosarcoma.

BACKGROUND: Ovarian carcinosarcoma (OCS) is an exceptionally aggressive and understudied ovarian cancer type harbouring distinct carcinomatous and sarcomatous compartments. Here, we seek to identify shared and compartment-specific events that may represent potential therapeutic targets and candidate drivers of sarcomatous compartment formation through epithelial-to-mesenchymal transition (EMT). METHODS: We performed multiomic profiling (exome sequencing, RNA-sequencing, microRNA profiling) of paired carcinomatous and sarcomatous components in 12 OCS cases. RESULTS: While paired sarcomatous and carcinomatous compartments demonstrate substantial genomic similarities, multiple loci are recurrently copy number-altered between components; regions containing GNAS and SRC are recurrently gained within the sarcomatous compartment. CCNE1 gain is a common event in OCS, occurring more frequently than in high grade serous ovarian carcinoma (HGSOC). Transcriptomic analysis suggests increased MAPK activity and subtype switching toward poor prognosis HGSOC-derived transcriptomic subtypes within the sarcomatous component. The two compartments show global differences in microRNA profiles, with differentially expressed microRNAs targeting EMT-related genes (SIRT1, ZEB2) and regulators of pro-tumourigenic pathways (TGFß, NOTCH); chrX is a highly enriched target of these microRNAs and is also frequently deleted across samples. The sarcomatous component harbours significantly fewer CD8-positive cells, suggesting poorer immune engagement. CONCLUSION: CCNE1 gain and chrX loss are frequent in OCS. SRC gain, increased GNAS expression and microRNA dysregulation represent potential mechanisms driving sarcomatous compartment formation.

Development of Homologous Recombination Functional Assays for Targeting the DDR.

Identification of tumours that have homologous recombination deficiency (HRD) has become of increasing interest following the licensing of PARP inhibitors. Potential methods to assess HRD status include; clinical selection for platinum sensitive disease, mutational/methylation status, genomic scars/signature and functional RAD51 assays. Homologous recombination (HR) is a dynamic process with the potential to evolve over a disease course, particularly in relation to previous treatment. This is one of the major drawbacks of genomic scars/signatures, as they only demonstrate historic HR status. Functional HR assays have the benefit of giving a real time HR status readout and therefore have the potential for clearer identification of patients who may benefit from PARP inhibitors at that specific time point. However, the development of RAD51 foci assays ready for clinical practice has been challenging. Pre-clinical considerations have included; controlling for variation in tumour proliferation, tissue type and whether DNA damage induction is required. Furthermore, the assays require correlation with clinical outcomes, an understanding of how they complement current testing modalities and validation of test performance in large cohorts. Despite these challenges, given the profound benefit from PARP inhibitors seen in those with an HRD phenotype to date, the ongoing development and validation of these functional HR assays remains of high clinical importance.

Aromatase inhibition plus/minus Src inhibitor saracatinib (AZD0530) in advanced breast cancer therapy (ARISTACAT): a randomised phase II study.

PURPOSE: The development of oestrogen resistance is a major challenge in managing hormone-sensitive metastatic breast cancer. Saracatinib (AZD0530), an oral Src kinase inhibitor, prevents oestrogen resistance in animal models and reduces osteoclast activity. We aimed to evaluate the efficacy of saracatinib addition to aromatase inhibitors (AI) in patients with hormone receptor-positive metastatic breast cancer. METHODS: This phase II multicentre double-blinded randomised trial allocated post-menopausal women to AI with either saracatinib or placebo (1:1 ratio). Patients were stratified into an "AI-sensitive/naïve" group who received anastrozole and "prior-AI" group who received exemestane. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and toxicity. RESULTS: 140 patients were randomised from 20 UK centres to saracatinib/AI (n = 69) or placebo/AI (n = 71). Saracatinib was not associated with an improved PFS (3.7 months v. 5.6 months placebo/AI) and did not reduce likelihood of bony progression. There was no benefit in OS or ORR. Effects were consistent in "AI-sensitive/naive" and "prior-AI" sub-groups. Saracatinib was well tolerated with dose reductions in 16% and the main side effects were gastrointestinal, hypophosphatemia and rash. CONCLUSION: Saracatinib did not improve outcomes in post-menopausal women with metastatic breast cancer. There was no observed beneficial effect on bone metastases. CRUKE/11/023, ISRCTN23804370.

Long-Term Effects of Teriparatide Followed by Antiresorptive Therapy on Clinical Outcomes in Patients with Severe Spinal Osteoporosis.

Teriparatide (TPTD) is the most widely used anabolic agent in the treatment of patients with osteoporosis although its use is restricted in many countries. A recent randomised trial confirmed that TPTD was superior to risedronate at preventing vertebral fractures over a 2-year period. There is limited information on the relative effectiveness of TPTD compared with standard care in routine clinical practice. In this paper, we report the results of an extended observational study of 724 women referred to a specialist clinic with severe osteoporosis over an 11.5-year period, who were considered for TPTD therapy. Of these patients, 496 (68.5%) were treated with TPTD, whereas the remaining 228 (31.5%) received other treatments. This was either because they were unwilling or unable to self-inject (52.6%), because they had already been established on oral bisphosphonates (31.1%) or because of contraindications (12.7%). The TPTD group were younger than the standard care group (69.6 vs. 74.1 years) and had a lower 10-year fracture risk (25.7% vs. 28.6%). Those treated with TPTD had a greater increase in BMD at the lumbar spine compared with standard care (13.3% vs. 8.2%, p < 0.001) after approximately 2 years and had a lower incidence of vertebral fractures (4.8% vs. 10.1%, p = 0.01) over the course of our observation. There was no difference between groups with respect to either BMD change at the femoral neck or incidence of non-vertebral fractures. This study confirms that TPTD is superior to standard care at reducing the risk of vertebral fracture in patients with severe osteoporosis.

Low-grade epithelial ovarian cancer: a number of distinct clinical entities?

PURPOSE OF REVIEW: The purpose of this study is to summarize the contemporary understanding of low-grade epithelial ovarian cancers. RECENT FINDINGS: Low-grade serous ovarian cancer is biologically distinct from high-grade serous ovarian cancer. It is associated with a high incidence of K-RAS and B-RAF mutations. Although described as indolent due to median progression-free and overall survivals of 20 and 99 months, respectively, with a median age of diagnosis of 43 years, it accounts for a significant number of patient-years lost. Retrospective studies suggest response rates of 5% for chemotherapy and 9% for antioestrogen therapy. A prospective study of the mitogen-activated protein kinase kinase inhibitor selumetinib (response rate 15%) and retrospective bevacizumab studies suggest that these may be more effective approaches.Limited retrospective clinical data and even more sparse molecular data suggest that similar distinctions may exist between low-grade endometrioid and mucinous ovarian cancers and their respective high-grade counterparts, but more research is required in order to clarify the biological differences and the implications that these have for management. SUMMARY: The results of phase III mitogen-activated protein kinase kinase inhibitor studies in low-grade serous ovarian cancer and further clinical and biological assessment of low-grade endometrioid and mucinous ovarian cancers are urgently required.

Teriparatide treatment of severe osteoporosis reduces the risk of vertebral fractures compared with standard care in routine clinical practice.

Teriparatide (TPTD) is often used for the treatment of patients with severe osteoporosis, but its effectiveness in this patient group has not been specifically studied. Here, we report upon the results of an observational study involving 323 patients with severe osteoporosis (bone density T-score of -4 or less) who were treated at a specialist osteoporosis clinic with TPTD (n = 217) or standard care (n = 106) over a 5.5-year period. The standard care group did not receive TPTD because they declined to self-inject (59.4%), had a contraindication (7.5%), or were already stabilized on oral bisphosphonates (33%). The two groups were matched for the severity of osteoporosis, fracture risk, and most other clinical variables. The annual percentage change in lumbar spine bone mineral density (BMD) was greater in the TPTD group (8.2 ± 6.0 vs. 5.0 ± 8.4, p = 0.002), but there was no difference in response of hip BMD. During follow-up, 3/217 (1.38%) TPTD-treated patients had new vertebral fractures compared with 7/106 (6.6%) receiving standard care (p = 0.011), but there was no difference between the groups in the rate of nonvertebral fractures (11.1 vs. 8.5%, p = 0.47). Logistic regression analysis adjusting for baseline characteristics showed that the risk of vertebral fractures in TPTD-treated patients was significantly reduced compared with standard care (odds ratio = 0.12, 95% confidence interval 0.03-0.55, p = 0.007). Treatment of severe spinal osteoporosis with TPTD substantially reduces the risk of vertebral fractures compared with standard care and may be the preferred treatment in this patient group.