Ovarian cancer is the second most common cause of gynecologic cancer death in women around the world. The outcomes are complicated, because the disease is often diagnosed late and composed of several subtypes with distinct biological and molecular properties (even within the same histological subtype), and there is inconsistency in availability of and access to treatment. Upfront treatment largely relies on debulking surgery to no residual disease and platinum‐based chemotherapy, with the addition of antiangiogenic agents in patients who have suboptimally debulked and stage IV disease. Major improvement in maintenance therapy has been seen by incorporating inhibitors against poly (ADP‐ribose) polymerase (PARP) molecules involved in the DNA damage‐repair process, which have been approved in a recurrent setting and recently in a first‐line setting among women with BRCA1/BRCA2 mutations. In recognizing the challenges facing the treatment of ovarian cancer, current investigations are enlaced with deep molecular and cellular profiling. To improve survival in this aggressive disease, access to appropriate evidence‐based care is requisite. In concert, realizing individualized precision medicine will require prioritizing clinical trials of innovative treatments and refining predictive biomarkers that will enable selection of patients who would benefit from chemotherapy, targeted agents, or immunotherapy. Together, a coordinated and structured approach will accelerate significant clinical and academic advancements in ovarian cancer and meaningfully change the paradigm of care.

The basic helix-loop-helix (bHLH) transcription factors HEB and E2A are critical mediators of gene regulation during lymphocyte development. We have cloned a new transcription factor, called HEBAlt, from a pro-T cell cDNA library. HEBAlt is generated by alternative transcriptional initiation and splicing from the HEB gene locus, which also encodes the previously characterized E box protein HEBCan. HEBAlt contains a unique N-terminal coding exon (the Alt domain) that replaces the first transactivation domain of HEBCan. Downstream of the Alt domain, HEBAlt is identical to HEBCan, including the DNA binding domain. HEBAlt is induced in early thymocyte precursors and down-regulated permanently at the double negative to double positive (DP) transition, whereas HEBCan mRNA expression peaks at the DP stage of thymocyte development. HEBAlt mRNA is up-regulated synergistically by a combination of HEBCan activity and Delta-Notch signaling. Retroviral transduction of HEBAlt or HEBCan into hemopoietic stem cells followed by OP9-DL1 coculture revealed that HEBAlt-transduced precursors generated more early T lineage precursors and more DP pre-T cells than control transduced cells. By contrast, HEBCan-transduced cells that maintained high level expression of the HEBCan transgene were inhibited in expansion and progression through T cell development. HEB−/− fetal liver precursors transduced with HEBAlt were rescued from delayed T cell specification, but HEBCan-transduced HEB−/− precursors were not. Therefore, HEBAlt and HEBCan are functionally distinct transcription factors, and HEBAlt is specifically required for the efficient generation of early T cell precursors.

Purpose: PARP inhibitors (PARPi) are standard-of-care therapy for high-grade serous ovarian cancer (HGSOC). We investigated combining cediranib (antiangiogenic) with olaparib (PARPi) at emergence of PARPi resistance.Patients and Methods: The proof-of-concept EVOLVE study (NCT-02681237) assessed cediranib-olaparib combination therapy after progression on a PARPi. Women with HGSOC and radiographic evidence of disease progression were enrolled into one of three cohorts: platinum sensitive after PARPi; platinum resistant after PARPi; or progression on standard chemotherapy after progression on PARPi (exploratory cohort). Patients received olaparib tablets 300 mg twice daily with cediranib 20 mg once daily until progression or unacceptable toxicity. The coprimary endpoints were objective response rate (RECIST v1.1) and progression-free survival (PFS) at 16 weeks. Archival tissue (PARPi-na€ ve) and baseline biopsy (post-PARPi) samples were mandatory. Genomic mechanisms of resistance were assessed by whole-exome and RNA sequencing.Results: Among 34 heavily pretreated patients, objective responses were observed in 0 of 11 (0%) platinum-sensitive patients, 2 of 10 (20%) platinum-resistant patients, and 1 of 13 (8%) in the exploratory cohort. Sixteen-week PFS rates were 55%, 50%, and 39%, respectively. The most common grade 3 toxicities were diarrhea (12%) and anemia (9%). Acquired genomic alterations at PARPi progression were reversion mutations in BRCA1, BRCA2, or RAD51B (19%); CCNE1 amplification (16%); ABCB1 upregulation (15%); and SLFN11 downregulation (7%). Patients with reversion mutations in homologous recombination genes and/or ABCB1 upregulation had poor outcomes.Conclusions: This is currently the largest post-PARPi study identifying genomic mechanisms of resistance to PARPis. In this setting, the activity of cediranib-olaparib varied according to the PARPi resistance mechanism.

There was an error published in Development 139, 373-384.In the legend to Fig. 10, the authors incorrectly stated that donor cells were injected intrathymically rather than intravenously. The correct figure legend appears below. The authors apologise to readers for this mistake.

The development of T cells from multipotent progenitors in the thymus occurs by cascades of interactions between signaling molecules and transcription factors, resulting in the loss of alternative lineage potential and the acquisition of the T-cell functional identity. These processes require Notch signaling and the activity of GATA3, TCF1, Bcl11b, and the E-proteins HEB and E2A. We have shown that HEB factors are required to inhibit the thymic NK cell fate and that HEBAlt allows the passage of T-cell precursors from the DN to DP stage but is insufficient for suppression of the NK cell lineage choice. HEB factors are also required to enforce the death of cells that have not rearranged their TCR genes. The synergistic interactions between Notch1, HEBAlt, HEBCan, GATA3, and TCF1 are presented in a gene network model, and the influence of thymic stromal architecture on lineage choice in the thymus is discussed.

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BackgroundDrug resistance in breast cancer is the major obstacle to effective treatment with chemotherapy. While upregulation of multidrug resistance genes is an important component of drug resistance mechanisms in vitro, their clinical relevance remains to be determined. Therefore, identifying pathways that could be targeted in the clinic to eliminate anthracycline-resistant breast cancer remains a major challenge.MethodsWe generated paired native and epirubicin-resistant MDA-MB-231, MCF7, SKBR3 and ZR-75-1 epirubicin-resistant breast cancer cell lines to identify pathways contributing to anthracycline resistance. Native cell lines were exposed to increasing concentrations of epirubicin until resistant cells were generated. To identify mechanisms driving epirubicin resistance, we used a complementary approach including gene expression analyses to identify molecular pathways involved in resistance, and small-molecule inhibitors to reverse resistance. In addition, we tested its clinical relevance in a BR9601 adjuvant clinical trial.ResultsCharacterisation of epirubicin-resistant cells revealed that they were cross-resistant to doxorubicin and SN-38 and had alterations in apoptosis and cell-cycle profiles. Gene expression analysis identified deregulation of histone H2A and H2B genes in all four cell lines. Histone deacetylase small-molecule inhibitors reversed resistance and were cytotoxic for epirubicin-resistant cell lines, confirming that histone pathways are associated with epirubicin resistance. Gene expression of a novel 18-gene histone pathway module analysis of the BR9601 adjuvant clinical trial revealed that patients with low expression of the 18-gene histone module benefited from anthracycline treatment more than those with high expression (hazard ratio 0.35, 95 % confidence interval 0.13–0.96, p = 0.042).ConclusionsThis study revealed a key pathway that contributes to anthracycline resistance and established model systems for investigating drug resistance in all four major breast cancer subtypes. As the histone modification can be targeted with small-molecule inhibitors, it represents a possible means of reversing clinical anthracycline resistance.Trial registrationClinicalTrials.gov identifier NCT00003012. Registered on 1 November 1999.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0676-6) contains supplementary material, which is available to authorized users.

5521 Background: PARP inhibitors (PARPi) are approved therapies in high grade serous ovarian cancer (HGSOC). There are few studies after PARPi progression and correlation with dynamic changes in resistance. We hypothesized that PARPi resistance could be overcome by adding an anti-angiogenic. Methods: We report the first phase 2 trial assessing the combination of olaparib and cediranib after PARPi failure in HGSOC. This investigator initiated study included three cohorts of 10 evaluable patients (pts): i) platinum sensitive post PARPi (PS), ii) platinum resistant post PARPi (PR) and iii) exploratory cohort of pts re-challenged with chemotherapy post PARPi progression (PE) (NCT02681237). The primary objective was to determine objective response rate by RECIST v1.1 and progression free survival (PFS) at 16 weeks. Secondary objectives were to evaluate safety, PFS, overall survival (OS) and mechanisms of PARPi resistance. Pts who had radiographic progression on any PARPi were eligible. Archival tumor at initial diagnosis and baseline tumor biopsy at PARPi progression were mandatory. Pts received olaparib tablets 150mg BID with cediranib 20mg QD until progression or unacceptable toxicity. CT scans were performed every 8 weeks. Whole exome and RNA sequencing were performed on paired tumors tissues. Results: Thirty-four pts were enrolled. BRCA1/2 mutations were found in 9/11 PS, 8/10 PR and 7/13 PE pts. By RECIST1.1, four partial responses were observed (2 in PR and 2 in PE cohorts) and 18 stable disease. The 16−week PFS was 54.5% (31.8−93.6) in PS, 50% (26.9−92.9) in PR and 36% (15.6−82.8) in PE, respectively. OS at 1 year was 81.8% (61.9−100) in PS, 64.8% (39.3−100) in PR and 39.1% (14.7−100) in PE. Main related adverse events were anemia, hypertension, diarrhea and fatigue, grade 3 < 10%. Molecular analyses identified different mechanisms of PARPi resistance in ~77% of evaluable pts with matched pre-post PARPi progression biopsies such as reversion mutations in BRCA1/2 and other homologous repair (HR) genes; BRCA, HR and MDR upregulation, CCNE amplification and RIG-I like receptor downregulation. Conclusions: Treatment with olaparib-cediranib after PARPi failure was feasible and met the predefined bar for efficacy in each cohort. This is the largest clinical trial prospectively evaluating PARPi failure and correlating tissue genomic mechanisms of resistance. Clinical trial information: NCT02681237.