Xevinapant combined with pembrolizumab in patients with advanced, pretreated colorectal and pancreatic cancer: results of the phase 1b/2 CATRIPCA trial.

PURPOSE: Xevinapant is an orally available inhibitor of apoptosis proteins (IAP) inhibitor. Preclinical data suggest that IAP antagonism may synergize with immune checkpoint blockers (ICB) by modulating the NF-KB pathway in immune cells. PATIENTS AND METHODS: Adult patients (pts) with non MSI-H advanced/metastatic PDAC or CRC were enrolled in this phase 1b/2 and received pembrolizumab 200mg q3w, IV and ascending doses of oral xevinapant (100, 150 and 200mg daily for 14 days on/7 days off). Dose escalation followed a 3+3 design with a 21-day dose-limiting toxicity (DLT) evaluation period. Following the determination of the recommended phase II dose (RP2D), 14 patients with PDAC and 14 patients with CRC were enrolled in expansion cohorts to assess preliminary efficacy. RESULTS: Forty-one pts (26 males) with a median age of 64 years were enrolled: 13 in the dose escalation and 28 in the two expansion cohorts. No DLT was observed during dose-escalation. The RP2D was identified as xevinapant 200mg/d + pembrolizumab 200mg q3w. The most common adverse events (AE) were fatigue (37%), gastrointestinal AE (decreased appetite in 37%, nausea in 24%, stomatitis in 12 % and diarrhea and vomiting in 10% each), and cutaneous AE (pruritus, dry skin and rash seen in 20, 15 and 15% of patients respectively). The best overall response according to RECIST1.1 was partial response (PR, confirmed) in one (3%) , stable disease (SD) in four (10%) and progressive disease in 35 (88%). CONCLUSIONS: Xevinapant combined with pembrolizumab was well tolerated with no unexpected adverse events. However, anti-tumor activity was low.

p4EBP1 staining predicts outcome in ER-positive endocrine-resistant metastatic breast cancer patients treated with everolimus and exemestane.

BACKGROUND: To identify patients most likely to respond to everolimus, a mammalian target of rapamycin (mTOR) inhibitor, a prospective biomarker study was conducted in hormone receptor-positive endocrine-resistant metastatic breast cancer patients treated with exemestane-everolimus therapy. METHODS: Metastatic tumor biopsies were processed for immunohistochemical staining (p4EBP1, PTEN, pAKT, LKB1, and pS6K). ESR1, PIK3CA and AKT1 gene mutations were detected by NGS. The primary endpoint was the association between the p4EBP1 expression and clinical benefit rate (CBR) at 6 months of everolimus plus exemestane treatment. RESULTS: Of 150 patients included, 107 were evaluable for the primary endpoint. p4EBP1 staining above the median (Allred score ≥6) was associated with a higher CBR at 6 months (62% versus 40% in high-p4EBP1 versus low-p4EBP1, χ2 test, p = 0.026) and a longer progression-free survival (PFS) (median PFS of 9.2 versus 5.8 months in high-p4EBP1 versus low-p4EBP1; p = 0.02). When tested with other biomarkers, only p4EBP1 remained a significant predictive marker of PFS in multivariate analysis (hazard ratio, 0.591; p = 0.01). CONCLUSIONS: This study identified a subset of patients with hormone receptor-positive endocrine-resistant metastatic breast cancer and poor outcome who would derive less benefit from everolimus and exemestane. p4EBP1 may be a useful predictive biomarker in routine clinical practice. CLINICAL TRIAL REGISTRATION: NCT02444390.

Thioredoxins m regulate plastid glucose-6-phosphate dehydrogenase activity in Arabidopsis roots under salt stress.

Plants contain several NADPH-producing enzymes including glucose-6-phosphate dehydrogenases (G6PDH) with different sub-cellular localizations. The activity of plastidial G6PDHs is redox-regulated by thioredoxins (TRX). Although specific TRXs are known to regulate chloroplastic isoforms of G6PDH, little information is available for plastidic isoforms found in heterotrophic organs or tissues. Here, we investigated TRX regulation of the two G6PDH plastidic isoforms of Arabidopsis roots during exposure to a mild salt stress. We report that in vitro m-type TRXs are the most efficient regulators of the G6PDH2 and G6PDH3 mainly found in Arabidopsis roots. While expression of the corresponding G6PD and plastidic TRX genes was marginally affected by salt, it impaired root growth of several of the corresponding mutant lines. Using an in situ assay for G6PDH, G6PDH2 was found to be the major contributor to salt-induced increases in activity, while data from ROS assays further provide in vivo evidence that TRX m acts in redox regulation during salt stress. Taken together, our data suggest that regulation of plastid G6PDH activity by TRX m may be an important player regulating NADPH production in Arabidopsis roots undergoing salt stress.

Impact of surgery and chemotherapy in ovarian sex cord-stromal tumors from the multicentric Salomé study including 469 patients. A TMRG and GINECO group study.

OBJECTIVE: Identifying prognostic factors and evaluating the impact of adjuvant chemotherapy in patients with sex cord stromal tumors (SCST) is crucial. In this study, we aimed to address these challenges. METHODS: We conducted a retrospective analysis of data from 13 centers of the French Rare malignant gynecological tumors (TMRG) network. We enrolled 469 adult patients with malignant SCST who received upfront surgery since 2011 to July 2015. RESULTS: 75% were diagnosed with adult Granulosa cell tumors, and 23% had another subtype. With a median follow-up of 6.4 years, 154 patients (33%) developed a first recurrence, 82 (17%) two recurrences, and 49 (10%) three recurrences. Adjuvant chemotherapy was administered in 14.7% of patients at initial diagnosis. In relapse, perioperative chemotherapy was administered in 58.5%, 28.2%, and 23.8% of patients, respectively, in the first, second, and third relapse. In the first-line therapy, age under 70 years, FIGO stage, and complete surgery were associated with longer progression-free survival (PFS). Chemotherapy had no impact on PFS in early-stage disease (FIGO I-II). The PFS was similar using BEP or other chemotherapy regimens (HR 0.88 [0.43; 1.81]) in the first-line therapy. In case of recurrence, PFS was statistically prolonged by complete surgery, but perioperative chemotherapy use did not impact PFS. CONCLUSION: Chemotherapy use did not impact survival in the first-line or relapse setting in SCST. Only surgery and its quality demonstrated benefit for PFS in ovarian SCST in any lines of treatment.

S-Nitrosylation of the histone deacetylase HDA19 stimulates its activity to enhance plant stress tolerance in Arabidopsis.

Arabidopsis histone deacetylase HDA19 is required for gene expression programs of a large spectrum of plant developmental and stress-responsive pathways. How this enzyme senses cellular environment to control its activity remains unclear. In this work, we show that HDA19 is post-translationally modified by S-nitrosylation at 4 Cysteine (Cys) residues. HDA19 S-nitrosylation depends on the cellular nitric oxide level, which is enhanced under oxidative stress. We find that HDA19 is required for cellular redox homeostasis and plant tolerance to oxidative stress, which in turn stimulates its nuclear enrichment, S-nitrosylation and epigenetic functions including binding to genomic targets, histone deacetylation and gene repression. The Cys137 of the protein is involved in basal and stress-induced S-nitrosylation, and is required for HDA19 functions in developmental, stress-responsive and epigenetic controls. Together, these results indicate that S-nitrosylation regulates HDA19 activity and is a mechanism of redox-sensing for chromatin regulation of plant tolerance to stress.

Immunotherapy for Soft Tissue Sarcomas: Anti-PD1/PDL1 and Beyond.

Sarcomas gather a heterogeneous group of mesenchymal malignant tumors including more than 150 different subtypes. Most of them represent aggressive tumors with poor prognosis at the advanced stage, despite the better molecular characterization of these tumors and the development of molecular-driven therapeutic strategies. During the last decade, immunotherapy has been developed to treat advanced cancers, mainly thanks to immune checkpoint inhibitors (ICI) such as anti-PD1/PDL1 and later to adoptive immune cell therapies. In this review, we aim to summarize the state of the art of immunotherapy in soft tissue sarcomas (STS). Overall, the clinical trials of ICI that included a wide diversity of STS subtypes reported limited efficacy with some outlying responders. Both emerging biomarkers are of interest in selecting good candidates and in the development of combination therapies. Finally, the recent breakthroughs of innovative adoptive therapies in STS seem highly promising.

Expanding the molecular spectrum of tenosynovial giant cell tumors.

Background: While great advances in clinical and pathological description of tenosynovial giant cell tumors (TGCT) have been made, TGCT molecular heterogeneity represents an ongoing challenge. The canonical oncogenic fusion CSF1::COL6A3 is not systematically observed, suggesting that other oncogenic mechanisms are involved in tumorigenesis. This study aims to explore by RNA sequencing a retrospective series of tumors diagnosed as TGCT, in order to provide a better description of their molecular landscape and to correlate molecular features with clinical data. Methods: We analyzed clinicopathological data and performed whole-exome RNA sequencing on 41 TGCT samples. Results: RNAseq analysis showed significant higher CSF1 and CSF1-R expression than a control panel of 2642 solid tumors. RNA sequencing revealed fusion transcripts in 14 patients including 6 not involving CSF1 and some previously unreported fusions. Unsupervised clustering on the expression profiles issued from this series suggested two distinct subgroups: one composed of various molecular subtypes including CSF1 and FN1 rearranged samples and one composed of four tumors harboring an HMGA2::NCOR2 fusion, suggesting distinct tumor entities. Overall, 15 patients received at least one systemic anti-CSF1R treatment and clinical improvement was observed in 11 patients, including patients from both clusters. Discussion: This study reported molecular heterogeneity in TGCT, contrasting with the clinical and pathological homogeneity and the ubiquitous high CSF1 and CSF1R expression levels. Whether molecular diversity may impact the efficacy of systemic treatments needs to be further investigated.

Adenylates regulate Arabidopsis plastidial thioredoxin activities through the binding of a CBS domain protein.

Cystathionine-ß-synthase (CBS) domains are found in proteins of all living organisms and have been proposed to play a role as energy sensors regulating protein activities through their adenosyl ligand binding capacity. In plants, members of the CBSX protein family carry a stand-alone pair of CBS domains. In Arabidopsis (Arabidopsis thaliana), CBSX1 and CBSX2 are targeted to plastids where they have been proposed to regulate thioredoxins (TRXs). TRXs are ubiquitous cysteine thiol oxido-reductases involved in the redox-based regulation of numerous enzymatic activities as well as in the regeneration of thiol-dependent peroxidases. In Arabidopsis, 10 TRX isoforms have been identified in plastids and divided into five sub-types. Here, we show that CBSX2 specifically inhibits the activities of m-type TRXs toward two chloroplast TRX-related targets. By testing activation of NADP-malate dehydrogenase and reduction of 2-Cys peroxiredoxin, we found that TRXm1/2 inhibition by CBSX2 was alleviated in the presence of AMP or ATP. We also determined, by pull-down assays, a direct interaction of CBSX2 with reduced TRXm1 and m2 that was abolished in the presence of adenosyl ligands. In addition, we report that, compared with wild-type plants, the Arabidopsis T-DNA double mutant cbsx1 cbsx2 exhibits growth and chlorophyll accumulation defects in cold conditions, suggesting a function of plastidial CBSX proteins in plant stress adaptation. Together, our results show an energy-sensing regulation of plastid TRX m activities by CBSX, possibly allowing a feedback regulation of ATP homeostasis via activation of cyclic electron flow in the chloroplast, to maintain a high energy level for optimal growth.

CIC-DUX4 sarcomas.

PURPOSE OF REVIEW: CIC-DUX4 sarcoma (CDS) is a high-grade undifferentiated round cells sarcoma that belongs to the undifferentiated round cell sarcomas family. It represents less than one percent of sarcomas, defining a rarest among rare malignancies. It affects young adults, displaying soft tissue mass. Considered very aggressive, a high proportion of cases display an advanced disease with lung metastasis at diagnosis. Here we discuss recent progress in molecular characterization of CDS, the main tracks of CDS biology and the current and future prospects of therapeutic approaches. RECENT FINDINGS: CDS is characterized by a specific oncogenic translocation CIC::DUX4 that induce ETV4 overexpression. Patients with CDS show an aggressive clinical course and have a significantly unfavorable outcome compared to Ewing sarcoma. As of today, there is a lack of consensus on whether they should be treated with an Ewing-like approach, as currently done by most sites, or regarded as high-grade soft tissue sarcoma (STS). Anyway, when feasible, combination regimens including anthracycline and alkylating agents should be favored and patients should not benefit from a therapeutic de-escalation. Overall, registration within clinical trials and prospective registries is recommended. SUMMARY: Overall, CDS showed a poor prognosis regardless of the patterns of treatment that warrant biological studies to better understand the disease.

Reasons for acceptance and refusal of early palliative care in patients included in early-phase clinical trials in a regional comprehensive cancer centre in France: protocol for a qualitative study.

INTRODUCTION: A few studies have highlighted the potential synergy between early palliative care and inclusion in an early-phase clinical trial that may improve quality of life, reduce symptoms of exhaustion related to the side effects of treatment and allow patients to complete their treatment protocol. The primary objective of this qualitative study is to evaluate the reasons for acceptance or refusal of early palliative care in patients included in early-phase clinical trials. METHOD AND ANALYSIS: All patients from the Centre Léon Bérard (Comprehensive Cancer Centre in Lyon, France) who consent to one of the early-phase clinical trials proposed at the centre will be invited to participate in this study. The cohort will consist of a subgroup (n=20) of patients who accept palliative care together with their clinical trial, and a second subgroup (n=20) of patients who decline it. Patients will be interviewed in exploratory interviews conducted by a psychology researcher before the start of their clinical trial. The interviews will be audio-recorded. Patients will also be asked to complete quality of life and anxiety/depression questionnaires both before the beginning of the treatment and at the end of their clinical trial. The content of the interviews will be analysed thematically. Descriptive and comparative statistical analysis of both cohorts will also be conducted. ETHICS AND DISSEMINATION: Personal data will be collected and processed in accordance with the laws and regulations in force. All patients will give informed consent to participate. This study complies with reference methodology MR004 of the Commission Nationale de l'Informatique et des Libertés. The protocol has received the validation of an ethics committee (Groupe de Réflexion Ethique du CLB, number: 2020-006). The results will be disseminated through conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT04717440.

[Bispecific antibodies targeting CD3 in oncology and hematology]. / Anticorps bispécifiques ciblant CD3 en oncologie solide et onco-hématologie.

Bispecific therapies targeting CD3, so-called T-cell engagers (TCE), belong to the new spectrum of anti-tumor immunotherapies stimulating T-lymphocytes. TCE are unique constructs targeting the MHC-independent CD3 epsilon subunit (CD3e) and a tumor antigen. To date, only blinatumomab have reached market agreements in lymphoid malignancies with constructs targeting CD3exCD19. Other TCE are in advances development, with promising results targeting CD20 and BSMA in lymphoma and myeloma. These successes have relaunched the development of TCE in solid tumors, bringing mixed results so far (notably in terms of tolerance). Still, TCE pave the way to new immunotherapy in tumors considered to be refractory to inhibitors of immune checkpoints such as prostate cancer or colorectal cancer.

Nouvelles stratégies thérapeutiques dans les cancers du sein HER2-surexprimé: New therapeutic strategies in HER2-positive breast cancer.

Breast cancer with HER2-amplification accounts for 20 % of breast cancers. The management of patients has dramatically changed with the advent of anti-HER2 treatment, especially the monoclonal antibodies since 2000 in the metastatic and (neo)-adjuvant setting, leading to an improvement of patient outcomes. If therapeutic arsenal has been gradually enhanced with the targeting of HER receptors family, resistances to these treatments are observed, hence the development of new therapeutic strategies. This review provides an updated look of novel therapeutic strategies in HER2-positive breast cancer, as well as future perspectives, both in the adjuvant and metastatic setting.

PARP-inhibitors in epithelial ovarian cancer: Actual positioning and future expectations.

Poly-(ADP)-ribose polymerase inhibitors (PARPi) are a class of oral anticancer drugs first developed as "synthetically lethal" in cancers harboring BRCA1/BRCA2 inactivating mutations. In high-grade serous or endometrioid ovarian cancers (HGOC), PARPi demonstrated benefit as maintenance therapy in relapsing BRCA-mutated and non-mutated tumors. Recently, they extended their indications to frontline maintenance therapy. This review summarizes the current place of PARPi (i) as maintenance or single agent in recurrent disease and (ii) frontline maintenance with different settings. We reviewed the course of biomarker identification, the challenge of overcoming resistance to PARPi and future combinations with targeted therapies, including anti-angiogenic, immune checkpoint inhibitors and DNA damage response inhibitors.

[New therapeutic strategies in HER2-positive breast cancer]. / Nouvelles stratégies thérapeutiques dans les cancers du sein HER2-surexprimé.

Breast cancer with HER2-amplification accounts for 20% of breast cancers. The management of patients has dramatically changed with the advent of anti-HER2 treatment, especially the monoclonal antibodies since 2000 in the metastatic and (neo)-adjuvant setting, leading to an improvement of patient outcomes. If therapeutic arsenal has been gradually enhanced with the targeting of HER receptors family, resistances to these treatments are observed, hence the development of new therapeutic strategies. This review provides an updated look of novel therapeutic strategies in HER2-positive breast cancer, as well as future perspectives, both in the adjuvant and metastatic setting.

Poly(ADP-ribose) polymerase inhibitors in combination with anti-angiogenic agents for the treatment of advanced ovarian cancer.

Homologous recombination deficiency and VEGF expression are key pathways in high-grade ovarian cancer. Recently, three randomized practice changing trials were published: the PAOLA-1, PRIMA and VELIA trials. The use of PARP inhibitors (PARPi) following chemotherapy has become standard of care in first line. Combination of PARPi with anti-angiogenic agents has demonstrated synergistic activity in preclinical study. This review summarizes the body of evidence supporting the efficacy and safety of the combination of PARPi and anti-angiogenic drugs in first-line homologous recombination deficiency high-grade ovarian cancer leading to US FDA and EMA approvals. This double maintenance is supported by: a large benefit with bevacizumab + olaparib compared with olaparib alone, a rationale for additive effect, and a good safety and cost-effective profile.

Lay abstract Ovarian cancers often present difficulties to repair their DNA and are highly vascularized tumors. Recently, three randomized practice changing trials were published: the PAOLA-1, PRIMA and VELIA trials. They use one type of therapy to target the difficulty of ovarian cancer to repair their DNA which is called poly(ADP-ribose) polymerase inhibitor. This type of therapy has become standard of care after chemotherapy. In this review, we discuss the advantage of combining anti-angiogenic agents to poly(ADP-ribose) polymerase inhibitors to target the fact that tumors are highly vascularized. First, data from laboratory suggest synergistic activity of the combination. Then, clinical data are also in favor of the combination due to additive efficacy, and a good safety and cost-effective profile.

SRF Fusions Other Than With RELA Expand the Molecular Definition of SRF-fused Perivascular Tumors.

Pericytic tumors encompass several entities sharing morphologic and immunohistochemical features. A subset of perivascular myoid tumors associated with the SRF-RELA fusion gene was previously described. Herein, we report a series of 13 tumors belonging to this group, in which we have identified new fusion genes by RNA-sequencing, thus expanding the molecular spectrum of this entity. All patients except 1 were children and infants. The tumors, frequently located in the head (n=8), had a mean size of 38 mm (range 10 to 150 mm) and were mostly (n=9) well-circumscribed. Exploration of the follow-up data (ranging from 3 to 68 mo) confirmed the benign behavior of these tumors. These neoplasms presented a spectrum of morphologies, ranging from perivascular patterns to myoid appearance. Tumor cells presented mitotic figures but without marked atypia. Some of these tumors could mimic sarcoma. The immunohistochemical profiles confirmed a pericytic differentiation with the expression of the smooth muscle actin and the h-caldesmon, as well as the frequent positivity for pan-cytokeratin. The molecular analysis identified the expected SRF-RELA fusion gene, in addition to other genetic alterations, all involving SRF fused to CITED1, CITED2, NFKBIE, or NCOA2. The detection of SRF-NCOA2 fusions in spindle cell rhabdomyosarcoma of the infant has previously been described, representing a risk of misdiagnosis, although the cases reported herein did not express MyoD1. Finally, clustering analyses confirmed that this group of SRF-fused perivascular myoid tumors forms a distinct entity, different from other perivascular tumors, spindle cell rhabdomyosarcomas of the infant, and smooth muscle tumors.

Therapeutic relevance of molecular screening program in patients with metastatic sarcoma: Analysis from the ProfiLER 01 trial.

BACKGROUND: Advanced sarcoma is a group of heterogeneous disease with poor prognosis and poor efficacy of medical treatment. They represent a promising group of tumors to assess molecular-based therapy (MBT) strategy. PATIENTS AND METHODS: Genomic profiles of patients with advanced sarcoma included in the ProfiLER program were established by NGS using a 69 genes panel and CGH array. A weekly molecular board reviewed genomic reports to select relevant genomic alterations and propose recommendations for MBT. RESULTS: A genomic profile was available for 158 of 164 patients. At least 1 relevant genomic alteration was reported for 106 patients (67%), with frequent multiple alterations (68%). In total, 289 relevant genomic alterations were identified in 143 different genes; 139 homozygous deletions, 86 gene amplifications and 64 somatic mutations. The most frequently impacted genes were TP53, Rb1, CDKN2A, CDK4, MDM2, and PTEN. MBT was recommended for 47 patients and initiated for 13 patients. One objective response was observed for an angiosarcoma treated with pazopanib for FLT4 amplification; 4 patients had a stable disease, including a long-lasting 33 months stabilization. CONCLUSION: Genomic profiling for advanced sarcoma is feasible, even for bone sarcoma. A small proportion of patients are eventually treated with MBT, similar to other tumor types. We could not demonstrate this strategy to be beneficial to patients. Our data suggest that molecular profiling should not be used in routine practice but warrants further exploration in clinical trials, focusing on sarcoma with complex genomic, and adding transcriptomic analysis to the copy number and mutational analyses.