TPS11592
Background: Single agent or combination chemotherapy regimens, typically including doxorubicin or gemcitabine, represent standard of care options for first- and second-line therapy in ...patients (pts) with metastatic LMS. However, response rates (ORR) and progression-free (PFS)/overall survival (OS) remain poor. Lurbinectedin (PharmaMar S.A. and Jazz Pharmaceuticals) uniquely binds DNA, inducing DNA double strand breaks leading to apoptosis and delaying progression through phase S/G2 of the cell cycle. Lurbinectedin is a novel structural analog of trabectedin with improved toxicity profile, potency, and pharmacokinetics. In a prior pilot study, we showed that the combination of lurbinectedin and doxorubicin (L+D) was safe, with early signs of clinical activity, particularly in LMS. Thus, we designed this investigator-initiated/investigator-sponsored phase 1b lead-in to optimize doses of L+D, to be followed by a randomized (1:1) phase 2 study of L+D versus doxorubicin monotherapy in anthracycline-naïve LMS. Methods: Pts age > 18 years with locally advanced or metastatic, unresectable LMS (non-GIST soft-tissue sarcoma histologies allowed in Phase 1b), without prior anthracycline or lurbinectedin/trabectedin, ECOG PS < 3, measurable disease by RECIST 1.1, and normal organ function, are eligible. Phase 1b dosing will include a fixed dose of lurbinectedin and two dose levels of doxorubicin. The Phase 1b lead-in follows a standard 3+3 design where dose escalation will occur if 0/3 or 1/6 patients experience a dose-limiting toxicity (DLT). Tumor assessments are conducted every two cycles. Once the recommended phase 2 dose (RP2D) is confirmed, Phase 2 will be initiated. Fifty pts will be randomized 1:1 including doxorubicin +/- lurbinectedin. Randomization will be stratified by uterine v. non-uterine origin of LMS. Pts progressing on single agent doxorubicin will be allowed to cross over to lurbinectedin monotherapy. The Phase 2 primary endpoint is PFS. Secondary endpoints include disease control rate, ORR, OS, PFS2 (for doxorubicin monotherapy patients who cross to lurbinectedin monotherapy). Archival tumor, germline DNA, and ctDNA will be collected for correlative studies exploring genomic markers of sensitivity/resistance. We will provide respective point estimate along with 90% confidence interval for each of the arms. Log-rank test will be performed to test the difference in survival (both PFS and OS) between groups. Regression analyses of survival data will be based on the Cox proportional hazards model. The first pt in dose-level 1 of the Phase 1b lead-in was enrolled in February 2022. Clinical trial information: NCT05099666.
Endogenous retroelements (EREs) constitute about 42% of the human genome and have been implicated in common human diseases such as autoimmunity and cancer. The dominant paradigm holds that EREs are ...expressed in embryonic stem cells (ESCs) and germline cells but are repressed in differentiated somatic cells. Despite evidence that some EREs can be expressed at the RNA and protein levels in specific contexts, a system-level evaluation of their expression in human tissues is lacking.
Using RNA sequencing data, we analyzed ERE expression in 32 human tissues and cell types, including medullary thymic epithelial cells (mTECs). A tissue specificity index was computed to identify tissue-restricted ERE families. We also analyzed the transcriptome of mTECs in wild-type and autoimmune regulator (AIRE)-deficient mice. Finally, we developed a proteogenomic workflow combining RNA sequencing and mass spectrometry (MS) in order to evaluate whether EREs might be translated and generate MHC I-associated peptides (MAP) in B-lymphoblastoid cell lines (B-LCL) from 16 individuals.
We report that all human tissues express EREs, but the breadth and magnitude of ERE expression are very heterogeneous from one tissue to another. ERE expression was particularly high in two MHC I-deficient tissues (ESCs and testis) and one MHC I-expressing tissue, mTECs. In mutant mice, we report that the exceptional expression of EREs in mTECs was AIRE-independent. MS analyses identified 103 non-redundant ERE-derived MAPs (ereMAPs) in B-LCLs. These ereMAPs preferentially derived from sense translation of intronic EREs. Notably, detailed analyses of their amino acid composition revealed that ERE-derived MAPs presented homology to viral MAPs.
This study shows that ERE expression in somatic tissues is more pervasive and heterogeneous than anticipated. The high and diversified expression of EREs in mTECs and their ability to generate MAPs suggest that EREs may play an important role in the establishment of self-tolerance. The viral-like properties of ERE-derived MAPs suggest that those not expressed in mTECs can be highly immunogenic.
Continuous hourly measurements of gas-phase ammonia (NH3(g)) were taken from 13 July to 7 August 2014 on a research cruise throughout Baffin Bay and the eastern Canadian Arctic Archipelago. ...Concentrations ranged from 30 to 650 ng m−3 (40–870 pptv) with the highest values recorded in Lancaster Sound (74°13′ N, 84°00′ W). Simultaneous measurements of total ammonium (NHx), pH and temperature in the ocean and in melt ponds were used to compute the compensation point (χ), which is the ambient NH3(g) concentration at which surface–air fluxes change direction. Ambient NH3(g) was usually several orders of magnitude larger than both χocean and χMP (< 0.4–10 ng m3) indicating these surface pools are net sinks of NH3. Flux calculations estimate average net downward fluxes of 1.4 and 1.1 ng m−2 s−1 for the open ocean and melt ponds, respectively. Sufficient NH3(g) was present to neutralize non-sea-salt sulfate (nss-SO42−) in the boundary layer during most of the study. This finding was corroborated with a historical data set of PM2.5 composition from Alert, Nunavut (82°30′ N, 62°20′ W) wherein the median ratio of NH4+/nss-SO42− equivalents was greater than 0.75 in June, July and August. The GEOS-Chem chemical transport model was employed to examine the impact of NH3(g) emissions from seabird guano on boundary-layer composition and nss-SO42− neutralization. A GEOS-Chem simulation without seabird emissions underestimated boundary layer NH3(g) by several orders of magnitude and yielded highly acidic aerosol. A simulation that included seabird NH3 emissions was in better agreement with observations for both NH3(g) concentrations and nss-SO42− neutralization. This is strong evidence that seabird colonies are significant sources of NH3 in the summertime Arctic, and are ubiquitous enough to impact atmospheric composition across the entire Baffin Bay region. Large wildfires in the Northwest Territories were likely an important source of NH3, but their influence was probably limited to the Central Canadian Arctic. Implications of seabird-derived N-deposition to terrestrial and aquatic ecosystems are also discussed.
Isomelezitose (IMZ) is of interest as a potential osmoprotectant, but it has not been previously characterised even though the structurally similar trisaccharide melezitose has been previously shown ...to have excellent protective qualities. The recent discovery that sucrose can be converted to IMZ during glucansucrase reactions suggests that IMZ might become an economical choice as an osmoprotectant for microbial inoculants, such as biological control agents (BCAs). Because of this opportunity, its osmoprotective function was explored in this work using two strains of Pseudomonas fluorescens that are BCAs used to control maladies of potatoes stored postharvest. BCA cell viability and growth recovery rate after drying and storage at 25
o
C were assessed. The data showed that IMZ and impure IMZ reaction products can function similarly to melezitose and trehalose to significantly reduce viable cell and activity losses during air drying and storage. Biocontrol treatments formulated with IMZ retained the ability to suppress Fusarium dry rot disease by up to 50% under severe disease challenge, even after storage 28 d at 25
o
C in vacuum-sealed bags. Biocontrol treatments with IMZ suppressed disease by 15-35% more thancontrols without any added osmoprotectant. Neither IMZ nor two impure enzyme reaction products impacted germination of dry rot causative Fusarium sambucinum conidia or subsequent hyphal growth under gnotobiotic conditions. For the first time, the osmoprotective capability of IMZ has been demonstrated and shown to be potentially superior to others previously reported, including the structurally related compound melezitose and the currently marketed disaccharide trehalose.
BackgroundFibronectin (FN) is a ubiquitously expressed, high-molecular weight, extracellular matrix glycoprotein. The extra domain B splice variant of FN (EDB+FN) is a novel therapeutic target that ...is upregulated in the tumor microenvironment (TME) of multiple solid tumor types with restricted expression in normal tissues. PYX-201 is an investigational antibody drug conjugate consisting of a site-specific engineered EDB+FN-targeting monoclonal antibody conjugated to vc0101, which shows improved linker-payload stability and bystander activity in preclinical studies. The linker-payload vc0101 is completely synthetic and delivers auristatin PF-06380101 (Aur0101), a microtubule depolymerizing agent with potent anti-mitotic and cytotoxic properties. PYX-201 may have multiple mechanisms of action: promoting cell destruction by directly binding to EDB+FN, releasing payload into the TME and into nearby cancer cells, and potentiating immune cell infiltration upon release of the payload. PYX-201 has been shown to induce tumor regression in xenograft mouse models of non-small cell lung cancer (NSCLC) and pancreatic cancer. In a syngeneic model of breast cancer, a mouse analogue of PYX-201 induced upregulation of PD-L1 and infiltration of CD3+ T cells in tumors.1 MethodsPYX-201 is being evaluated in a first-in-human, open-label, non-randomized, Phase 1 dose-escalation (Part 1) study in participants with advanced solid tumors. Part 1 utilizes a Bayesian optimal interval design to explore ascending doses of PYX-201 administered as an intravenous infusion to evaluate safety and efficacy and to identify the recommended Part 2 dose(s). The study is designed to characterize safety and pharmacokinetics and will incorporate a robust translational biomarker plan. Upon completion of Part 1 and depending upon data obtained, a Part 2 dose expansion part of the study may be initiated. The PYX-201–101 study began enrolling participants in February 2023 and will be conducted in the US and Europe. Adverse events are assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 and protocol-specific ophthalmic complications table. Tumor response is determined according to Response Evaluation Criteria in Solid Tumors 1.1 criteria and safety findings are reviewed by the dose escalation steering committee, which will monitor safety and recommends dose(s) for Part 2. The study population will include participants with NSCLC, hormone receptor positive breast cancer, triple negative breast cancer, head and neck squamous cell carcinoma, ovarian cancer, thyroid cancer, pancreatic ductal adenocarcinoma, soft tissue sarcoma, hepatocellular carcinoma, and kidney cancer.Trial RegistrationNCT05720117ReferenceHooper AT, Marquette K, Chang CP, Golas J, Jain S, Lam MH, Guffroy M, Leal M, Falahatpisheh H, Mathur D, Chen T. Anti-Extra Domain B Splice Variant of Fibronectin Antibody-Drug Conjugate Eliminates Tumors with Enhanced Efficacy When Combined with Checkpoint Blockade. Molecular Cancer Therapeutics. 2022 Sep 6;21(9):1462–72.
To evaluate sitravatinib, an inhibitor of multiple receptor tyrosine kinases (RTK), for the treatment of well-differentiated/dedifferentiated liposarcoma (WD/DD LPS).
This multicenter, open-label, ...Phase II trial enrolled patients with advanced WD/DD LPS who had received at least one prior systemic regimen and had progression within 12 weeks of enrollment. Patients received sitravatinib 150 mg (later amended to 120 mg) orally daily. A Simon two-stage design was used to evaluate for an improvement in the primary endpoint, progression-free rate at 12 weeks (PFR12), from 20% to 40%. Secondary endpoints included antitumor activity and safety. A subset of patients underwent paired biopsies analyzed using reverse-phase protein array.
Twenty-nine patients enrolled. Median age was 62 years and 31% had received 3 or more prior lines. Most patients (93%) had DDLPS or mixed WD/DD LPS. Overall, 12 of 29 patients (41%) were alive and progression-free at 12 weeks and the study met the primary endpoint. There were no confirmed responses. Median progression-free survival was 11.7 weeks 95% confidence interval (CI): 5.9-35.9 and median overall survival was 31.7 weeks (95% CI: 18.1-90.1). The most common treatment-related adverse events were diarrhea (59%), hypertension (52%), hoarseness (41%), mucositis (31%), and nausea (31%). Baseline expression of phospho-RTKs was not significantly different between patients with and without clinical benefit from sitravatinib, but the number of samples was small.
Sitravatinib provided a PFR12 of 41% and meaningful disease control in a subset of patients with advanced, progressive WD/DD LPS.
The Cotton Consensus (CC) criteria for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) may not capture post-ERCP morbidity. PAN-PROMISE, a patient-reported outcome ...measure (PROM), was developed to quantify acute pancreatitis-related morbidity. This study aims to determine the value of PAN-PROMISE in independently defining ERCP-related morbidity.
We conducted a prospective cohort study of patients undergoing ERCP at 2 academic centers from September 2021 to August 2022. We administered PAN-PROMISE and assessed quality of life and work productivity at baseline, 48 to 72 hours, 7 days, and 30 days following ERCP. PEP was defined by a 3-physician committee using the CC criteria. We defined high morbidity following ERCP (elevated PROM) by an increase of PAN-PROMISE score of >7 at 7 days post-procedure. The McNemar test assessed discordance between PEP and elevated-PROM.
A total of 679 patients were enrolled. Choledocholithiasis (30%) and malignant biliary obstruction (29%) were the main indications for ERCP. Thirty-two patients (4.7%) developed PEP. One hundred forty-seven patients (21.6%) had an elevated PROM, whereas only 20 of them (13.4%) had PEP by the CC criteria (P < .001 for discordance). An elevated PROM strongly correlated with lower physical quality of life and increased direct and indirect health care costs ($80 and $25 per point increase in PAN-PROMISE, respectively). Patients with pancreatic cancer (odds ratio, 4.52; 95% confidence interval, 1.68-10.74) and primary sclerosing cholangitis (odds ratio, 1.79; 95% confidence interval, 1.29-2.45) had the highest odds of elevated PROM.
A substantial number of patients experience significant morbidity after ERCP despite not developing PEP or other adverse events. Future studies are needed to characterize better the reasons behind this increase in symptoms and potential interventions to reduce the symptom burden post-ERCP.
gov number, NCT05310409.
Autophagy, an essential intracellular recycling process, is linked to the pathogenesis of various diseases including Crohn’s disease (CD). Factors that lead to the development of impaired autophagy ...during intestinal inflammation remain largely unexplored. Here, we report the impact of the interaction between serotonin 5-hydroxytryptamine;(5-HT) and autophagy in colitis in mouse and human studies. In mice, increased gut 5-HT inhibited autophagy and led to enhanced colitis susceptibility. Reciprocally, mice with reduced 5-HT exhibited up-regulated autophagy via the mammalian target of rapamycin pathway, which resulted in significantly decreased colitis. Deletion of autophagy gene, Atg7, in an epithelial-specific manner, in concert with reduced 5-HT, promoted the development of a colitogenic microbiota and abolished the protective effects conferred by reduced 5-HT. Notably, in control and patient peripheral blood mononuclear cells, we uncovered that 5-HT treatment inhibited autophagy. Our findings suggest 5-HT as a previously unidentified therapeutic target in intestinal inflammatory disorders such as CD that exhibits dysregulated autophagy.
PDF
