Safety and clinical activity of a new anti-PD-L1 antibody as monotherapy or combined with targeted therapy in advanced solid tumors: the PACT phase Ia/Ib trial

Cancer shared this article with you from Inoreader Safety and clinical activity of a new anti-PD-L1 antibody as monotherapy or combined with targeted therapy in advanced solid tumors: the PACT phase Ia/Ib trial Via Clinical Cancer Research Online First Articles Purpose: This phase Ia/Ib PACT study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of a new PD-L1 inhibitor, LY3300054, as monotherapy or in combination with ramucirumab, abemaciclib, or merestinib (a type II MET kinase inhibitor) in patients with advanced, refractory solid tumors (NCT02791334). Patients and methods: Patients were enrolled into cohorts of escalating LY3300054 dose (phase Ia) as monotherapy (N=15) or combined with ramucirumab (N=10), abemaciclib (N=24), or merestinib (N=12). The phase Ib dose expansion enrolled eight patients with melanoma in the monotherapy arm and 12 patients with pancreatic cancer in the merestinib combination arm. Combination treatments were administered concurrently from day 1 of each cycle. A 14-day lead-in abemaciclib arm was also explored. Primary endpoints were dose-limiting toxicity (DLT) and safety. Results: Treatment-related adverse events included fatigue and nausea in the mon otherapy arm (13% for each), hypothyroidism (30%) in the ramucirumab arm, diarrhea (54%) in the abemaciclib arm, and nausea (25%) in the merestinib arm. DLTs associated with hepatoxicity were observed in three of four patients in the abemaciclib lead-in cohorts. No DLTs or grade 3 or 4 hepatoxicity were reported in the concurrent abemaciclib arm. Pharmacokinetic characteristics were comparable to other PD-L1 inhibitors. One patient in each arm experienced a partial response per RECIST v1.1 lasting ≥7 months. Conclusions: LY3300054 was well tolerated without unexpected safety concerns when administered alone or concurrently with ramucirumab, abemaciclib, or merestinib. Lead-in abemaciclib before combining with LY3300054 was not feasible due to hepatotoxicity. Durable clinical benefits were seen in all regimens. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Combined Inhibition of G{alpha}q and MEK Enhances Therapeutic Efficacy in Uveal Melanoma.

Cancer shared this article with you from Inoreader Combined Inhibition of G{alpha}q and MEK Enhances Therapeutic Efficacy in Uveal Melanoma. Via Clinical Cancer Research Online First Articles Purpose: All uveal melanoma and a fraction of other melanoma subtypes are driven by activation of the Gαq pathway. Targeting these melanomas has proven difficult despite advances in the molecular understanding of key driver signaling pathways in the disease pathogenesis. Inhibitors of Gαq have shown promising preclinical results, but their therapeutic activity in distinct Gαq mutational contexts and in vivo have remained elusive. Experimental Design: We used an isogenic melanocytic cellular system to systematically examine hotspot mutations in GNAQ (e.g., G48V, R183Q, Q209L) and CYSLTR2 (L129Q) found in human uveal melanoma. This cellular system and human uveal melanoma cell lines were used in vitro and in vivo xenograft studies to assess the efficacy of Gαq inhibition as a single agent and in combination with MEK inhibition. Results: We demonstrate that the Gαq inhibitor YM-254890 inhibited downstream signaling and in vitro growth in all mutants. In vivo, YM-254890 slowed tumor growth but did not cause regression in human uveal melanoma xenografts. Through comprehensive transcriptome analysis, we observed that YM-254890 caused inhibition of the MAPK signaling with evidence of rebound by 24 hours and combination treatment of YM-254890 and a MEK inhibitor led to sustained MAPK inhibition. We further demonstrate that the combination caused synergistic growth inhibition in vitro and tumor shrinkage in vivo. Conclusions: These data suggest that the combination of Gαq and MEK inhibition provides a promising therapeutic strategy and improved therapeutic window of broadly targeting Gαq in uveal melanoma. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Therapeutic potential of NTRK3 inhibition in desmoplastic small round cell tumor

Cancer shared this article with you from Inoreader Therapeutic potential of NTRK3 inhibition in desmoplastic small round cell tumor Via Clinical Cancer Research Online First Articles Purpose: Desmoplastic small round cell tumor (DSRCT) is a highly lethal intra-abdominal sarcoma of adolescents and young adults. DSRCT harbors a t(11;22)(p13:q12) that generates the EWSR1-WT1 chimeric transcription factor, the key oncogenic driver of DSRCT. EWSR1-WT1 rewires global gene expression networks and activates aberrant expression of targets that together mediate oncogenesis. EWSR1-WT1 also activates a neural gene expression program. Experimental Design: Among these neural markers, we find prominent expression of neurotrophic tyrosine kinase receptor 3 (NTRK3), a druggable receptor tyrosine kinase. We investigated the regulation of NTRK3 by EWSR1-WT1 and its potential as a therapeutic target in vitro and in vivo, the latter using novel patient-derived models of DSRCT. Results: We find that EWSR1-WT1 binds upstream of NTRK3 and activates its transcription. NTRK3 mRNA is highly expressed in DSRCT compared to other major chimeric t ranscription factor-driven sarcomas and most DSRCT are strongly immunoreactive for NTRK3 protein. Remarkably, expression of NTRK3 kinase domain mRNA in DSRCT is also higher than in cancers with NTRK3 fusions. Abrogation of NTRK3 expression by RNAi silencing reduces growth of DSRCT cells and pharmacologic targeting of NTRK3 with entrectinib is effective in both in vitro and in vivo models of DSRCT. Conclusions: Our results indicate that EWSR1-WT1 directly activates NTRK3 expression in DSRCT cells, which are dependent on its expression and activity for growth. Pharmacologic inhibition of NTRK3 by entrectinib significantly reduces growth of DSRCT cells both in vitro and in vivo, providing a rationale for clinical evaluation of NTRK3 as a therapeutic target in DSRCT. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Recommendation regarding the cranial upper border of level IIb in delineating clinical target volumes (CTV) for nasopharyngeal carcinoma

Cancer shared this article with you from Inoreader Recommendation regarding the cranial upper border of level IIb in delineating clinical target volumes (CTV) for nasopharyngeal carcinoma Via Latest Results for Radiation Oncology Abstract Purpose To recommend a cranial border for level IIb in delineating clinical target volumes (CTV) for nasopharyngeal carcinoma (NPC) patients receiving intensity-modulated radiotherapy and to help reach a consensus on contouring level IIb in CTV. Methods From 2012 to 2016, 331 nonmetastatic NPC patients treated with IMRT were retrospectively enrolled. Based on the AJCC 8th staging system of NPC, there were 15 stage I, 76 stage II, 103 stage III, and 137 stage IV patients. The distribution of cervical lymph nodes in NPC was assessed based on imaging. Comparisons of the safety and parotid dose parameters between patients with and without a reduction in the size of level IIb were conducted using SPSS 25.0 and R 2.14.2 software. Results Metastasis rates in the most commonly involved lymph nodes, the lateral retropharyngeal and IIb nodes, were 82.8% and 64.0%, respectively. Among patients with level IIb involvement, the upper borders of the metastatic nodes were beyond the caudal edge of C1 in 13.7% of cases. The parotid gland D50 and V26 values were significantly reduced after modifying the upper bound of level IIb used to delineate the CTV (P = 0.000). Conclusion In principle, the upper bound of level IIb should reach the lateral skull base during delineation of the cervical CTV for NPC. To protect the parotid glands, however, individualized reduction of the upper bound of level IIb is recommended for patients who meet certain criteria. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Impact of prior cancer history on the survival of patients with larynx cancer

Cancer shared this article with you from Inoreader Impact of prior cancer history on the survival of patients with larynx cancer Via Latest Results for BMC Cancer Abstract Background Patients with a prior history of cancer are commonly excluded from clinical trial. Increasing number of studies implied that a prior cancer did not adversely affect the clinical outcome among various types of cancer patients. However, the impact of prior cancer on survival of larynx cancer patients remains largely unknown. The aim of this study was to evaluate the prevalence of prior cancer and assess its impact on survival of patients diagnosed with larynx cancer. Methods Patients with larynx cancer as the first or second primary malignancy diagnosed from 2004 to 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was conducted to balance baseline characteristics. Kaplan-Meier method, multivariate Cox proportional hazard model, and multivariate competing risk model were performed for survival analysis. Results A total of 24,812 eligible patients with larynx cancer were included in the study, wherein a total of 2436 patients (9.8%) had a prior history of cancer. Prostate (36%), lung and bronchus (10%), urinary bladder (7%), and breast (6%) were the most common types of prior cancer. A prior cancer history served as a risk factor for overall survival (AHR =1.30; 95% CI [1.21–1.41]; P < 0.001) but a protective factor for cancer-specific mortality (AHR = 0.83; 95% CI [0.72–0.94]; P = 0.004) in comparison with those without prior cancer. The subgroup analysis showed that a prior history of cancer adversely affected overall survival of patients with larynx cancer in most subgroups stratified by timing and types of prior cancer, as well as by different clinicopathologic features. Conclusion Our study indicated an adverse survival impact of a prior history of cancer on patients with larynx cancer. Except for a few particular prior cancer, clinical trials should be considered prudently for laryngeal cancer patients with prior cancers. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Whole-brain irradiation differentially modifies neurotransmitters levels and receptors in the hypothalamus and the prefrontal cortex

Cancer shared this article with you from Inoreader Whole-brain irradiation differentially modifies neurotransmitters levels and receptors in the hypothalamus and the prefrontal cortex Via Latest Results for Radiation Oncology Abstract Background Whole-brain radiotherapy is a primary treatment for brain tumors and brain metastasis, but it also induces long-term undesired effects. Since cognitive impairment can occur, research on the etiology of secondary effects has focused on the hippocampus. Often overlooked, the hypothalamus controls critical homeostatic functions, some of which are also susceptible after whole-brain radiotherapy. Therefore, using whole-brain irradiation (WBI) in a rat model, we measured neurotransmitters and receptors in the hypothalamus. The prefrontal cortex and brainstem were also analyzed since they are highly connected to the hypothalamus and its regulatory processes. Methods Male Wistar rats were exposed to WBI with 11 Gy (Biologically Effective Dose = 72 Gy). After 1 month, we evaluated changes in gamma-aminobutyric acid (GABA), glycine, taurine, aspartate, glutamate, and glutamine in the hypothalamus, prefrontal cortex, and brainstem according to an HPLC method. Ratios of Glutamate/GABA and Glutamine/Glutamate were calculated. Through Western Blott analysis, we measured the expression of GABAa and GABAb receptors, and NR1 and NR2A subunits of NMDA receptors. Changes were analyzed comparing results with sham controls using the non-parametric Mann–Whitney U test (p < 0.05). Results WBI with 11 Gy induced significantly lower levels of GABA, glycine, taurine, aspartate, and GABAa receptor in the hypothalamus. Also, in the hypothalamus, a higher Glutamate/GABA ratio was found after irradiation. In the prefrontal cortex, WBI induced significant increases of glutamine and glutamate, Glutamine/Glutamate ratio, and increased expression of both GABAa receptor and NMDA receptor NR1 subunit. The brainstem showed no statistically significant changes after irradiation. Conclusion Our findings confirm that WBI can affect rat brain regions differently and opens new avenues for study. After 1 month, WBI decreases inhibitory neurotransmitters and receptors in the hypothalamus and, conversely, increases excitatory neurotransmitters and receptors in the prefrontal cortex. Increments in Glutamate/GABA in the hypothalamus and Glutamine/Glutamate in the frontal cortex indicate a neurochemical imbalance. Found changes could be related to several reported radiotherapy secondary effects, suggesting new prospects for therapeutic targets. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The impact of lifecourse socio-economic position and individual social mobility on breast cancer risk

Cancer shared this article with you from Inoreader The impact of lifecourse socio-economic position and individual social mobility on breast cancer risk Via Latest Results for BMC Cancer Abstract Background Women with an advantaged socioeconomic position (SEP) have a higher risk of developing breast cancer (BC). The reasons for this association do not seem to be limited to reproductive factors and remain to be understood. We aimed to investigate the impact of lifecourse SEP from childhood and social mobility on the risk of BC considering a broad set of potential mediators. Methods We used a discovery-replication strategy in two European prospective cohorts, E3N (N = 83,436) and EPIC-Italy (N = 20,530). In E3N, 7877 women were diagnosed with BC during a median 24.4 years of follow-up, while in EPIC-Italy, 893 BC cases were diagnosed within 15.1 years. Hazard ratios (HR) were estimated using Cox proportional hazard models on imputed data. Results In E3N, women with higher education had a higher risk of BC (HR [95%CI] = 1.21 [1.12, 1.30]). This association was attenuated by adjusting for reproductive factors, in particular age at first childbirth (HR[95%CI] = 1.13 [1.04, 1.22]). Health behaviours, anthropometric variables, and BC screening had a weaker effect on the association. Women who remained in a stable advantaged SEP had a higher risk of BC (HR [95%CI] = 1.24 [1.07; 1.43]) attenuated after adjustment for potential mediators (HR [95%CI] = 1.13 [0.98; 1.31]). These results were replicated in EPIC-Italy. Conclusions These results confirm the important role of reproductive factors in the social gradient in BC risk, which does not appear to be fully explained by the large set of potential mediators, including cancer screening, suggesting that further research is needed to identify additional mechanisms. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.