Arginine deprivation is a novel antimetabolite strategy for the treatment of arginine-dependent cancers that exploits differential expression and regulation of key urea cycle enzymes. Several studies have focused on inactivation of argininosuccinate synthetase 1 (ASS1) in a range of malignancies, including melanoma, hepatocellular carcinoma (HCC), mesothelial and urological cancers, sarcomas, and lymphomas. Epigenetic silencing has been identified as a key mechanism for loss of the tumor suppressor role of ASS1 leading to tumoral dependence on exogenous arginine. More recently, dysregulation of argininosuccinate lyase has been documented in a subset of arginine auxotrophic glioblastoma multiforme, HCC and in fumarate hydratase-mutant renal cancers. Clinical trials of several arginine depletors are ongoing, including pegylated arginine deiminase (ADI-PEG20, Polaris Group) and bioengineered forms of human arginase. ADI-PEG20 is furthest along the path of clinical development from combinatorial phase 1 to phase 3 trials and is described in more detail. The challenge will be to identify tumors sensitive to drugs such as ADI-PEG20 and integrate these agents into multimodality drug regimens using imaging and tissue/fluid-based biomarkers as predictors of response. Lastly, resistance pathways to arginine deprivation require further study to optimize arginine-targeted therapies in the oncology clinic.
PURPOSE The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is frequently activated in triple-negative breast cancer (TNBC). The AKT inhibitor capivasertib has shown preclinical activity in TNBC models, and drug sensitivity has been associated with activation of PI3K or AKT and/or deletions of PTEN. The PAKT trial was designed to evaluate the safety and efficacy of adding capivasertib to paclitaxel as first-line therapy for TNBC. PATIENTS AND METHODS This double-blind, placebo-controlled, randomized phase II trial recruited women with untreated metastatic TNBC. A total of 140 patients were randomly assigned (1:1) to paclitaxel 90 mg/m2 (days 1, 8, 15) with either capivasertib (400 mg twice daily) or placebo (days 2-5, 9-12, 16-19) every 28 days until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), PFS and OS in the subgroup with PIK3CA/ AKT1/ PTEN alterations, tumor response, and safety. RESULTS Median PFS was 5.9 months with capivasertib plus paclitaxel and 4.2 months with placebo plus paclitaxel (hazard ratio [HR], 0.74; 95% CI, 0.50 to 1.08; 1-sided P = .06 [predefined significance level, 1-sided P = .10]). Median OS was 19.1 months with capivasertib plus paclitaxel and 12.6 months with placebo plus paclitaxel (HR, 0.61; 95% CI, 0.37 to 0.99; 2-sided P = .04). In patients with PIK3CA/ AKT1/ PTEN-altered tumors (n = 28), median PFS was 9.3 months with capivasertib plus paclitaxel and 3.7 months with placebo plus paclitaxel (HR, 0.30; 95% CI, 0.11 to 0.79; 2-sided P = .01). The most common grade ≥ 3 adverse events in those treated with capivasertib plus paclitaxel versus placebo plus paclitaxel, respectively, were diarrhea (13% v 1%), infection (4% v 1%), neutropenia (3% v 3%), rash (4% v 0%), and fatigue (4% v 0%). CONCLUSION Addition of the AKT inhibitor capivasertib to first-line paclitaxel therapy for TNBC resulted in significantly longer PFS and OS. Benefits were more pronounced in patients with PIK3CA/ AKT1/ PTEN-altered tumors. Capivasertib warrants further investigation for treatment of TNBC.
In this study, we tested the hypothesis that chronic administration of phencyclidine (PCP), an N-methyl-D-aspartate (NMDA) receptor antagonist, would cause a long-lasting behavioral sensitization associated with neuronal toxicity. Female Sprague-Dawley rats were administered PCP (20 mg/kg, i.p.) once a day for 5 days, withdrawn for 72 hr, placed in locomotor activity chambers, and challenged with 3.2 mg/kg PCP. Following assessment of locomotor activity, the rats were killed and their brains processed for analysis of apoptosis by either electron microscopy or terminal dUTP nick-end labeling (TUNEL). In study I, PCP challenge produced a much more robust and long-lasting increase in locomotor activity in rats chronically treated with PCP than in those chronically treated with saline. In study II, clozapine pretreatment blunted the degree of sensitization caused by PCP. In study I, a marked increase in TUNEL-positive neurons was found in layer II of the olfactory tubercle and piriform cortex of rats chronically treated with PCP. Many of these neurons had crescent-shaped nuclei consistent with apoptotic condensation and margination of nuclear chromatin under the nuclear membrane. Acute PCP had no effect. Electron microscopy revealed that PCP caused nuclear condensation and neuronal degeneration consistent with apoptosis. Cell counts in layer II of the piriform cortex revealed that chronic PCP treatment resulted in the loss of almost 25% of the cells in this region. However, an increase in glial fibrillary acidic protein (GFAP)-positive cells in the molecular layer suggests that this neurotoxicity also may involve necrosis. In study II, the PCP-induced neuronal degeneration was essentially completely abolished by clozapine pretreatment. This pattern of degeneration was found to coincide with the distribution of the mRNA of the NR1 subunit of the NMDA receptor. The relevance of these data to a PCP model of chronic NMDA receptor hypofunction is discussed.
To assess the efficacy of simple aspiration as a treatment for pneumothorax, 40 consecutive pneumothoraces (28 spontaneous, 12 iatrogenic, all estimated at greater than or equal to 20% collapse on visual inspection of the chest X-ray) in 38 symptomatic patients were treated initially by small-lumen catheter (SLC) aspiration. SLC aspiration avoided the need for large-lumen intercostal catheter (LIC) underwater drainage in 28 cases (70%)--20 of 28 spontaneous and eight of 12 iatrogenic pneumothoraces. Outcome was not predicted by clinical variables or pneumothorax size, whereas an initial aspirate volume of less than or equal to 4 L (n = 33) was predictable of success in 28 cases (85%). Minor local subcutaneous emphysema and vasovagal reactions were encountered infrequently but with similar frequency to LIC drainage. No episodes of re-expansion pulmonary oedema occurred. The results confirm previous reports of the efficacy of simple aspiration as a treatment for spontaneous or iatrogenic pneumothorax. Initial treatment by SLC aspiration is recommended for all but life-threatening presentations of pneumothorax. Although not encountered in this study, the potential risk of re-expansion pulmonary oedema suggests that patients should be observed closely for four hours after aspiration.
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