Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors.

PURPOSE: The pan-Class I PI3K inhibitor buparlisib (BKM120) has shown activity in a range of preclinical cancer models. This first-in-man study was initiated to identify the maximum tolerated dose (MTD) of buparlisib (100 mg/day) and to assess safety and preliminary efficacy. METHODS: Patients with advanced solid tumors (N = 83) enrolled in a Phase I dose-escalation and -expansion study of single-agent buparlisib. Patients in the dose-expansion arm (n = 43) had tumor samples with PIK3CA and/or PTEN alterations. RESULTS: The most common cancers were colorectal (n = 31) and breast cancer (n = 21). Median number of prior antineoplastic regimens was four (range: 1-12). Grade 3/4 adverse events (AEs) included asthenia (12.0 %) and performance status decrease (9.6 %). Treatment-related AEs (all grades) included decreased appetite, diarrhea, nausea (each in 33 % of patients), hyperglycemia (31 %) and rash (29 %). One confirmed partial response (PR; triple-negative breast cancer) and three unconfirmed PRs (parotid gland carcinoma, epithelioid hemangiothelioma, ER + breast cancer) were reported. Tumor molecular status did not predict clinical benefit in the full study cohort, or among the colorectal or breast cancer subpopulations. Pharmacodynamic biomarkers ((18)F-FDG-PET, C-peptide, pS6) demonstrated dose-dependent changes; however, tumor heterogeneity precluded a clear correlation with clinical benefit. CONCLUSION: Buparlisib was well tolerated up to the 100 mg/day dose and showed preliminary activity in patients with advanced cancers. Future studies in more homogeneous patient populations will evaluate buparlisib in combination with other agents and further investigate the use of predictive biomarkers.

Endotoxin-induced cytokine and chemokine expression in the HIV-1 transgenic rat.

BACKGROUND: Repeated exposure to a low dose of a bacterial endotoxin such as lipopolysaccharide (LPS) causes immune cells to become refractory to a subsequent endotoxin challenge, a phenomenon known as endotoxin tolerance (ET). During ET, there is an imbalance in pro- and anti-inflammatory cytokine and chemokine production, leading to a dysregulated immune response. HIV-1 viral proteins are known to have an adverse effect on the immune system. However, the effects of HIV-1 viral proteins during ET have not been investigated. METHODS: In this study, HIV-1 transgenic (HIV-1Tg) rats and control F344 rats (n = 12 ea) were randomly treated with 2 non-pyrogenic doses of LPS (LL) to induce ET, or saline (SS), followed by a high challenge dose of LPS (LL+L, SS+L) or saline (LL+S, SS+S). The gene expression of 84 cytokines, chemokines, and their receptors in the brain and spleen was examined by relative quantitative PCR using a PCR array, and protein levels in the brain, spleen, and serum of 7 of these 84 genes was determined using an electrochemiluminescent assay. RESULTS: In the spleen, there was an increase in key pro-inflammatory (IL1α, IL-1ß, IFN-γ) and anti-inflammatory (IL-10) cytokines, and inflammatory chemokines (Ccl2, Ccl7, and Ccl9,) in response to LPS in the SS+L and LL+L (ET) groups of both the HIV-1Tg and F344 rats, but was greater in the HIV-1Tg rats than in the F344. In the ET HIV-1Tg and F344 (LL+L) rats in the spleen, the LPS-induced increase in pro-inflammatory cytokines was diminished and that of the anti-inflammatory cytokine was enhanced compared to the SS+L group rats. In the brain, IL-1ß, as well as the Ccl2, Ccl3, and Ccl7 chemokines were increased to a greater extent in the HIV-1Tg rats compared to the F344; whereas Cxcl1, Cxcl10, and Cxcl11 were increased to a greater extent in the F344 rats compared to the HIV-1Tg rats in the LL+L and SS+L groups. CONCLUSION: Our data indicate that the continuous presence of HIV-1 viral proteins can have tissue-dependent effects on endotoxin-induced cytokine and chemokine expression in the ET state.

Morphine-induced conditioned place preference and associated behavioural plasticity in HIV-1 transgenic rats.

The prevalence of morphine addiction in HIV-1 infected persons is higher than the healthy population. The mu-opioid receptor (MOR) which mediates the actions of morphine is shown to be up-regulated in the HIV-1 transgenic (HIV-1Tg) rat. In this study, we used the conditioned place preference (CPP) test to investigate if HIV-1Tg rats are more sensitive to the addictive properties of morphine compared to F344 control animals. Morphine-CPP was successfully established in the HIV-1Tg and F344 rats at the dose of 3.5 mg/kg. Interestingly, the animals that had morphine paired with one side of the two-chamber CPP apparatus (the white chamber) failed to show any decline in preference for the morphine-paired chamber after 17 to 20 days of extinction testing. An analysis of the change in preference that occurs within a session as a result of the habituation of exploratory behaviour suggested that morphine enhanced a natural preference for the white chamber. We suggest that the morphine CPP procedure may sometimes result in a behavioural plasticity that does not conform to the predictive learning model of classical conditioning and may reflect a form of associative learning known as evaluative conditioning. The animals that had morphine paired with the other chamber (the black chamber) showed extinction. Moreover greater resistance to extinction was observed in the HIV-1Tg rats. Following extinction the HIV-1Tg and F344 groups were each divided into two groups. One group was tested for reinstatement following a 1 mg/kg and 3.5 mg/kg morphine prime on 2 consecutive days, respectively. The second group was tested for reinstatement after exposure to foot shock. Reinstatement with drug-prime or with the foot shock stressor was not observed.