Buparlisib,an oral pan-PI3K inhibitor for the treatment of breast cancer

Introduction: Deregulation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) intracellular signaling pathway is common in breast cancer (BC) and has been found to be potentially implicated in resistance to endocrine and anti-HER2 therapies. Targeting the PI3K/Akt/mTOR pathway may remove this inhibition and restore sensitivity to these compounds. Buparlisib (BKM120) is a potent oral pan-class I PI3K inhibitor that is being extensively evaluated in multiple tumor types.

Areas covered: This review briefly summarizes the pharmacodynamics and pharmacokinetics of buparlisib, focusing on preclinical and clinical data in BC and on ongoing randomized trials.

Expert opinion: Overall, buparlisib is a safe and tolerable drug and, despite its peculiar toxicity profile, it is suitable for studies in combination with other anticancer agents in BC. Early-phase clinical trials in BC have provided evidence of antitumor activity. Several trials are being conducted in all the biological subsets of BC, including combinations with endocrine therapy, anti-HER2 agents, PARP-inhibitors and chemotherapy. While clinical results are eagerly awaited, biological material suitable for both genomic and non-genomic analyses is being collected. The authors expect an intense investigation of the potential biomarkers that explain response or resistance to buparlisib and inspire strategies to rationally explore the therapeutic potential of this drug.     

New-Onset Diabetes and Preexisting Diabetes Are Associated With Comparable Reduction in Long-Term Survival After Liver Transplant: A Machine Learning Approach

Objective

To identify key predictors and survival outcomes of new-onset diabetes after transplant (NODAT) in liver transplant (LT) recipients by using the Scientific Registry of Transplant Recipients.

The splicing-factor oncoprotein SF2/ASF activates mTORC1

The splicing factor SF2/ASF is an oncoprotein that is up-regulated in many cancers and can transform immortal rodent fibroblasts when slightly overexpressed. The mTOR signaling pathway is activated in many cancers, and pharmacological blockers of this pathway are in clinical trials as anticancer drugs. We examined the activity of the mTOR pathway in cells transformed by SF2/ASF and found that this splicing factor activates the mTORC1 branch of the pathway, as measured by S6K and eIF4EBP1 phosphorylation. This activation is specific to mTORC1 because no activation of Akt, an mTORC2 substrate, was detected. mTORC1 activation by SF2/ASF bypasses upstream PI3K/Akt signaling and is essential for SF2/ASF-mediated transformation, as inhibition of mTOR by rapamycin blocked transformation by SF2/ASF in vitro and in vivo. Moreover, shRNA-mediated knockdown of mTOR, or of the specific mTORC1 and mTORC2 components Raptor and Rictor, abolished the tumorigenic potential of cells overexpressing SF2/ASF. These results suggest that clinical tumors with SF2/ASF up-regulation could be especially sensitive to mTOR inhibitors.     

芦荟凝胶多糖对急性放射性皮肤损伤模型的修复作用及机制研究

目的研究芦荟凝胶多糖基于磷脂酰肌醇3-激酶(PI3K)-蛋白激酶B(Akt)-雷帕霉素靶蛋白(mTOR)信号通路对急性放射性皮肤损伤模型的修复作用。方法选取40只雄性Wistar大鼠,10只为正常组(等体积生理盐水),其余30只建立急性放射性皮肤损伤模型,随机分为模型组、低剂量组、高剂量组,每组10只。模型组和正常组均给予等体积生理盐水干预,低剂量组、高剂量组分别以单层纱布浸润0.4 mg/mL、0.8 mg/mL的芦荟凝胶多糖外敷干预。记录创面愈合时间、放射性皮肤损伤评级,检测创面微血管密度、血管内皮生长因子(VEGF)含量,病理学观察创面组织细胞形态,Western blot检测PI3K-Akt-mTOR信号通路相关蛋白表达。结果低剂量组和高剂量组创面愈合时间均短于模型组,且高剂量组创面愈合时间显著短于低剂量组(P<0.05);与模型组相比,正常组大鼠0级较多,Ⅳ级较少;低剂量组和高剂量组大鼠Ⅳ级较少(P<0.05)。模型组、低剂量组、高剂量组创面微血管密度、VEGF、PI3K、Akt蛋白表达量低于正常组,mTOR蛋白表达量高于正常组;低剂量组、高剂量组创面微血管密度、VEGF、PI3K、Akt蛋白表达量高于模型组,mTOR蛋白表达量低于模型组;高剂量组创面微血管密度、VEGF、PI3K、Akt蛋白表达量高于低剂量组,mTOR蛋白表达量低于低剂量组。结论高剂量芦荟凝胶多糖可通过调控PI3K-Akt-mTOR信号通路促进急性放射性皮肤损伤模型创面新生血管形成,加快创面修复。     

Mammalian target of rapamycin inhibition after solid organ transplantation: can it,and does it,reduce cancer risk?

The mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus has been increasingly used as immunosuppressants for recipients of solid organ transplants. Over the years, potential advantages unique to this class of immunosuppressants have been recognized, including chemoprevention by virtue of their antiproliferative effects. Prevention of malignancy after transplant through mTOR inhibitor‐based immunosuppression may have a specific practical application in transplant recipients with preexisting malignancy including hepatocellular carcinoma or cholangiocarcinoma. This review will reveal how the biochemistry of the mTOR pathway, as it pertains to chemoprevention, can support a clinical role for mTOR inhibitors in the prevention of malignancies, recurrent or de novo, after solid organ transplantation in selected patients.     

Rapamycin ameliorates the CTLA4‐Ig–mediated defect in CD8+ T cell immunity during gammaherpesvirus infection

Latent viral infections are a major concern among immunosuppressed transplant patients. During clinical trials with belatacept, a CTLA4‐Ig fusion protein, patients showed an increased risk of Epstein–Barr virus‐associated posttransplant lymphoproliferative disorder, thought to be due to a deficient primary CD8⁺ T cell response to the virus. Using a murine model of latent viral infection, we observed that rapamycin treatment alone led to a significant increase in virus‐specific CD8⁺ T cells, as well as increased functionality of these cells, including the ability to make multiple cytokines, while CTLA4‐Ig treatment alone significantly dampened the response and inhibited the generation of polyfunctional antigen‐specific CD8⁺ T cells. However, the addition of rapamycin to the CTLA4‐Ig regimen was able to quantitatively and qualitatively restore the antigen‐specific CD8⁺ T cell response to the virus. This improvement was physiologically relevant, in that CTLA4‐Ig treated animals exhibited a greater viral burden following infection that was reduced to levels observed in untreated immunocompetent animals by the addition of rapamycin. These results reveal that modulation of T cell differentiation though inhibition of mTOR signaling can restore virus‐specific immune competence even in the absence of CD28 costimulation, and have implications for improving protective immunity in transplant recipients.