The phosphoinositide 3 (PI3)-kinase/Akt signaling pathway has always been a focus of interest in breast cancer due to its role in cell growth, cell proliferation, cell migration and deregulated ...apoptosis. Its activation has been linked to endocrine resistance and worse prognosis in certain subgroups of breast cancer. In addition, deregulation of the PI3K/Akt pathway including PIK3CA activating mutation is frequently present in breast cancer. Multiple efforts have been carried out to target this pathway, initially with pan-PI3K inhibitors with some hint of activity but hampered by their limiting side-effects. A recent large randomized trial in patients with endocrine-resistant PIK3CA-mutant hormone receptor (HR)-positive tumors led to the approval of the first PI3K inhibitor, alpelisib, in combination with fulvestrant. The specificity of alpelisib against the p110α catalytic isoform provided additional efficacy and a better toxicity profile. In this review, we summarize the main research with PI3K inhibitors in breast cancer and we provide some insight of potential future combinations of this treatment in breast cancer patients.
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•Involvement of PI3k/Akt pathway in stroke pathophysiology.•Modulation of PI3K/Akt pathway Nrf2 pathway activation is a therapeutic potential.•GSK-3β, NF-κB, HIF-1α and growth factors ...like BDNF are potential targets.•Selective PI3K activators and inhibitors.
The cerebral ischemic reperfusion injury may leads to morbidity and mortality in patients. phosphatidylinositol 3-kinase (PI3K) signaling pathway has been believed to work in association with its downstream targets, other receptors, and pathways that may offer antioxidant, anti-inflammatory, anti-apoptotic effects, neuroprotective role in neuronal excitotoxicity. This review elaborates the mechanistic interventions of the PI3K pathway in cerebral ischemic injury in context to nuclear factor erythroid 2–related factor 2 (Nrf2) regulation, Hypoxia-inducible factor 1 signaling (HIF-1), growth factors, Endothelial NOS (eNOS) proinflammatory cytokines, Erythropoietin (EPO), Phosphatase and tensin homologous protein of chromosome 10 gene (PTEN) signaling, NF-κB/Notch signaling, c-Jun N-terminal kinase (JNK) and Glycogen synthase kinase-3β (GSK-3β) signaling pathway. Evidences showing the activation of PI3K inhibits apoptotic pathway, which results in its neuroprotective effect in ischemic injury. Despite discussing the therapeutic role of the PI3K pathway in treating cerebral ischemic injury, the review also enlighten the selective modulation of PI3K pathway with activators and inhibitors which may provide promising results in clinical and preclinical settings.
The PI3K-AKT-mTOR pathway is frequently activated in cancer. PI3K inhibitors, including the pan-PI3K inhibitor buparlisib (BKM120) and the PI3Kα-selective inhibitor alpelisib (BYL719), currently in ...clinical development by Novartis Oncology, may therefore be effective as anticancer agents. Early clinical studies with PI3K inhibitors have demonstrated preliminary antitumor activity and acceptable safety profiles. However, a number of unanswered questions regarding PI3K inhibition in cancer remain, including: what is the best approach for different tumor types, and which biomarkers will accurately identify the patient populations most likely to benefit from specific PI3K inhibitors? This review summarizes the strategies being employed by Novartis Oncology to help maximize the benefits of clinical studies with buparlisib and alpelisib, including stratification according to PI3K pathway activation status, selective enrollment/target enrichment (where patients with PI3K pathway-activated tumors are specifically recruited), nonselective enrollment with mandatory tissue collection, and enrollment of patients who have progressed on previous targeted agents, such as mTOR inhibitors or endocrine therapy. An overview of Novartis-sponsored and Novartis-supported trials that are utilizing these approaches in a range of cancer types, including breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, lymphoma, and glioblastoma multiforme, is also described.
The etiology of asthma remains elusive, with no known cure. Based on accumulating evidence, autophagy, a self-degradation process that maintains cellular metabolism and homeostasis, participates in ...the development of asthma. Mycobacterium vaccae vaccine (M. vaccae), an immunomodulatory agent, has previously been shown to effectively alleviate airway inflammation and airway remodeling. However, its therapeutic effect on asthma via the regulation of autophagy remains unknown. Therefore, this study aimed to investigate the impact of M. vaccae in attenuating asthma airway inflammation via autophagy-mediated pathways.
Balb/c mice were used to generate an ovalbumin (OVA)-immunized allergic airway model and were subsequently administered either M. vaccae or M. vaccae + rapamycin (an autophagy activator) prior to each challenge. Next, airway inflammation, mucus secretion, and airway remodeling in mouse lung tissue were assessed via histological analyses. Lastly, the expression level of autophagy proteins LC3B, Beclin1, p62, and autolysosome was determined both in vivo and in vitro, along with the expression level of p-PI3K, PI3K, p-Akt, and Akt in mouse lung tissue.
The findings indicated that aerosol inhalation of M. vaccae in an asthma mouse model has the potential to decrease eosinophil counts, alleviate airway inflammation, mucus secretion, and airway remodeling through the inhibition of autophagy. Likewise, M. vaccae could reduce the levels of OVA-specific lgE, IL-5, IL-13, and TNF-α in asthma mouse models by inhibiting autophagy. Furthermore, this study revealed that M. vaccae also suppressed autophagy in IL-13-stimulated BEAS-2B cells. Moreover, M. vaccae may activate the PI3K/Akt signaling pathway in the lung tissue of asthmatic mice.
In summary, the present study suggests that M. vaccae may contribute to alleviating airway inflammation and remodeling in allergic asthma by potentially modulating autophagy and the PI3K/Akt signaling pathway. These discoveries offer a promising avenue for the development of therapeutic interventions targeting allergic airway inflammation.
•The etiology of asthma remains elusive, with no known cure.•Mycobacterium vaccae attenuates asthma through the inhibition of the autophagy•Mycobacterium vaccae may activate the PI3K/Akt pathway to ameliorate asthma
VPS34-IN1 induces apoptosis of ER+ breast cancer cells via activating PERK/ATF4/CHOP pathway.
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VPS34-IN1 is a specific selective inhibitor of Class III Phosphatidylinositol 3-kinase ...(PI3K) and has been shown to exhibit a significant antitumor effect in leukemia and liver cancer. In current study, we focused on the anticancer effect and potential mechanism of VPS34-IN1 in estrogen receptor positive (ER+ ) breast cancer. Our results revealed that VPS34-IN1 inhibited the viability of ER+ breast cancer cells in vitro and in vivo. Flow cytometry and western blot analyses showed that VPS34-IN1 treatment induced breast cancer cell apopotosis. Interestingly, VPS34-IN1 treatment activated protein kinase R (PKR)-like ER kinase (PERK) branch of endoplasmic reticulum (ER) stress. Furthermore, knockdown of PERK by siRNA or inhibition of PERK activity by chemical inhibitor GSK2656157 could attenuate VPS34-IN1-mediated apoptosis in ER+ breast cancer cells. Collectively, VPS34-IN1 has an antitumor effect in breast cancer, and it may result from activating PERK/ATF4/CHOP pathway of ER stress to induce cell apoptosis. These findings broaden our understanding of the anti-breast cancer effects and mechanisms of VPS34-IN1 and provide new ideas and reference directions for the treatment of ER+ breast cancer.
Purpose of Review
The phosphatidylinositol 3-kinase (PI3K) pathway is the most common aberrantly activated pathway in breast cancer, making it an attractive therapeutic target. In this review, we ...will discuss the rationale for targeting PI3K/AKT signaling and the development of PI3K/AKT inhibitors in breast cancer.
Recent Findings
Although the initial clinical trials with pan-PI3K inhibitors were challenged by high toxicities and modest antitumor effect, there has been continued effort to develop agents more precisely targeting PI3K isoforms to improve therapeutic index. Alpelisib in combination with fulvestrant is now available in the clinic for postmenopausal women with advanced or metastatic hormone receptor (HR)-positive, HER2-negative,
PIK3CA
-mutated breast cancer. In addition, promising data has been observed in randomized phase II trials of AKT inhibitors in combination with fulvestrant or paclitaxel in metastatic HR-positive, HER2-negative disease and triple negative breast cancer (TNBC), respectively.
Summary
The high frequency of genetic alterations in the PI3K pathway has provided the rationale for development of inhibitors targeting PI3K/AKT. Despite initial disappointment with several randomized trials of pan-PI3K inhibitors in HR-positive breast cancer, there has been continued effort to more precisely target PI3K isoforms, which has led to clinical benefit for patients with advanced breast cancer.
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