Aberrations in various cellular signaling pathways are instrumental in regulating cellular metabolism, tumor development, growth, proliferation, metastasis and cytoskeletal reorganization. The fundamental cellular signaling cascade involved in these processes, the phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR), closely related to the mitogen-activated protein kinase (MAPK) pathway, is a crucial and intensively explored intracellular signaling pathway in tumorigenesis. Various activating mutations in oncogenes together with the inactivation of tumor suppressor genes are found in diverse malignancies across almost all members of the pathway. Substantial progress in uncovering PI3K/AKT/mTOR alterations and their roles in tumorigenesis has enabled the development of novel targeted molecules with potential for developing efficacious anticancer treatment. Two approved anticancer drugs, everolimus and temsirolimus, exemplify targeted inhibition of PI3K/AKT/mTOR in the clinic and many others are in preclinical development as well as being tested in early clinical trials for many different types of cancer. This review focuses on targeted PI3K/AKT/mTOR signaling from the perspective of novel molecular targets for cancer therapy found in key pathway members and their corresponding experimental therapeutic agents. Various aberrant prognostic and predictive biomarkers are also discussed and examples are given. Novel approaches to PI3K/AKT/mTOR pathway inhibition together with a better understanding of prognostic and predictive markers have the potential to significantly improve the future care of cancer patients in the current era of personalized cancer medicine.

• MeSH
• 1-fosfatidylinositol-3-kinasa metabolismus   MeSH
• cílená molekulární terapie * MeSH
• inhibitory fosfoinositid-3-kinasy MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• nádory farmakoterapie   enzymologie   patologie   MeSH
• protinádorové látky terapeutické užití   MeSH
• protoonkogenní proteiny c-akt antagonisté a inhibitory   metabolismus   MeSH
• racionální návrh léčiv MeSH
• signální transdukce účinky léků   MeSH
• TOR serin-threoninkinasy antagonisté a inhibitory   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Sarcoma is a heterogeneous group of malignancies often resistant to conventional chemotherapy and radiation therapy. The phosphatidylinositol-3-kinase/ protein kinase B /mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway has emerged as a critical cancer target due to its central role in regulating key cellular processes such as cell growth, proliferation, survival, and metabolism. Dysregulation of this pathway has been implicated in the development and progression of bone sarcomas (BS) and soft tissue sarcomas (STS). PI3K/Akt/mTOR inhibitors have shown promising preclinical and clinical activity in various cancers. These agents can inhibit the activation of PI3K, Akt, and mTOR, thereby reducing the downstream signaling events that promote tumor growth and survival. In addition, PI3K/Akt/mTOR inhibitors have been shown to enhance the efficacy of other anticancer therapies, such as chemotherapy and radiation therapy. The different types of PI3K/Akt/mTOR inhibitors vary in their specificity, potency, and side effect profiles and may be effective depending on the specific sarcoma type and stage. The molecular targeting of PI3K/Akt/mToR pathway using drugs, phytochemicals, nanomaterials (NMs), and microbe-derived molecules as Pan-PI3K inhibitors, selective PI3K inhibitors, and dual PI3K/mTOR inhibitors have been delineated. While there are still challenges to be addressed, the preclinical and clinical evidence suggests that these inhibitors may significantly improve patient outcomes. Further research is needed to understand the potential of these inhibitors as sarcoma therapeutics and to continue developing more selective and effective agents to meet the clinical needs of sarcoma patients.

• MeSH
• fosfatidylinositol-3-kinasy * metabolismus   MeSH
• inhibitory fosfoinositid-3-kinasy farmakologie   terapeutické užití   MeSH
• inhibitory proteinkinas farmakologie   chemie   terapeutické užití   MeSH
• lidé MeSH
• mTOR inhibitory farmakologie   terapeutické užití   MeSH
• protinádorové látky * farmakologie   chemie   terapeutické užití   MeSH
• protoonkogenní proteiny c-akt * metabolismus   antagonisté a inhibitory   MeSH
• sarkom * farmakoterapie   metabolismus   patologie   MeSH
• signální transdukce * účinky léků   MeSH
• TOR serin-threoninkinasy * antagonisté a inhibitory   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

INTRODUCTION: Despite advances in the treatment of metastatic breast cancer, the lack of response or relapse/progression during the course of therapy continue to present a challenge towards deeper understanding of dysregulated signaling pathways in breast cancer. Consequently, there is an unmet medical need for the development of new agents to overcome the resistance to therapy and improve the treatment outcome. AREAS COVERED: In this review, the mechanism of action and the role of intracellular PI3K/AKT/mTOR signaling pathway inhibition in breast cancer patients are described. Everolimus has been approved in combination with exemestane for the treatment of hormone-receptor-positive advanced breast cancer after failure of nonsteroidal aromatase inhibitor therapy. The aim of this paper is to focus on the safety and efficacy of mTOR inhibitors in the treatment of breast cancer. Current strategies of major adverse event management and prevention are delineated. EXPERT OPINION: Study results demonstrate clearly that the inhibition of the PI3K/AKT/mTOR pathway represents a promising approach to improve the efficacy of other targeted therapies in estrogen receptor-positive breast cancer patients with an acceptable safety profile. Although side effects are not uncommon, these are usually mild to moderate in severity and manageable with supportive care and dose adjustments.

• MeSH
• chemorezistence MeSH
• cílená molekulární terapie MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory prsu farmakoterapie   patologie   MeSH
• protinádorové látky aplikace a dávkování   škodlivé účinky   farmakologie   MeSH
• racionální návrh léčiv MeSH
• signální transdukce účinky léků   MeSH
• TOR serin-threoninkinasy antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The present study reviews recent developments of molecular-targeted therapies in the treatment of recurrent and/or metastatic head and neck squamous cell carcinoma. It also highlights ongoing research regarding predictive markers of sensitivity or resistance to anti-epidermal growth factor receptor agents and discusses some promising novel targets in head and neck squamous cell carcinoma, as well as clinical trial design challenges. RECENT FINDINGS: Phase III randomized studies have brought the proof that cetuximab, an anti-epidermal growth factor receptor agent, is able to improve survival, either in combination with radiation therapy or in first-line treatment for recurrent and/or metastatic head and neck squamous cell carcinoma. In addition, promising results have been obtained with antiangiogenic therapies in phase II trials. Some clinical and molecular markers of resistance to anti-epidermal growth factor receptor agents have been identified, but they have not yet been validated for clinical practice. Other interesting targets, such as insulin-like growth factor 1R or the PI3K/AKT/mTOR pathway, have been shown in vitro to play key roles in head and neck squamous cell carcinoma, and their inhibition warrants further evaluations. SUMMARY: Proof of the concept that molecular-targeted therapy is a valid therapeutic approach for head and neck squamous cell carcinoma has emerged with anti-epidermal growth factor receptor agents. Nevertheless, identification of predictive biomarkers of resistance or sensitivity to these therapies remains the main challenge in the optimal selection of patients most likely to benefit from them.

• MeSH
• erbB receptory antagonisté a inhibitory   MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• inhibitory angiogeneze terapeutické užití   MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   mortalita   MeSH
• monoklonální protilátky terapeutické užití   MeSH
• nádorové biomarkery analýza   MeSH
• nádory hlavy a krku farmakoterapie   metabolismus   mortalita   MeSH
• proteinkinasy metabolismus   MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• randomizované kontrolované studie jako téma MeSH
• receptor IGF typ 1 účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• spinocelulární karcinom farmakoterapie   metabolismus   mortalita   MeSH
• Check Tag
• lidé MeSH

Generally, patients with renal cell carcinoma (RCC) are viewed as potential candidates for antiangiogenic targeted therapy. Tubulocystic RCC (TCRC) is a recently described entity which may behave aggressively, and the rationale for antiangiogenic therapy in this group of renal tumors has yet to be determined. Seven TCRCs and five non-tumor tissue samples from seven patients were subjected to relative expression analysis of mRNA levels of 16 genes involved in three angiogenic signal pathways: (1) VHL/HIF, (2) RTK/mitogen-activated protein kinase (MAPK), and (3) PI3K/Akt/mTOR. Two of them, pathways (2) and (3), are often targeted by antiangiogenic agents. We also determined the mutation and methylation status of the VHL gene. Finally, the levels of vascular endothelial growth factor A (VEGFA), HIF-1α, HIF-2α proteins, and phosphorylated mTOR protein were also determined. The comparison of tumor and control samples revealed no changes of mRNA levels of the following genes: VHL, HIF-1α, HIF-2α, PTEN, Akt2, Akt3, mTOR, VEGFA, KDR, HRas, C-Jun, EGFR, and FGF2. Significantly elevated mRNA level of TP53 was found, while the mRNA levels of FLT1 and C-FOS were reduced in tumor samples. No mutations or methylation in the VHL gene were found. Changes in levels of studied proteins VEGFA, HIF-1α, HIF-2α, and increased phosphorylation of mTOR protein were not found. Three studied angiogenic pathways (VHL/HIF, RTK/MAPK, and PI3K/Akt/mTOR) seem not to be upregulated in TCRC samples, so there appears to be no rationale for a general recommendation of antiangiogenic targeted therapeutic protocols for patients with these tumors.

• MeSH
• cílená molekulární terapie metody   MeSH
• dospělí MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus   MeSH
• fosforylace MeSH
• inhibitory angiogeneze farmakologie   terapeutické užití   MeSH
• karcinom z renálních buněk krevní zásobení   farmakoterapie   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorový supresorový protein VHL metabolismus   MeSH
• nádory ledvin krevní zásobení   farmakoterapie   metabolismus   MeSH
• patologická angiogeneze farmakoterapie   genetika   MeSH
• senioři MeSH
• signální transdukce účinky léků   genetika   MeSH
• TOR serin-threoninkinasy metabolismus   MeSH
• transkripční faktory bHLH metabolismus   MeSH
• vaskulární endoteliální růstový faktor A metabolismus   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH