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Book ; Online: Targeting PI3K/mTOR signaling in cancer

Arcaro, Alexandre

2014

Abstract: The phosphatidylinositol 3-kinase (PI3K)/mTOR pathway integrates signals from growth factors with nutrient signals and other conditions and controls multiple cell responses, including proliferation, survival and metabolism. Deregulation of the PI3K ... ...

Abstract	The phosphatidylinositol 3-kinase (PI3K)/mTOR pathway integrates signals from growth factors with nutrient signals and other conditions and controls multiple cell responses, including proliferation, survival and metabolism. Deregulation of the PI3K pathway has been extensively investigated in connection to cancer. Somatic or inherited mutations frequently occur in tumor suppressor genes (PTEN, TSC1/2, LKB1) and oncogenes (PIK3CA, PIK3R1, AKT) in the PI3K/mTOR pathway. The fact that the PI3K/mTOR pathway is deregulated in a large number of human malignancies, and its importance for different cellular responses, makes it an attractive drug target. Pharmacological PI3K inhibitors have played a very important role in studying cellular responses involving these enzymes. Currently, a wide range of selective PI3K inhibitors have been tested in preclinical studies and some have entered clinical trials in oncology. Rapamycin and its analogs targeting mTOR are effective in many preclinical cancer models. Although rapalogs are approved for the treatment of some cancers, their efficacy in clinical trials remains the subject of debate. Due to the complexity of the PI3K/mTOR signaling pathway, developing an effective anti-cancer therapy remains a challenge. The biggest challenge in curing cancer patients with various signaling pathway abnormalities is to target multiple components of different signal transduction pathways with mechanism-based combinatorial treatments
Keywords	Science (General) ; Biology (General) ; Medicine (General) ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Size	1 electronic resource (93 p.)
Publisher	Frontiers Media SA
Document type	Book ; Online
Note	English ; Open Access
HBZ-ID	HT020090028
ISBN	9782889192441 ; 288919244X
Database	ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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Article ; Online: Targeted therapies for small cell lung cancer: Where do we stand?

Arcaro, Alexandre

Critical reviews in oncology/hematology

2015 Volume 95, Issue 2, Page(s) 154–164

Abstract: Small cell lung cancer (SCLC) accounts for 15% of lung cancer cases and is associated with a dismal prognosis. Standard therapeutic regimens have been improved over the past decades, but without a major impact on patient survival. The development of ... ...

Abstract	Small cell lung cancer (SCLC) accounts for 15% of lung cancer cases and is associated with a dismal prognosis. Standard therapeutic regimens have been improved over the past decades, but without a major impact on patient survival. The development of targeted therapies based on a better understanding of the molecular basis of the disease is urgently needed. At the genetic level, SCLC appears very heterogenous, although somatic mutations targeting classical oncogenes and tumor suppressors have been reported. SCLC also possesses somatic mutations in many other cancer genes, including transcription factors, enzymes involved in chromatin modification, receptor tyrosine kinases and their downstream signaling components. Several avenues have been explored to develop targeted therapies for SCLC. So far, however, there has been limited success with these targeted approaches in clinical trials. Further progress in the optimization of targeted therapies for SCLC will require the development of more personalized approaches for the patients.
MeSH term(s)	Antineoplastic Agents/therapeutic use ; Drug Delivery Systems/methods ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Mutation ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Precision Medicine/methods ; Small Cell Lung Carcinoma/drug therapy ; Small Cell Lung Carcinoma/genetics ; Small Cell Lung Carcinoma/metabolism ; Small Cell Lung Carcinoma/pathology
Chemical Substances	Antineoplastic Agents ; Neoplasm Proteins
Language	English
Publishing date	2015-08
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	605680-5
ISSN	1879-0461 ; 0737-9587 ; 1040-8428
ISSN (online)	1879-0461
ISSN	0737-9587 ; 1040-8428
DOI	10.1016/j.critrevonc.2015.03.001
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Targeting PI3K/mTOR Signaling in Cancer.

Arcaro, Alexandre

Frontiers in oncology

2014 Volume 4, Page(s) 84

Language	English
Publishing date	2014-04-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2014.00084
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Article: Targeting the insulin-like growth factor-1 receptor in human cancer.

Arcaro, Alexandre

Frontiers in pharmacology

2013 Volume 4, Page(s) 30

Abstract: The insulin-like growth factor (IGF) signaling system plays a crucial role in human cancer and the IGF-1 receptor (IGF-1R) is an attractive drug target against which a variety of novel anti-tumor agents are being developed. Deregulation of the IGF ... ...

Abstract	The insulin-like growth factor (IGF) signaling system plays a crucial role in human cancer and the IGF-1 receptor (IGF-1R) is an attractive drug target against which a variety of novel anti-tumor agents are being developed. Deregulation of the IGF signaling pathway frequently occurs in human cancer and involves the establishment of autocrine loops comprising IGF-1 or IGF-2 and/or IGF-1R over-expression. Epidemiologic studies have documented a link between elevated IGF levels and the development of solid tumors, such as breast, colon, and prostate cancer. Anti-cancer strategies targeting the IGF signaling system involve two main approaches, namely neutralizing antibodies and small molecule inhibitors of the IGF-1R kinase activity. There are numerous reports describing anti-tumor activity of these agents in pre-clinical models of major human cancers. In addition, multiple clinical trials have started to evaluate the safety and efficacy of selected IGF-1R inhibitors, in combination with standard chemotherapeutic regimens or other targeted agents in cancer patients. In this mini review, I will discuss the role of the IGF signaling system in human cancer and the main strategies which have been so far evaluated to target the IGF-1R.
Language	English
Publishing date	2013-03-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2013.00030
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Involvement of autophagy in the response of tumor cells to PtdIns3K inhibitors: therapeutic implications.

Arcaro, Alexandre

Autophagy

2013 Volume 9, Issue 4, Page(s) 607–608

Abstract: The phosphoinositide 3-kinase (PI3K) pathway plays a crucial role in cell proliferation and survival and is frequently activated by genetic and epigenetic alterations in human cancer. An arsenal of pharmacological inhibitors of key signaling enzymes in ... ...

Abstract	The phosphoinositide 3-kinase (PI3K) pathway plays a crucial role in cell proliferation and survival and is frequently activated by genetic and epigenetic alterations in human cancer. An arsenal of pharmacological inhibitors of key signaling enzymes in this pathway, including class I(A) PI3K isoforms, has been developed in the past decade and several compounds have entered clinical testing in cancer patients. The PIK3CA/p110α isoform is the most studied enzyme of the family and a validated cancer target. The induction of autophagy by PI3K pathway inhibitors has been documented in various cancers, although a clear picture about the significance of this phenomenon is still missing, especially in the in vivo situation. A better understanding of the contribution of autophagy to the action of PI3K inhibitors on tumors cells is important, since it may limit or enhance the action of these compounds, depending on the cellular context.
MeSH term(s)	Animals ; Apoptosis/drug effects ; Autophagy/drug effects ; Cell Line, Tumor ; Humans ; Neoplasms/drug therapy ; Neoplasms/enzymology ; Neoplasms/pathology ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	Phosphoinositide-3 Kinase Inhibitors ; Protein Kinase Inhibitors ; TOR Serine-Threonine Kinases (EC 2.7.1.1)
Language	English
Publishing date	2013-01-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.4161/auto.23461
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: IGF signaling as a therapeutic target in pediatric solid tumors of the central and peripheral nervous system.

Grotzer, Michael A / Guerreiro, Ana S / Bourquin, Jean-Pierre / Arcaro, Alexandre

Expert review of endocrinology & metabolism

2019 Volume 2, Issue 5, Page(s) 677–688

Abstract: Similar to many other growth factor systems, the IGF system consists of more than a single ligand interacting with a single receptor. There are three ligands (IGF-I, IGF-II and insulin) that interact with at least four receptors. In addition, the IGF ... ...

Abstract	Similar to many other growth factor systems, the IGF system consists of more than a single ligand interacting with a single receptor. There are three ligands (IGF-I, IGF-II and insulin) that interact with at least four receptors. In addition, the IGF system also involves six well-characterized binding proteins that regulate IGF action. Type I IGF receptor-mediated signaling plays a fundamental role in cell growth and malignant transformation and is an important mediator of anti-apoptotic signals. This review describes the roles of IGF signaling in childhood tumors of the CNS and PNS, including neuroblastoma, medulloblastoma, atypical teratoid/rhabdoid tumors and craniopharyngioma. Moreover, it describes strategies to disrupt the IGF signaling as a potential cancer therapy.
Language	English
Publishing date	2019-02-08
Publishing country	England
Document type	Journal Article
ISSN	1744-8417
ISSN (online)	1744-8417
DOI	10.1586/17446651.2.5.677
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Targeting phosphoinositide 3-kinase signalling in lung cancer.

Wojtalla, Anna / Arcaro, Alexandre

Critical reviews in oncology/hematology

2011 Volume 80, Issue 2, Page(s) 278–290

Abstract: Lung cancer is the leading cause of cancer-related mortality worldwide and more than 1 million people annually die in consequence of lung cancer. Although an improvement in lung cancer treatment could be achieved, especially in the last decade, the ... ...

Abstract	Lung cancer is the leading cause of cancer-related mortality worldwide and more than 1 million people annually die in consequence of lung cancer. Although an improvement in lung cancer treatment could be achieved, especially in the last decade, the development of additional therapeutic strategies is urgently required in order to provide improved survival benefit for patients. Lung cancer formation is caused by genetic modifications commonly caused by tobacco smoking. Numerous studies have demonstrated the role of extracellular growth factors in lung cancer cell proliferation, metastasis, and chemoresistance. Mutations and amplifications in molecules related to receptor tyrosine signalling, such as EGFR, ErbB2, c-Met, c-Kit, VEGFR, PI3K, and PTEN are only some of the alterations known to contribute to the development of lung cancer. The phosphoinositide 3-kinase (PI3K) pathway, fundamental for cell development, growth, and survival, is known to be frequently altered in neoplasia, including carcinomas of the lung. Based on the high frequency of alterations, which include mutations and amplifications, leading to over-activation of certain upstream/downstream mediators, targeting components of the PI3K signalling pathway is considered to be a promising therapeutic approach in cancer treatment. In this article we will summarize the current knowledge about the involvement of PI3K signalling in lung cancer and discuss the development of targeted therapies involving PI3K pathway inhibitors.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/enzymology ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; Humans ; Lung/drug effects ; Lung/enzymology ; Lung Neoplasms/drug therapy ; Lung Neoplasms/enzymology ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Phosphatidylinositol 3-Kinases/metabolism ; Signal Transduction/drug effects ; Small Cell Lung Carcinoma/drug therapy ; Small Cell Lung Carcinoma/enzymology
Chemical Substances	Antineoplastic Agents ; Enzyme Inhibitors ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-)
Language	English
Publishing date	2011-11
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	605680-5
ISSN	1879-0461 ; 0737-9587 ; 1040-8428
ISSN (online)	1879-0461
ISSN	0737-9587 ; 1040-8428
DOI	10.1016/j.critrevonc.2011.01.007
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: The phosphoinositide 3-kinase pathway in human cancer: genetic alterations and therapeutic implications.

Arcaro, Alexandre / Guerreiro, Ana S

Current genomics

2009 Volume 8, Issue 5, Page(s) 271–306

Abstract: The phosphoinositide 3-kinase (PI3K) pathway is frequently activated in human cancer and represents an attractive target for therapies based on small molecule inhibitors. PI3K isoforms play an essential role in the signal transduction events activated by ...

Abstract	The phosphoinositide 3-kinase (PI3K) pathway is frequently activated in human cancer and represents an attractive target for therapies based on small molecule inhibitors. PI3K isoforms play an essential role in the signal transduction events activated by cell surface receptors including receptor tyrosine kinases (RTKs) and G-protein-coupled receptors (GPCRs). There are eight known PI3K isoforms in humans, which have been subdivided into three classes (I-III). Therefore PI3Ks show considerable diversity and it remains unclear which kinases in this family should be targeted in cancer. The class I(A) of PI3K comprises the p110alpha, p110beta and p110delta isoforms, which associate with activated RTKs. In human cancer, recent reports have described activating mutations in the PIK3CA gene encoding p110alpha, and inactivating mutations in the phosphatase and tensin homologue (PTEN) gene, a tumour suppressor and antagonist of the PI3K pathway. The PIK3CA mutations described in cancer constitutively activate p110alpha and, when expressed in cells drive oncogenic transformation. Moreover, these mutations cause the constitutive activation of downstream signaling molecules such as Akt/protein kinase B (PKB), mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase (S6K) that is commonly observed in cancer cells. In addition to p110alpha, the other isoforms of the PI3K family may also play a role in human cancer, although their individual functions remain to be precisely identified. In this review we will discuss the evidence implicating individual PI3K isoforms in human cancer and their potential as drug targets in this context.
Language	English
Publishing date	2009-04-22
Publishing country	United Arab Emirates
Document type	Journal Article
ZDB-ID	2033677-9
ISSN	1875-5488 ; 1389-2029
ISSN (online)	1875-5488
ISSN	1389-2029
DOI	10.2174/138920207782446160
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Article ; Online: Emerging metabolic targets in the therapy of hematological malignancies.

Leni, Zaira / Parakkal, Geetha / Arcaro, Alexandre

BioMed research international

2013 Volume 2013, Page(s) 946206

Abstract: During the last decade, the development of anticancer therapies has focused on targeting neoplastic-related metabolism. Cancer cells display a variety of changes in their metabolism, which enable them to satisfy the high bioenergetic and biosynthetic ... ...

Abstract	During the last decade, the development of anticancer therapies has focused on targeting neoplastic-related metabolism. Cancer cells display a variety of changes in their metabolism, which enable them to satisfy the high bioenergetic and biosynthetic demands for rapid cell division. One of the crucial alterations is referred to as the "Warburg effect", which involves a metabolic shift from oxidative phosphorylation towards the less efficient glycolysis, independent of the presence of oxygen. Although there are many examples of solid tumors having altered metabolism with high rates of glucose uptake and glycolysis, it was only recently reported that this phenomenon occurs in hematological malignancies. This review presents evidence that targeting the glycolytic pathway at different levels in hematological malignancies can inhibit cancer cell proliferation by restoring normal metabolic conditions. However, to achieve cancer regression, high concentrations of glycolytic inhibitors are used due to limited solubility and biodistribution, which may result in toxicity. Besides using these inhibitors as monotherapies, combinatorial approaches using standard chemotherapeutic agents could display enhanced efficacy at eradicating malignant cells. The identification of the metabolic enzymes critical for hematological cancer cell proliferation and survival appears to be an interesting new approach for the targeted therapy of hematological malignancies.
MeSH term(s)	Antineoplastic Agents/metabolism ; Antineoplastic Agents/therapeutic use ; Cell Division ; Cell Proliferation/drug effects ; Hematologic Neoplasms/metabolism ; Hematologic Neoplasms/pathology ; Humans ; Molecular Targeted Therapy ; Oxidative Phosphorylation ; Oxygen/metabolism ; Tissue Distribution
Chemical Substances	Antineoplastic Agents ; Oxygen (S88TT14065)
Language	English
Publishing date	2013-08-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2698540-8
ISSN	2314-6141 ; 2314-6133
ISSN (online)	2314-6141
ISSN	2314-6133
DOI	10.1155/2013/946206
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Questioning the role of selected somatic PIK3C2B mutations in squamous non-small cell lung cancer oncogenesis.

Kind, Marcus / Klukowska-Rötzler, Jolanta / Berezowska, Sabina / Arcaro, Alexandre / Charles, Roch-Philippe

PloS one

2017 Volume 12, Issue 10, Page(s) e0187308

Abstract: PI3K signaling is frequently dysregulated in NSCLC-SQCC. In contrast to well characterized components of the PI3K signaling network contributing to the formation of SQCC, potential oncogenic effects of alterations in PIK3C2B are poorly understood. Here, ... ...

Abstract	PI3K signaling is frequently dysregulated in NSCLC-SQCC. In contrast to well characterized components of the PI3K signaling network contributing to the formation of SQCC, potential oncogenic effects of alterations in PIK3C2B are poorly understood. Here, a large cohort (n = 362) of NSCLC-SQCC was selectively screened for four reported somatic mutations in PIK3C2B via Sanger sequencing. In addition, two mutations leading to an amino acid exchange in the kinase domain (C1181, H1208R) were examined on a functional level. None of the mutations were identified in the cohort while well characterized hotspot PIK3CA mutations were observed at the expected frequency. Ultimately, kinase domain mutations in PI3KC2β were found to have no altering effect on downstream signaling. A set of SQCC tumors sequenced by The Cancer Genome Atlas (TCGA) equally indicates a lack of oncogenic potential of the kinase domain mutations or PIK3C2B in general. Taken together, this study suggests that PIK3C2B might only have a minor role in SQCC oncogenesis.
MeSH term(s)	Carcinogenesis ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/pathology ; Class II Phosphatidylinositol 3-Kinases/genetics ; Cohort Studies ; HEK293 Cells ; Humans ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Mutation
Chemical Substances	Class II Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; PIK3C2B protein, human (EC 2.7.1.137)
Language	English
Publishing date	2017-10-31
Publishing country	United States
Document type	Journal Article ; Validation Study
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0187308
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