Development Of Phosphatidylinositol 3-kinase Inhibitors Research Articles

PI3K Inhibitors in Advanced Breast Cancer: The Past, The Present, New Challenges and Future Perspectives.

Simple SummaryMolecular aberrations in the phosphatidylinositol 3-kinase (PI3K) pathway are often observed in breast cancer and represent a key regulator of many cellular processes, promoting tumor cell growth and survival. The first clinical trials leading to the development of pan-PI3K inhibitors showed certain preclinical activity; nevertheless, the toxicity profile limited further analysis of this drugs’ class. To improve the antitumor effect and therapeutic index, additional clinical trials have been performed to develop the PI3K isoform-specific inhibitors and new schedule combinations with a good toxicity profile. However, further efforts are needed to discover other potentially actionable genetic alterations that remain a challenge to reach the goal of personalized and precision medicine.Breast cancer is the leading cause of death in the female population and despite significant efforts made in diagnostic approaches and treatment strategies adopted for advanced breast cancer, the disease still remains incurable. Therefore, development of more effective systemic treatments constitutes a crucial need. Recently, several clinical trials were performed to find innovative predictive biomarkers and to improve the outcome of metastatic breast cancer through innovative therapeutic algorithms. In the pathogenesis of breast cancer, the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of rapamycin (mTOR) axis is a key regulator of cell proliferation, growth, survival, metabolism, and motility, making it an interest and therapeutic target. Nevertheless, the PI3K/AKT/mTOR cascade includes a complex network of biological events, needing more sophisticated approaches for their use in cancer treatment. In this review, we described the rationale for targeting the PI3K pathway, the development of PI3K inhibitors and the future treatment directions of different breast cancer subtypes in the metastatic setting.

Copanlisib in the Treatment of Relapsed Follicular Lymphoma: Utility and Experience from the Clinic.

The phosphatidylinositol-3-kinase (PI3K) pathway is ubiquitous to multiple cellular processes and is intricately implicated in lymphomagenesis. The development of PI3K inhibitors has broadened treatment options for relapsed and/or refractory follicular lymphoma (FL) and currently three PI3K inhibitors have been approved in the third-line setting for FL, including idelalisib (oral), duvelisib (oral), and copanlisib (intravenous), with other agents under investigation. In this review, we discuss the clinical advance of copanlisib through preclinical to Phase III trials, its unique cellular targets and side effect profile that have poised it as a safer and equally efficacious option when compared to the older-generation oral PI3Kis, and its utility to the clinician as part of the therapeutic armamentarium for relapsed and/or refractory FL.

Abstract IA25: Development of PI3K inhibitors in breast cancer

Abstract The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is crucial to many aspects of cell growth and survival. PI3K pathway is frequently deregulated in breast cancer due to genetic or epigenetic alterations in components of this pathway and contributes to treatment resistance. Notably, PIK3CA mutation is the most frequent genetic event in estrogen receptor-positive (ER+) breast cancer, while loss of PTEN expression is commonly observed in triple-negative disease (TNBC). There has been significant interest in developing PI3K inhibitors in breast cancer. Several randomized clinical trials assessing the benefit of adding PI3K inhibitors to fulvestrant in patients with advanced ER+ breast cancer, including BELLE-2, BELLE-3, FERGI, and SANDPIPER, have been reported. Significant improvement in progression-free survival (PFS) has been observed in these trials. However, dose-limiting toxicities of pan-PI3K inhibitors are common, which limit their clinical application. Isoform selective inhibitors, such as alpha selective PI3K inhibitor, are in clinical trials with the hope to reduce toxicity. There is ongoing effect in the investigation of predictors of response and mechanisms of treatment resistance. This presentation will summarize clinical trial data in breast cancer and challenges in the development of PI3K inhibitors in breast cancer. Citation Format: Cynthia X. Ma. Development of PI3K inhibitors in breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr IA25.

Treating cancer with phosphatidylinositol-3-kinase inhibitors: increasing efficacy and overcoming resistance

The discovery of the phosphatidylinositol-3-kinase (PI3K) pathway was a major advance in understanding growth factor signaling. The high frequency of PI3K pathway mutations in many cancers has encouraged a new field targeting cancer driver mutations. Although there have been many successes, targeting PI3K itself has proven challenging, in part because of its multiple isoforms with distinct roles. Despite promising preclinical results, development of PI3K inhibitors as pharmacologic anticancer agents has been limited by modest single-agent efficacy and significant adverse effects. If we could overcome these limitations, PI3K inhibitors would be a powerful cancer-fighting tool. Data from phase III clinical trials yields insight into some of the problems with PI3K inhibitors. Recent advances have shed light on the mechanisms of tumor resistance to PI3K inhibitors via feedback pathways that cause elevated insulin levels that then activate the same PI3K pathways that are the targets of inhibition. Improving our understanding of the complex regulatory feedback pathways that activate in response to PI3K inhibition will reveal ways to increase the efficacy of PI3K inhibitors and reduce adverse effects, increasing the usefulness of this class as a treatment option for multiple cancer types.

A novel phosphatidylinositol 3-kinase (PI3K) inhibitor directs a potent FOXO-dependent, p53-independent cell cycle arrest phenotype characterized by the differential induction of a subset of FOXO-regulated genes.

IntroductionThe activation of the phosphoinositide 3-kinase (PI3K)/AKT signalling pathway is one the most frequent genetic events in breast cancer, consequently the development of PI3K inhibitors has attracted much attention. Here we evaluate the effect of PI3K inhibition on global gene expression in breast cancer cells.MethodsWe used a range of methodologies that include in silico compound analysis, in vitro kinase assays, cell invasion assays, proliferation assays, genome-wide transcription studies (Agilent Technologies full genome arrays), gene set enrichment analysis, quantitative real-time PCR, immunoblotting in addition to chromatin immunoprecipitation.ResultsWe defined the physico-chemical and the biological properties of ETP-45658, a novel potent PI3K inhibitor. We demonstrated that ETP-45658 potently inhibited cell proliferation within a broad range of human cancer cells, most potently suppressing the growth of breast cancer cells via inhibiting cell cycle. We show that this response is Forkhead box O (FOXO) protein dependent and p53 independent. Our genome-wide microarray analysis revealed that the cell cycle was the most affected biological process after exposure to ETP-45658 (or our control PI3K inhibitor PI-103), that despite the multiple transcription factors that are regulated by the PI3K/AKT signalling cascade, only the binding sites for FOXO transcription factors were significantly enriched and only a subset of all FOXO-dependent genes were induced. This disparity in gene transcription was not due to differential FOXO promoter recruitment.ConclusionsThe constitutive activation of PI3Ks and thus the exclusion of FOXO transcription factors from the nucleus is a key feature of breast cancer. Our results presented here highlight that PI3K inhibition activates specific FOXO-dependent genes that mediate cell cycle arrest in breast cancer cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0482-y) contains supplementary material, which is available to authorized users.

Clinical development of phosphatidylinositol 3-kinase inhibitors for non-Hodgkin lymphoma

Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is extensively explored in cancers. It functions as an important regulator of cell growth, survival and metabolism. Activation of this pathway also predicts poor prognosis in numerous human malignancies. Drugs targeting this signaling pathway have been developed and have shown preliminary clinical activity. Accumulating evidence has highlighted the important role of PI3K in non-Hodgkin lymphoma (NHL), especially in the disease initiation and progression. Therapeutic functions of PI3K inhibitors in NHL have been demonstrated both in vivo and in vitro. This review will summarize recent advances in the activation of PI3K signaling in different types of NHL and the applications of PI3K inhibitors in NHL treatment.

Development of PI3K inhibitors: lessons learned from early clinical trials

The phosphatidylinositol 3-kinase (PI3K) pathway has an important role in cell metabolism, growth, migration, survival and angiogenesis. Drug development aimed at targetable genetic aberrations in the PI3K/AKT/mTOR pathway has been fomented by observations that alterations in this pathway induce tumour formation and that inappropriate PI3K signalling is a frequent occurrence in human cancer. Many of the agents developed have been evaluated in early stage clinical trials. This Review focuses on early clinical and translational data related to inhibitors of the PI3K/AKT/mTOR pathway, as these data will likely guide the further clinical development of such agents. We review data from those trials, delineating the safety profile of the agents--whether observed sequelae could be mechanism-based or off-target effects--and drug efficacy. We describe predictive biomarkers explored in clinical trials and preclinical mechanisms of resistance. We also discuss key unresolved translational questions related to the clinical development of inhibitors of the PI3K/AKT/mTOR pathway and propose designs for biomarker-driven trials to address those issues.

Clinical development of phosphatidylinositol 3-kinase inhibitors for cancer treatment.

The phosphatidylinositol 3-kinase (PI3K) pathway is commonly deregulated in cancer. In recent years, the results of the first phase I clinical trials with PI3K inhibitors have become available. In comparison to other targeted agents such v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors in melanoma or crizotinib in anaplastic lymphoma receptor tyrosine kinase (ALK) translocated tumors, the number of objective responses to PI3K inhibitors is less dramatic. In this review we propose possible strategies to optimize the clinical development of PI3K inhibitors: by exploring the potential role of PI3K isoform-specific inhibitors in improving the therapeutic index, molecular characterization as a basis for patient selection, and the relevance of performing serial tumor biopsies to understand the associated mechanisms of drug resistance. The main focus of this review will be on PI3K isoform-specific inhibitors by describing the functions of different PI3K isoforms, the preclinical activity of selective PI3K isoform-specific inhibitors and the early clinical data of these compounds.

PI3K: A potential therapeutic target for cancer

Phosphatidylinositol 3-kinase (PI3K), one member of lipid kinase family, has been demonstrated to play a key role in regulating cell proliferation, adhesion, survival, and motility. Recent studies indicate that PI3K related signaling pathway is one of the most commonly activated pathways in human cancers. Accordingly, pharmacological inhibition of key nodes in this signaling cascade has been a focus in developmental therapeutics. To date, Inhibitors targeting PI3K or nodes in this pathway, AKT and mTOR, are best studied and have reached clinical trials. In this review, we will focus on recent progress on understanding of PI3Ks signaling pathway and the development of PI3K inhibitors.

ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system

JFCR39 is an informatic anticancer drug discovery system that utilizes a panel of 39 human cancer cells coupled with a drug-activity database. This system not only provides disease-oriented information but can also predict the mechanism of action of a given antitumor agent. Development of a phosphatidylinositol 3-kinase (PI3K) inhibitor as an anticancer drug candidate has attracted a great deal of attention from both academia and industry because PI3K is known to be closely involved in carcinogenesis. ZSTK474 was identified as a PI3K inhibitor using JFCR39 system in combination with COMPARE analysis program. These findings were based on the similar fingerprint (growth inhibition profiles for JFCR39 human cancer cell line panel) with that of a classical PI3K inhibitor LY294002. Biochemical experiments confirmed ZSTK474 to be a potent pan-class I PI3K inhibitor, with high selectivity over other classes of PI3K and protein kinases. We previously reported the in vitro and in vivo antitumor efficacy of ZSTK474, together with the G(0)/G(1) arrest and antiangiogenic activity. Here, we review the JFCR39 system and summarize recent studies on PI3K biology and the development of PI3K inhibitors before discussing ZSTK474 in some detail.

Inhibition profiles of phosphatidylinositol 3-kinase inhibitors against PI3K superfamily and human cancer cell line panel JFCR39

As accumulating evidences suggest close involvement of phosphatidylinositol 3-kinase (PI3K) in various diseases particularly cancer, considerable competition occurs in development of PI3K inhibitors. Consequently, novel PI3K inhibitors such as ZSTK474, GDC-0941 and NVP-BEZ235 have been developed. Even though all these inhibitors were reported to inhibit class I PI3K but not dozens of protein kinases, whether they have different molecular targets remained unknown. To investigate such molecular target specificity, we have determined the inhibitory effects of these novel inhibitors together with classical PI3K inhibitor LY294002 on PI3K superfamily (including classes I, II, and III PI3Ks, PI4K and PI3K-related kinases) by using several novel non-radioactive biochemical assays. As a result, ZSTK474 and GDC-0941 indicated highly similar inhibition profiles for PI3K superfamily, with class I PI3K specificity much higher than NVP-BEZ235 and LY294002. We further investigated their growth inhibition effects on JFCR39, a human cancer cell line panel which we established for molecular target identification, and analysed their cell growth inhibition profiles (fingerprints) by using COMPARE analysis programme. Interestingly, we found ZSTK474 exhibited a highly similar fingerprint with GDC-0941 ( r = 0.863), more similar than with that of either NVP-BEZ235 or LY294002, suggesting that ZSTK474 shares more in molecular targets with GDC-0941 than with either of the other two PI3K inhibitors, consistent with the biochemical assay result. The biological implication of the difference in molecular target specificity of these PI3K inhibitors is under investigation.