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Phosphoinositide 3-kinase inhibitors in lymphoma.

ABSTRACT: The phosphoinositide 3-kinase (PI3K) pathway, with downstream targets including Akt and mammalian target of rapamycin, has been implicated in numerous human cancers, including hematologic malignancies and lymphomas. The development and refinement of PI3K inhibitors directed toward this pathway show promising clinical efficacy. This review will discuss the emerging body of clinical data in lymphoid malignancies and present future directions for research utilizing these inhibitors.The PI3K? inhibitor, idelalisib, has been most widely studied in lymphoma, and has shown promising results both as a single agent and in combination with other therapies. IPI-145, a dual inhibitor of PI3K? and PI3K?, has also shown efficacy and several clinical trials are underway. Other PI3K inhibitors are in active development, with several entering early phase clinical trials.The PI3K pathway appears to be important in lymphoma and targeting this pathway shows promising clinical efficacy.

SUBMITTER: Curran E

PROVIDER: S-EPMC4441952 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Phosphoinositide 3-kinase inhibitors in lymphoma.

Curran Emily E Smith Sonali M SM

Current opinion in oncology 20140901 5

<h4>Purpose of review</h4>The phosphoinositide 3-kinase (PI3K) pathway, with downstream targets including Akt and mammalian target of rapamycin, has been implicated in numerous human cancers, including hematologic malignancies and lymphomas. The development and refinement of PI3K inhibitors directed toward this pathway show promising clinical efficacy. This review will discuss the emerging body of clinical data in lymphoid malignancies and present future directions for research utilizing these i ...[more]

PMID: 25024054

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Project description:Lung cancer still represents the leading cause of cancer-related mortality. However, the recent advent of tyrosine kinase inhibitors (TKI), pioneering drugs against targetable mutations, have dramatically improved prognosis of advanced non-small cell lung cancer (NSCLC) patients. Anaplastic lymphoma kinase (ALK) gene rearrangements, identified in 3–7% of NSCLC cases, reflects in the constitutive activation of downstream signalling pathways, stimulating tumour cell proliferation, differentiation and survival. To accurately detect the wide spectrum of ALK rearrangements, the introduction of innovative techniques, like reverse transcriptase polymerase chain reaction (RT-PCR) or next generation sequencing (NGS) now allows for a more precise detection of variants and a more objective reading assessment, compared to the traditional diagnostic approaches. In some occasions, these new tools may dynamically monitor tumor evolution and even guide the choice of the most appropriate ALK inhibitor. In fact, among ALK TKIs available, crizotinib was the first to receive FDA accelerate approval for ALK rearranged NSCLC patients. Notwithstanding its response rate, ranging from 57% to 74%, the majority of patients progress within the first year of drug administration, due to acquired resistance. Both ALK-dependent and independent mechanisms of acquired resistance to TKIs have been identified. If the activation of multiple bypass signaling pathways constitutes the most common ALK-independent mechanism of resistance and one of the most difficult to overcome, ALK-dependent escape strategy mainly consists of mutations in the kinase domain, where the type of mutation largely depends on the TKI administered. Second and third generation TKIs are now available and are demonstrating high systemic and central nervous system (CNS) efficacy in clinical trials. Even though appropriate timing and sequencing of these compounds are still unclear, the large number of ALK inhibitors is now a precious resource aiming to prolong progression-free survival (PFS) and finally overall survival (OS). Here Authors provide an overview of the current approaches in the clinical management of advanced NSCLC patients harboring ALK rearrangement and discuss future perspectives to address current issues, highlighting the perception that ALK-rearranged advanced NSCLC patients benefit from maintained ALK inhibition for as long as possible.

Dataset Information

Phosphoinositide 3-kinase inhibitors in lymphoma.

Publications

Phosphoinositide 3-kinase inhibitors in lymphoma.

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