Lessons, Challenges and Future Therapeutic Opportunities for PI3K Inhibition in CLL

Guarente, Valerio; Sportoletti, Paolo

doi:10.3390/cancers13061280

Cited by 15 publications

(12 citation statements)

References 92 publications

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“…PI3K pathway dysregulation is one of the most common pathological events in cancer [38] and has been particularly related to leukemia and its therapeutic targets [39,40]. Children with DS have a dramatically higher risk of developing leukemia than the general population, such that this chromosomal disorder is considered the most common risk factor for developing acute lymphoblastic leukemia and acute myeloid leukemia [41].…”

Section: Discussionmentioning

confidence: 99%

Genetic Susceptibility to Periodontal Disease in Down Syndrome: A Case-Control Study

Fernández

Coo

Quintela

et al. 2021

IJMS

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Severe periodontitis is prevalent in Down syndrome (DS). This study aimed to identify genetic variations associated with periodontitis in individuals with DS. The study group was distributed into DS patients with periodontitis (n = 50) and DS patients with healthy periodontium (n = 36). All samples were genotyped with the “Axiom Spanish Biobank” array, which contains 757,836 markers. An association analysis at the individual marker level using logistic regression, as well as at the gene level applying the sequence kernel association test (SKAT) was performed. The most significant genes were included in a pathway analysis using the free DAVID software. C12orf74 (rs4315121, p = 9.85 × 10−05, OR = 8.84), LOC101930064 (rs4814890, p = 9.61 × 10−05, OR = 0.13), KBTBD12 (rs1549874, p = 8.27 × 10−05, OR = 0.08), PIWIL1 (rs11060842, p = 7.82 × 10−05, OR = 9.05) and C16orf82 (rs62030877, p = 8.92 × 10−05, OR = 0.14) showed a higher probability in the individual analysis. The analysis at the gene level highlighted PIWIL, MIR9-2, LHCGR, TPR and BCR. At the signaling pathway level, PI3K-Akt, long-term depression and FoxO achieved nominal significance (p = 1.3 × 10−02, p = 5.1 × 10−03, p = 1.2 × 10−02, respectively). In summary, various metabolic pathways are involved in the pathogenesis of periodontitis in DS, including PI3K-Akt, which regulates cell proliferation and inflammatory response.

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Section: Discussionmentioning

confidence: 99%

Genetic Susceptibility to Periodontal Disease in Down Syndrome: A Case-Control Study

Fernández

Coo

Quintela

et al. 2021

IJMS

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“…OGT promotes NRF1-mediated up-regulation of proteasome subunits ( 209 ), which may account in part for the intrinsic resistance of CLL cells to the proteasome inhibitor bortezomib and suggesting it may be overcome by inhibiting OGT ( 210 ). OGT inhibitors improve killing of cancer cells by PI3K inhibitors, suggesting OGT mediates resistance to PI3K inhibitors and possibly identifying a strategy to improve outcomes with kinase inhibitors in CLL patients ( 211 , 212 ).…”

Section: O-glcnacylation As a Therapeutic Targetmentioning

confidence: 99%

O-GlcNAcylation in Chronic Lymphocytic Leukemia and Other Blood Cancers

Spaner

2021

Front. Immunol.

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In the past decade, aberrant O-GlcNAcylation has emerged as a new hallmark of cancer. O-GlcNAcylation is a post-translational modification that results when the amino-sugar β-D-N-acetylglucosamine (GlcNAc) is made in the hexosamine biosynthesis pathway (HBP) and covalently attached to serine and threonine residues in intracellular proteins by the glycosyltransferase O-GlcNAc transferase (OGT). O-GlcNAc moieties reflect the metabolic state of a cell and are removed by O-GlcNAcase (OGA). O-GlcNAcylation affects signaling pathways and protein expression by cross-talk with kinases and proteasomes and changes gene expression by altering protein interactions, localization, and complex formation. The HBP and O-GlcNAcylation are also recognized to mediate survival of cells in harsh conditions. Consequently, O-GlcNAcylation can affect many of the cellular processes that are relevant for cancer and is generally thought to promote tumor growth, disease progression, and immune escape. However, recent studies suggest a more nuanced view with O-GlcNAcylation acting as a tumor promoter or suppressor depending on the stage of disease or the genetic abnormalities, proliferative status, and state of the p53 axis in the cancer cell. Clinically relevant HBP and OGA inhibitors are already available and OGT inhibitors are in development to modulate O-GlcNAcylation as a potentially novel cancer treatment. Here recent studies that implicate O-GlcNAcylation in oncogenic properties of blood cancers are reviewed, focusing on chronic lymphocytic leukemia and effects on signal transduction and stress resistance in the cancer microenvironment. Therapeutic strategies for targeting the HBP and O-GlcNAcylation are also discussed.

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“…The treatment of patients with CLL has evolved in the last years from conventional chemotherapeutic agents (e.g., fludarabine, fludarabine plus cyclophosphamide (FC), chlorambucil or bendamustine) combined with anti-CD20 antibodies (rituximab or obinutuzumab), to novel targeted agents. The targeted drugs currently approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are the Bruton's tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib, the Bcl-2 inhibitor venetoclax [21] and the phosphatidylinositol 3-kinase (PI3K) inhibitors idelalisib and duvelisib [22]. These drugs have shown higher clinical responses compared to standard chemoimmunotherapy and all of them seem to act in a TP53 independent manner.…”

Section: Introductionmentioning

confidence: 99%

Challenges with Approved Targeted Therapies against Recurrent Mutations in CLL: A Place for New Actionable Targets

López‐Oreja

Playà-Albinyana

Arenas

et al. 2021

Cancers

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Chronic lymphocytic leukemia (CLL) is characterized by a high degree of genetic variability and interpatient heterogeneity. In the last decade, novel alterations have been described. Some of them impact on the prognosis and evolution of patients. The approval of BTK inhibitors, PI3K inhibitors and Bcl-2 inhibitors has drastically changed the treatment of patients with CLL. The effect of these new targeted therapies has been widely analyzed in TP53-mutated cases, but few data exist about the response of patients carrying other recurrent mutations. In this review, we describe the biological pathways recurrently altered in CLL that might have an impact on the response to these new therapies together with the possibility to use new actionable targets to optimize treatment responses.

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Lessons, Challenges and Future Therapeutic Opportunities for PI3K Inhibition in CLL

Cited by 15 publications

References 92 publications

Genetic Susceptibility to Periodontal Disease in Down Syndrome: A Case-Control Study

Genetic Susceptibility to Periodontal Disease in Down Syndrome: A Case-Control Study

O-GlcNAcylation in Chronic Lymphocytic Leukemia and Other Blood Cancers

Challenges with Approved Targeted Therapies against Recurrent Mutations in CLL: A Place for New Actionable Targets

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