Immunotherapy for Aggressive and Metastatic Pituitary Neuroendocrine Tumors (PitNETs): State-of-the Art

Feola, Tiziana; Carbonara, Francesca; Verrico, Monica; Crescenzo, Rosa Maria Di; Gianno, Francesca; Colonnese, Claudio; Arcella, Antonietta; Alcubierre, Dario De; Tomao, Silverio; Esposito, Vincenzo; Giangaspero, Felice; Minniti, Giuseppe; Jaffrain-Rea, Marie Lise

doi:10.3390/cancers14174093

Cited by 9 publications

(6 citation statements)

References 48 publications

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“…With respect to aggressive and metastatic PitNET behavior, it is worth noting that aggressive invasive PIT1 PitNET (n.1) exhibited exclusive TrkAIII expression ( Figure 2 a), whereas the invasive metastatic PIT1 PitNET (n.11), reported previously to be responsive to immunotherapy [ 41 ], exhibited a ≈65 to 35% fs-TrkA to TrkAIII RT-PCR ratio.…”

Section: Resultsmentioning

confidence: 85%

A Study of Alternative TrkA Splicing Identifies TrkAIII as a Novel Potentially Targetable Participant in PitNET Progression

Sbaffone,

Jaffrain-Rea,

Cappabianca

et al. 2024

Biology

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Pituitary neuroendocrine tumors (PitNETs) are generally benign but comprise an aggressive, invasive, therapy-resistant, metastatic subset, underpinning a need for novel therapeutic targets. PitNETs exhibit low mutation rates but are associated with conditions linked to alternative splicing, an alternative oncogene pathway activation mechanism. PitNETs express the neurotrophin receptor TrkA, which exhibits oncogenic alternative TrkAIII splicing in other neuroendocrine tumors. We, therefore, assessed whether TrkAIII splicing represents a potential oncogenic participant in PitNETs. TrkAIII splicing was RT-PCR assessed in 53 PitNETs and TrkA isoform(s) expression and activation were assessed by confocal immunofluorescence. TrkAIII splicing was also compared to HIF1α, HIF2α, SF3B1, SRSF2, U2AF1, and JCPyV large T antigen mRNA expression, Xbp1 splicing, and SF3B1 mutation. TrkAIII splicing was detected in all invasive and most non-invasive PitNETs and was significantly elevated in invasive cases. In PitNET lineages, TrkAIII splicing was significantly elevated in invasive PIT1 PitNETs and high in invasive and non-invasive SF1 and TPIT lineages. Immunoreactivity consistent with TrkAIII activation characterized PitNET expressing TrkAIII mRNA, and invasive Pit1 PitNETs exhibited elevated HIF2α expression. TrkAIII splicing did not associate with SF3B1 mutations, altered SF3B1, SRSF2, and U2AF1 or JCPyV large T antigen expression, or Xbp1 splicing. Therefore, TrkAIII splicing is common in PitNETs, is elevated in invasive, especially PIT1 tumors, can result in intracellular TrkAIII activation, and may involve hypoxia. The data support a role for TrkAIII splicing in PitNET pathogenesis and progression and identify TrkAIII as a novel potential target in refractory PitNETs.

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Section: Resultsmentioning

confidence: 85%

A Study of Alternative TrkA Splicing Identifies TrkAIII as a Novel Potentially Targetable Participant in PitNET Progression

Sbaffone,

Jaffrain-Rea,

Cappabianca

et al. 2024

Biology

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show abstract

“…With respect to aggressive and metastatic PitNET behavior, it is worth noting that aggressive invasive PIT1 PitNET (n.1) exhibited exclusive TrkAIII expression (Figure 2a), whereas the invasive metastatic PIT1 PitNET (n.11), reported previously to be responsive to immunotherapy [41], exhibited a ≈65 to 35% fs-TrkA to TrkAIII RT-PCR ratio.…”

Section: Trkaiii Was the Only In-frame Alternative Trka Splice Varian...mentioning

confidence: 83%

A study of Alternative TrkA Splicing identifies TrkAIII as a novel potentially targetable participant in PitNET progression.Type of the Paper (Article)

Sbaffone,

Jaffrain-Rea,

Cappabianca

et al. 2024

Preprint

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PitNETs, although typically benign, comprise a small percentage of therapy-resistant aggressive, occasionally metastatic tumors, underpinning a need to identify novel therapeutic targets. PitNETs carry few mutations but associate with conditions that promote alternative splicing as an oncogenic alternative and express the TrkA neurotrophin receptor, which exhibits oncogenic alternative TrkAIII splicing in other tumors. Alternative TrkAIII splicing was assessed by RT-PCR in 53 PitNETs and compared to HIF1a, HIF2a, SF3B1, SRSF2, U2AF1 and JCPyV large T antigen mRNA expression, unconventional Xbp1 splicing, SF3B1 mutation, and TrkA isoform(s) immunoreactivity by confocal immunofluorescence (IF). Alternative TrkAIII mRNA splicing was detected in all invasive PitNET phenotypes, was significantly elevated in invasive compared to non-invasive PIT1 PitNETs, relatively high in invasive and non-invasive SF1 and TPIT PitNETs, and was associated with IF consistent with intracellular TrkAIII activation but not with hotspot SF3B1 mutations, altered SF3B1, SRSF2 and U2AF1 splice factor mRNA expression, JCPyV large T antigen expression or unconventional Xbp1 splicing. A potential role for hypoxia in TrkAIII mRNA splicing was supported by significant elevation of HIF2a mRNA expression in invasive PIT1 PitNETs. These data demonstrate that alternative TrkAIII splicing, potentially promoted by hypoxia, occurs frequently in PitNETs and may associate with IF consistent with intracellular TrkAIII activation, supporting a potential role for TrkAIII in PitNET pathogenesis and progression, identifying TrkAIII as a novel potential target in refractory PitNETs.

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“…LAG3 which is mainly expressed on activated T cells acts as a receptor protein ( Darvin et al, 2018 ) and has been identified as a promising target for immunotherapy in cancer in several studies ( Villadolid and Amin, 2015 ; Feola et al, 2022 ). It has been found to enhance tumour growth by inhibiting immune microenvironments ( Shi et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“… Ascierto et al (2017) found that monoclonal antibodies targeted towards LAG3 effectively treated melanoma populations. Furthermore, immunotherapy utilising immune checkpoint inhibitors (ICIs) has proven to be effective in almost 50% of cases targeting PDL1 in PitNET ( Feola et al, 2022 ). Here, we offer LAG3 as another novel ICI target for PitNETs.…”

Section: Discussionmentioning

confidence: 99%

Case report: Identification of potential prognosis-related LAG3 overexpression and DICER1 mutation in pituitary carcinoma: two cases

Zhang,

Li,

Liu

et al. 2023

Front. Neurosci.

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Metastatic PitNETs are a rare life-threatening condition with poor prognosis and documentation. Due to the scarce literature and lack of precise treatment, we hope to better characterise PitNET using the next-generation whole exon sequencing (WES) and RNA sequencing. This case study outlines a 54 years-old man and a 52 years-old woman who were both diagnosed with PitNET and analysis of peripheral blood and tumours were performed by WES and RNA sequencing. Analysis showed that DICER1 mutations in precancerous lesions and LAG3 overexpression were significant in aiding the prognosis and diagnosis of PitNETs. The first case with overexpressed LAG3 and DICER1 mutation died 26 months later, and the second case with LAG3 overexpression achieved partial remission. This study revealed that heightened expression of LAG3 offered promising targets for ICI and mutations in DICER1 could provide markers for effective diagnosis and prognosis.

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Immunotherapy for Aggressive and Metastatic Pituitary Neuroendocrine Tumors (PitNETs): State-of-the Art

Cited by 9 publications

References 48 publications

A Study of Alternative TrkA Splicing Identifies TrkAIII as a Novel Potentially Targetable Participant in PitNET Progression

A Study of Alternative TrkA Splicing Identifies TrkAIII as a Novel Potentially Targetable Participant in PitNET Progression

A study of Alternative TrkA Splicing identifies TrkAIII as a novel potentially targetable participant in PitNET progression.Type of the Paper (Article)

Case report: Identification of potential prognosis-related LAG3 overexpression and DICER1 mutation in pituitary carcinoma: two cases

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