Antitumor activity of the dual PI3K/MTOR inhibitor, PF-04691502, in combination with radiation in head and neck cancer

Tonlaar, Nathan; Galoforo, Sandra; Thibodeau, Bryan J.; Ahmed, Samreen; Wilson, Thomas G.; Cardenas, Paola Yumpo; Marples, Brian; Wilson, George

doi:10.1016/j.radonc.2017.08.001

Cited by 22 publications

(29 citation statements)

References 54 publications

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“…The phosphoinositide 3‐kinase (PIK3) and mammalian target of rapamycin (MTOR) signaling pathways have been found to have an important role in the pathogenesis of HNSCC and there is evidence that PIK3/MTOR antagonists are active against head and neck cancer cells . Our own studies have confirmed this activity in combination with conventional radiation treatment in low passage xenograft models of HNSCC. Our studies suggested that dual PI3K/MTOR inhibitors were more effective that specific PI3K inhibitors in our tumor models.…”

Section: Introductionmentioning

confidence: 52%

Prognostic significance of MTOR expression in HPV positive and negative head and neck cancers treated by chemoradiation

et al. 2019

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Background: The mechanistic target of rapamycin (MTOR) plays a key role in regulating cell growth and metabolism and is commonly overexpressed in head and neck cancer (HNSCC). This study investigated the association of MTOR with clinical outcome in human papilloma virus (HPV) positive and negative HNSCC patients treated by chemoradiation. Methods: A tissue microarray (TMA) consisting of cores from 109 HNSCC patients treated by definitive chemoradiation was constructed and stained with antibodies against p16 and MTOR and expression correlated with clinicopathological features and clinical outcome. Results: MTOR varied widely between tumor cores and was not associated with HPV status or clinicopathological features. There was a positive correlation with pre-treatment FDG uptake.(P = .01). In HPV negative patients, MTOR predicted for shorter locoregional control (P = .02), diseases free survival (P = .02), and overall survival (P = .04).MTOR expression was not associated with outcome in HPV positive patients. Conclusions: Prognostic significance of MTOR expression depends on HPV status.

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Section: Introductionmentioning

confidence: 52%

Prognostic significance of MTOR expression in HPV positive and negative head and neck cancers treated by chemoradiation

et al. 2019

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“…It is conceivable that this is due to the duration of in vitro culture. GBM cells were established recently and thus used in defined low passages (<P40), whereas half of the HNSCC cell lines were long-term cultures with more or less unknown passage [Detroit-562 as well as UT-SCC14 and UT-SCC15 (44) are the only exceptions; <P40]. Cell lines may acquire additional mutations overtime changing their protein expression.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Kynurenine Pathway in Human Malignancies Can Be Suppressed by the Cyclin-Dependent Kinase Inhibitor Dinaciclib

et al. 2020

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Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO2) are the key enzymes of tryptophan (TRP) metabolism in the kynurenine pathway (KP). Both enzymes function as indicators of immunosuppression and poor survival in cancer patients. Direct or indirect targeting of either of these substances seems thus reasonable to improve therapy options for patients. In this study, glioblastoma multiforme (GBM) as well as head and neck squamous cell carcinomas (HNSCC) were examined because of their different mechanisms of spontaneous and treatment-induced immune escape. Effects on gene expression and protein levels were examined. Accompanying assessment of TRP metabolites from treated GBM cell culture supernatants was conducted. Our results show a heterogeneous and inversely correlated expression profile of TRP-metabolizing genes among GBM and HNSCC cells, with low, but inducible IDO1 expression upon IFNγ treatment. TDO2 expression was higher in GBM cells, while genes encoding kynurenine aminotransferases were mainly confined to HNSCC cells. These data indicate that the KP is active in both entities, with however different enzymes involved in TRP catabolism. Upon treatment with Temozolomide, the standard of care for GBM patients, IDO1 was upregulated. Comparable, although less pronounced effects were seen in HNSCC upon Cetuximab and conventional drugs (i.e., 5-fluorouracil, Gemcitabine). Here, IDO1 and additional genes of the KP (KYAT1, KYAT2, and KMO) were induced. Vice versa, the novel yet experimental cyclin-dependent kinase inhibitor Dinaciclib suppressed KP in both entities. Our comprehensive data imply inhibition of the TRP catabolism by Dinaciclib, while conventional chemotherapeutics tend to activate this pathway. These data point to limitations of conventional therapy and highlight the potential of targeted therapies to interfere with the cells' metabolism more than anticipated.

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“…The UT-SCC-14 and UT-SCC-15 cell lines were provided by Dr. Reidar Grénman (Turku University Hospital, Turku, Finland). Both are low passage HPV-negative cell lines and their culture and molecular characterization have been previously described [20] . Buparlisib and binimetinib were kindly provided by Novartis Pharma (Basel, Switzerland).…”

Section: Methodsmentioning

confidence: 99%

“…Cells were irradiated as previously described with an Xstrahl X-ray System, Model RS225 (Xstrahl, UK) [20] .…”

Section: Methodsmentioning

confidence: 99%

Dual blockade of PI3K and MEK in combination with radiation in head and neck cancer

Blas

Wilson

Tonlaar

et al. 2018

Clinical and Translational Radiation Oncology

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Background and purposeIn this study we have combined fractionated radiation treatment (RT) with two molecular targeted agents active against key deregulated signaling pathways in head and neck cancer.Materials and methodsWe used two molecularly characterized, low passage HNSCC cell lines of differing biological characteristics to study the effects of binimetinib and buparlisib in combination with radiation in vitro and in vivo.ResultsBuparlisib was active against both cell lines in vitro whereas binimetinib was more toxic to UT-SCC-14. Neither agent modified radiation sensitivity in vitro. Buparlisib significantly inhibited growth of UT-SSC-15 alone or in combination with RT but was ineffective in UT-SCC-14. Binimetinib did cause a significant delay with RT in UT-SCC-14 and it significantly reduced growth of the UT-SCC-15 tumors both alone and with RT. The tri-modality treatment was not as effective as RT with a single effective agent.ConclusionsNo significant benefit was gained by the combined use of the two agents with RT even though each was efficacious when used alone.

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Antitumor activity of the dual PI3K/MTOR inhibitor, PF-04691502, in combination with radiation in head and neck cancer

Cited by 22 publications

References 54 publications

Prognostic significance of MTOR expression in HPV positive and negative head and neck cancers treated by chemoradiation

Prognostic significance of MTOR expression in HPV positive and negative head and neck cancers treated by chemoradiation

Activation of the Kynurenine Pathway in Human Malignancies Can Be Suppressed by the Cyclin-Dependent Kinase Inhibitor Dinaciclib

Dual blockade of PI3K and MEK in combination with radiation in head and neck cancer

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