Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer

Bauman, Julie E.; Duvvuri, Umamaheswar; Gooding, William E.; Rath, Tanya J.; Gross, Neil D.; Song, John I.; Jimeno, Antonio; Yarbrough, Wendell G.; Johnson, Faye M.; Wang, Lin; Chiosea, Simion I.; Sen, Malabika; Kass, Jason; Johnson, Jonas T.; Ferris, Robert L.; Kim, Seungwon; Hirsch, Fred R.; Ellison, Kim; Flaherty, John T.; Mills, Gordon B.; Grandis, Jennifer R.

doi:10.1172/jci.insight.90449

Cited by 45 publications

(40 citation statements)

References 44 publications

(59 reference statements)

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“…Recently, early clinical trial data in head and neck squamous cell carcinoma (HNSCC) revealed the presence of an EGFR-AS1 (c.2361G>A) synonymous mutation 4 , high baseline phospho-MAPK (ref. 5 ) and MAPK1p.E322K mutation 6 as additional potential biomarkers for erlotinib sensitivity. As HNSCC lacks predictive biomarkers for drug responses, in-depth studies were conducted on MAPK1p.E322K, the mutation found in a complete erlotinib responder.…”

Section: Introductionmentioning

confidence: 99%

Erlotinib sensitivity of MAPK1p.D321N mutation in head and neck squamous cell carcinoma

Ngan

Poon

et al. 2020

npj Genom. Med.

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Head and neck squamous cell carcinoma (HNSCC) lacks predictive biomarkers for drug responses. By targeted sequencing, we identified two MAPK1 mutations in recurrent HNSCC, MAPK1p.D321N, and p.R135K. We previously reported an exceptional erlotinib responder with MAPK1p.E322K. Here, by in silico and drug studies, we determined functions of these two recurrence-associated MAPK1 mutations. Residues D321, R135, and E322 are in 3D proximity. MAPK1p.D321N drives marked in vivo erlotinib sensitivity, while p.R135K's effect is moderate.npj Genomic Medicine (2020) 5:17 ; https://doi.

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Section: Introductionmentioning

confidence: 99%

Erlotinib sensitivity of MAPK1p.D321N mutation in head and neck squamous cell carcinoma

Ngan

Poon

et al. 2020

npj Genom. Med.

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“…Building from these results, Bauman et al [14] randomized subjects to a placebo arm or erlotinib with or without dasatinib, a small molecule inhibitor of Src family kinases. No significant treatment-altering toxicities were seen in any arm of the study.…”

Section: Anti-epidermal Growth Factor Receptor Based Window Trialsmentioning

confidence: 99%

“…Pharmacokinetics of the drug under study should also be factored into the timing of obtaining biologic samples. Unlike in breast cancer where Ki67 is commonly employed, HNSCC studies have not coalesced on particular biomarkers, nor do standardized protocols for obtaining biomarker data or evaluating their clinical impact exist as of yet [14,15] . Several window trials discussed here were not randomized or did not use data from control subjects, which has been known to complicate pharmacodynamic and predictive biomarker assessment [13] .…”

Section: Considerations In Designing Future Window Trialsmentioning

confidence: 99%

“…The window trials presented here used a variety of exams, including CT, MRI with different protocols, 18 FDG-PET, and investigational PET technologies. Additionally, criteria for assessing radiologic response included those from RECIST, modified RECIST [14] , EORTC (European Organization for Research and Treatment of Cancer) [15] , the World Health Organization [16] , and others. Researchers should also be aware that pseudoprogression during immunotherapy, or an initial tumor flare due to inflammatory processes provoked by the drug, may complicate image interpretation during the short timeframe of a window study [33,34] .…”

Section: Considerations In Designing Future Window Trialsmentioning

confidence: 99%

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Window of opportunity trials in head and neck cancer

Farlow

Birkeland

Swiecicki

et al. 2019

JCMT

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Head and neck squamous cell carcinoma (HNSCC) has a large global burden of disease and poor survival outcomes. Recent targeted therapies and immunotherapies have been explored in HNSCC, but there has been limited translation to clinical practice outside of recurrent or metastatic cases. Window of opportunity settings, where novel agents are administered between cancer diagnosis and planned definitive therapy, have begun to be employed in HNSCC. Tumor tissue biopsies are obtained at diagnosis and after the investigation treatment, along with other biospecimens and radiographic exams. Thus, this study design can characterize the safety profiles, pharmacodynamics, and initial tumor responses to novel therapies in a treatment-naïve subject. Early window studies have also identified potential biomarkers to predict sensitivity or resistance to treatments. However, these early investigations have revealed multiple challenges associated with this trial design. In this review, we discuss recent window of opportunity trials in HNSCC and how they inform design considerations for future studies.

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“…mTOR regulated a wide magnitude of cellular functions inclusive of cell proliferation, survival, migration, and angiogenesis. [11][12][13] Given the prosurvival outcome of PI3K/Akt pathway activation, it is unsurprising that mTOR is aberrantly activated in different cancers, including OS. 14 Indeed, an mTOR inhibitor has shown widespread effects in OS mostly by inhibition of cancer cell growth.…”

Section: Introductionmentioning

confidence: 99%

Role of crosstalk between STAT3 and mTOR signaling in driving sensitivity to chemotherapy in osteosarcoma cell lines

Wang

Tang

et al. 2020

IUBMB Life

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Osteosarcoma (OS) is a malignant bone neoplasm, mostly occurring in pediatric patients. OS is characterized by a highly aggressive and metastatically active tumor. Chemotherapy followed by surgical excision is the treatment of choice but is often associated with both chemoresistance and relapse. Hence, it is important to develop further understanding of OS pathogenesis and identify potential therapeutic targets. Both the signal transducer and activator of transcription 3 (STAT3) and mammalian target of rapamycin (mTOR) have been implicated in OS pathogenesis. Crosstalk between mTOR and STAT3 signaling has been shown to regulate hypoxia‐induced angiogenesis in other diseases. In this study, we determined using OS cell lines if there is a crosstalk between these two pathways and how that impacts sensitivity to treatment with Rapamycin. OS cell lines exhibited differential sensitivity to mTOR inhibitor Rapamycin. Evaluation of phosphorylated STAT3 showed that in Rapamycin‐sensitive 143B cells, the inhibitor decreased phosphorylation of STAT3 at Y705, but not at S727 whereas, in Rapamycin‐resistant U2OS cells, the inhibitor decreased S727 phosphorylation but not Y705. However, knockdown of STAT3 in U2OS cells made them sensitive to Rapamycin. Immunofluorescence (IF) analysis showed that mTOR is constitutively activated in the 143B cells but is suppressed in the U2OS cells, indicating that this might be their reason for being resistant to Rapamycin. Both cell lines were sensitive to treatment with the STAT3 inhibitor Napabucasin (NP). Treatment with NP inhibited STAT3 activation at Y705 and additionally inhibited mTOR activation, indicating crosstalk between STAT3 and mTOR signaling pathways. Rapamycin could effectively prevent lung metastasis in an orthotropic OS mice model using 143B cells. However, Rapamycin could not inhibit lung metastasis in mice injected with U2OS cells. The STAT3 inhibitor NP attenuated lung metastasis with the U2OS cells. Our results thus established yet undefined crosstalk of STAT3 and mTOR signaling pathways in OS and highlight the possibility of using mTOR inhibitors for treatment in patients with OS.

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Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer

Cited by 45 publications

References 44 publications

Erlotinib sensitivity of MAPK1p.D321N mutation in head and neck squamous cell carcinoma

Erlotinib sensitivity of MAPK1p.D321N mutation in head and neck squamous cell carcinoma

Window of opportunity trials in head and neck cancer

Role of crosstalk between STAT3 and mTOR signaling in driving sensitivity to chemotherapy in osteosarcoma cell lines

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