Phase I trial of palbociclib, a selective cyclin dependent kinase 4/6 inhibitor, in combination with cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma

Michel, Loren; Ley, Jessica; Wildes, Tanya M.; Schaffer, András; Robinson, Anthony; Chun, Se-Eun; Lee, Wooin; Lewis, James S.; Trinkaus, Kathryn; Adkins, Douglas R.

doi:10.1016/j.oraloncology.2016.05.011

Cited by 78 publications

(42 citation statements)

References 33 publications

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“…[5][6][7][8][9][10][11] We analyzed the combinatorial effects of palbociclib with the commonly used chemotherapy agents against CRC, as a prelude to possible translation. Chou-Talalay analysis revealed that palbociclib can synergize with a variety of chemotherapies under hypoxia (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…6,7 Our assessment of IC50 values indicated that the CDK4/6 inhibitor palbociclib reduces the viability of CRC cells regardless of the presence of hypoxia (Fig 1). 5-FU, oxaliplatin and irinotecan are the backbone standard chemotherapy agents used to treat patients with advanced CRC.…”

Section: Palbociclib Synergizes With Cpt11 and Reduces The Viability mentioning

confidence: 91%

“…5 The therapeutic effects of palbociclib have been demonstrated in numerous clinical trials for breast cancer, NSCLC, GBM, lymphoma, and leukemia, in combination with 5-FU and oxaliplatin in solid malignancies (NCT01522989) or with cetuximab in head and neck cancer. 6,7 A combined pharmacological inhibition of MEK and CDK4/6 led to substantial synergy in KRAS-mutated NSCLC in vivo. 8 Synergy of palbociclib with a MEK inhibitor has also been demonstrated in KRAS mutant colon cancer in vivo.…”

Section: Introductionmentioning

confidence: 99%

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The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

et al. 2017

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Hypoxia is an inherent impediment to cancer therapy. Palbociclib, a highly selective inhibitor for CDK4/6, has been tested in numerous clinical trials and has been approved by the FDA. We previously reported that CDK inhibitors can destabilize HIF1a regardless of the presence of hypoxia and can sensitize tumor cells to TRAIL through dual blockade of CDK1 and GSK-3b. To translate this knowledge into a cancer therapeutic strategy, we investigated the therapeutic effects and molecular mechanisms of CDK inhibition against colon cancer cells under normoxia and hypoxia. We found that palbociclib sensitizes colon cancer cells to hypoxia-induced apoptotic resistance via deregulation of HIF-1a accumulation. In addition to inhibition of cell proliferation, we observed that palbociclib promotes colon cancer cell death regardless of the presence of hypoxia at a comparatively high concentration via regulating ERK/GSK-3b signaling and GSK-3b expression. Furthermore, palbociclib synergized with irinotecan in a variety of colon cancer cell lines with various molecular subtypes via deregulating irinotecan-induced Rb phosphorylation and reducing HIF-1a accumulation under normoxia or hypoxia. Collectively, our findings provide a novel combination therapy strategy against hypoxic colon cancer cells that may be further translated in the clinic.

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Section: Discussionmentioning

confidence: 99%

Section: Palbociclib Synergizes With Cpt11 and Reduces The Viability mentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

et al. 2017

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“…In head and neck cancer, palbociclib has been tested in combination with cetuximab in a phase I trial and was well tolerated. Some preliminary efficacy was observed, and a phase II study is currently enrolling patients (NCT02499120) [22]. …”

Section: Targeted Therapies In Head and Neck Cancermentioning

confidence: 99%

“…Due to the limited number of patients, neither CCND1 nor Rb expression could be statistically evaluated with regard to tumor response, and the data were unclear for p16 (CDKN2A) expression [22]. In breast cancer, neither PIK3CA mutation status in a phase III trial nor CCND1 amplification, p16 expression, or Rb localization in a phase II trial were associated with response [21,54].…”

Section: Predictive Biomarkersmentioning

confidence: 99%

Targeted Therapy of Head and Neck Cancer

2016

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Head and neck squamous cell carcinoma (HNSCC) is one of the most common solid cancers worldwide. It is mainly caused by exposure to tobacco smoke and alcohol as well as infection with the human papilloma virus (HPV). The prognosis is poor, especially once it recurs or metastasizes. Current therapeutic options include surgery, radio- and chemotherapy. Epidermal growth factor receptor (EGFR) inhibitors are so far the only targeted agents that have been approved in head and neck cancer. Primary or secondary resistance is frequent or will eventually develop. Several driver mutations and other genomic aberrations have been described in HNSCC including EGFR overexpression and amplification. Yet, no predictive biomarkers for the application of EGFR inhibitors have been identified. Further targeted agents are in development for HNSCC, of which inhibitors of the PI3K pathway are the closest to clinical application. In recent years, the incidence of HPV-driven HNSCC has risen in Western countries. HPV-positive and -negative HNSCC are distinct molecular tumor entities, and consequences for targeted therapies have been discussed. This review looks at approved and investigational targeted treatment strategies as well as potential predictive biomarkers such as the HPV status to guide treatment.

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