pf-00299804 and saracatinib

The majority of patients with a squamous cell carcinoma of the head and neck present with locally advanced tumors. The first-line treatment of locally advanced tumor stages consists of a combined modality management. Despite these aggressive protocols, many patients develop locoregional recurrences or metastasis and place particularly high demands on the interdisciplinary treatment team. Treatment with a curative intent must be differentiated from a palliative one. In addition to prior treatment, resectability, age and performance status, patient wishes must be taken into consideration in treatment planning, especially considering that most therapies offer little to no overall survival benefit. Salvage surgery, chemo- and target therapies, and reirradiation are head and neck surgeon's and radiooncologist's weapons in the fight against these strong opponents. This review focuses on publications and meeting news from last year and reviews the current status of the clinical application of each treatment modality in recurrent or metastatic head and neck cancer.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzodioxoles; Carcinoma, Squamous Cell; Cetuximab; Combined Modality Therapy; Dasatinib; ErbB Receptors; Fluorouracil; Gefitinib; Head and Neck Neoplasms; Humans; Indoles; Neoplasm Recurrence, Local; Palliative Care; Pyrimidines; Pyrroles; Quinazolines; Quinazolinones; Salvage Therapy; Squamous Cell Carcinoma of Head and Neck; Sunitinib; Thiazoles

HER2 tyrosine kinase receptor is a validated target in breast cancer therapy. However, increasing evidence points to a major role of Δ16HER2 splice variant commonly coexpressed with HER2 and identified as a clinically important HER2 molecular alteration promoting aggressive metastatic breast cancer. Consistently, mice transgenic for the human Δ16HER2 isoform (Δ16HER2 mice) develop invasive mammary carcinomas with early onset and 100% penetrance. The present study provides preclinical evidence that Δ16HER2 expression confers de novo resistance to standard anti-HER2-therapies such as Lapatinib and acquired resistance to the selective Src inhibitor Saracatinib in breast cancer. Of note, Dacomitinib, an irreversible small molecule pan-HER inhibitor, was able to completely suppress Δ16HER2-driven breast carcinogenesis. Thus, only Dacomitinib may offer benefit in this molecularly defined patient subset by irreversibly inhibiting Δ16HER2 activation.

Topics: Alternative Splicing; Animals; Benzodioxoles; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Genetic Predisposition to Disease; Humans; Inhibitory Concentration 50; Lapatinib; Mammary Neoplasms, Experimental; Mice, Transgenic; Phenotype; Protein Isoforms; Protein Kinase Inhibitors; Quinazolines; Quinazolinones; Receptor, ErbB-2; Signal Transduction; Time Factors