Gail D. Lewis Phillips

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The vascular endothelium was once thought to function primarily in nutrient and oxygen delivery, but recent evidence suggests that it may play a broader role in tissue homeostasis. To explore the role of sinusoidal endothelial cells (LSECs) in the adult liver, we studied the effects of vascular endothelial growth factor (VEGF) receptor activation on mouse(More)
Trastuzumab (Herceptin®) is currently used as a treatment for patients whose breast tumors overexpress HER2/ErbB2. Trastuzumab-DM1 (T-DM1, trastuzumab emtansine) is designed to combine the clinical benefits of trastuzumab with a potent microtubule-disrupting drug, DM1 (a maytansine derivative). Currently T-DM1 is being tested in multiple clinical trials.(More)
The human epidermal growth factor receptor 2 (HER2)-targeted therapies trastuzumab (T) and lapatinib (L) show high efficacy in patients with HER2-positive breast cancer, but resistance is prevalent. Here we investigate resistance mechanisms to each drug alone, or to their combination using a large panel of HER2-positive cell lines made resistant to these(More)
Hormone-independent tumor growth and metastasis are associated with increased mortality in human prostate cancer. In this study, we evaluate a potential role for ligand-mediated activation of HER2 receptor tyrosine kinase in androgen-independent prostate cancers. HER2, HER3, and epidermal growth factor receptor were detected in the androgen-independent cell(More)
PURPOSE Targeting HER2 with multiple HER2-directed therapies represents a promising area of treatment for HER2-positive cancers. We investigated combining the HER2-directed antibody-drug conjugate trastuzumab emtansine (T-DM1) with the HER2 dimerization inhibitor pertuzumab (Perjeta). EXPERIMENTAL DESIGN Drug combination studies with T-DM1 and pertuzumab(More)
Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate consisting of the anti-HER2 antibody trastuzumab linked via a nonreducible thioether linker to themaytansinoid antitubulin agentDM1. T-DM1has shown favorable safety and efficacy in patients with HER2-positive metastatic breast cancer. In previous animal studies, T-DM1 exhibited better(More)
The cryptophycins are a potent class of cytotoxic agents that were evaluated as antibody drug conjugate (ADC) payloads. Free cryptophycin analog 1 displayed cell activity an order of magnitude more potent than approved ADC payloads MMAE and DM1. This potency increase was also reflected in the activity of the cryptophycin ADCs, attached via a either(More)
Monoclonal antibody therapeutics have been approved for over 30 targets and diseases, most commonly cancer. Antibodies have become the new backbone of the pharmaceutical industry, which previously relied on small molecules. Compared with small molecules, monoclonal antibodies (mAbs) have exquisite target selectivity and hence less toxicity as a result of(More)
Trastuzumab emtansine (T-DM1), an antibody–drug conjugate (ADC) comprised of trastuzumab linked to the antimitotic agent DM1, has shown promising results in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. Investigations of the mechanisms of the action of ADCs, including T-DM1, have been primarily descriptive or(More)
The reversible attachment of a small-molecule drug to a carrier for targeted delivery can improve pharmacokinetics and the therapeutic index. Previous studies have reported the delivery of molecules that contain primary and secondary amines via an amide or carbamate bond; however, the ability to employ tertiary-amine-containing bioactive molecules has been(More)