RESUMEN
The PI3K pathway is a key mechanism of trastuzumab resistance, but early attempts to indirectly target this pathway with mTOR inhibitors have had limited success. We present the results of a preclinical study of the selective alpha/delta isoform dominant PI3K inhibitor BAY 80-6946 tested alone and in combination with HER2-targeted therapies in HER2-positive cell lines, including models with acquired resistance to trastuzumab and/or lapatinib. A panel of HER2-positive breast cancer cells were profiled for their mutational status using Sequenom MassARRAY, PTEN status by Western blot, and anti-proliferative response to BAY 80-6946 alone and in combination with the HER2-targeted therapies trastuzumab, lapatinib and afatinib. Reverse phase protein array was used to determine the effect of BAY 80-6946 on expression and phosphorylation of 68 proteins including members of the PI3K and MAPK pathways. The Boyden chamber method was used to determine if BAY 80-6946 affected cellular invasion and migration. BAY 80-6946 has anti-proliferative and anti-invasive effects when used alone in our panel of cell lines (IC50s 3.9-29.4 nM). BAY 80-6946 inhibited PI3K signalling and was effective in cells regardless of their PI3K, P53 or PTEN status. The combination of HER2-targeted therapies and BAY 80-6946 inhibited growth more effectively than either therapy used alone (with clear synergism in many cases), and can restore sensitivity to trastuzumab and lapatinib in cells with acquired resistance to either trastuzumab and/or lapatinib. The addition of BAY 80-6946 to HER2-targeted therapy could represent an improved treatment strategy for patients with refractory metastatic HER2-positive breast cancer, and should be considered for clinical trial evaluation.
Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Neoplasias de la Mama/genética , Resistencia a Antineoplásicos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Pirimidinas/farmacología , Quinazolinas/farmacología , Receptor ErbB-2/genética , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Femenino , Humanos , Concentración 50 Inhibidora , Lapatinib , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Mutación , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/administración & dosificación , Quinazolinas/administración & dosificación , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , TrastuzumabRESUMEN
Approximately 20 % of human breast cancers (BC) overexpress HER2 protein, and HER2-positivity is associated with a worse prognosis. Although HER2-targeted therapies have significantly improved outcomes for HER2-positive BC patients, resistance to trastuzumab-based therapy remains a clinical problem. In order to better understand resistance to HER2-targeted therapies in HER2-positive BC, it is necessary to examine HER family signalling as a whole. An extensive literature search was carried out to critically assess the current knowledge of HER family signalling in HER2-positive BC and response to HER2-targeted therapy. Known mechanisms of trastuzumab resistance include reduced receptor-antibody binding (MUC4, p95HER2), increased signalling through alternative HER family receptor tyrosine kinases (RTK), altered intracellular signalling involving loss of PTEN, reduced p27kip1, or increased PI3K/AKT activity and altered signalling via non-HER family RTKs such as IGF1R. Emerging strategies to circumvent resistance to HER2-targeted therapies in HER2-positive BC include co-targeting HER2/PI3K, pan-HER family inhibition, and novel therapies such as T-DM1. There is evidence that immunity plays a key role in the efficacy of HER-targeted therapy, and efforts are being made to exploit the immune system in order to improve the efficacy of current anti-HER therapies. With our rapidly expanding understanding of HER2 signalling mechanisms along with the repertoire of HER family and other targeted therapies, it is likely that the near future holds further dramatic improvements to the prognosis of women with HER2-positive BC.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Receptor ErbB-2/genética , Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Fosfatidilinositol 3-Quinasas/genética , Transducción de Señal/efectos de los fármacos , TrastuzumabAsunto(s)
Ensayos Clínicos como Asunto/legislación & jurisprudencia , Comités de Ética en Investigación/legislación & jurisprudencia , Experimentación Humana/legislación & jurisprudencia , Responsabilidad Legal , Comité de Profesionales/legislación & jurisprudencia , Investigación/legislación & jurisprudencia , Toma de Decisiones en la Organización , Humanos , Mala Praxis/legislación & jurisprudencia , Sujetos de Investigación , Responsabilidad Social , Estados UnidosRESUMEN
OBJECTIVE: To review the medical, social, and financial risks caused by the birth of multiples that need to be addressed in policy and practice. RESULT(S): Many risks of multiple births are described in the literature. The medical risks to the offspring include death, low birth weight, deformational plagiocephaly, and other physical and mental disabilities. Risks to the women include premature labor, premature delivery, pregnancy-induced hypertension, toxemia, gestational diabetes, and vaginal-uterine hemorrhage. Children born in multiples face difficulty socializing, developmental delays, and behavioral problems, whereas their parents risk exhaustion, depression, and anxiety. In addition to personal costs faced by families, society often bears the financial costs of overburdened hospitals, caps on insurance and/or inability of parents to cover expenses. CONCLUSION(S): Multiple births present potential acute and long-term medical risks to the pregnant woman and her children. However, more long-term follow-up research and more research on outcomes with higher-order multiples are needed. In designing practices and policies to improve the success of IVF while reducing the risk of multiples, it is important to balance the many interests involved. At a minimum, providers and patients need to be educated about the risks of multiple gestation so that steps can be taken to prevent adverse outcomes.
Asunto(s)
Progenie de Nacimiento Múltiple , Embarazo Múltiple , Femenino , Fertilización In Vitro/economía , Fertilización In Vitro/tendencias , Humanos , Recién Nacido , Consentimiento Informado , Seguro de Salud , Progenie de Nacimiento Múltiple/psicología , Embarazo , Reducción de Embarazo Multifetal/psicología , Embarazo Múltiple/psicología , Factores de RiesgoAsunto(s)
Ética Médica , Regulación y Control de Instalaciones/organización & administración , Técnicas Reproductivas/legislación & jurisprudencia , Técnicas Reproductivas/normas , Actitud Frente a la Salud , Clonación de Organismos/legislación & jurisprudencia , Humanos , Consentimiento Informado/legislación & jurisprudencia , Defensa del Paciente/legislación & jurisprudencia , Técnicas Reproductivas/tendencias , Cambio Social , Valores Sociales , Madres Sustitutas/legislación & jurisprudencia , Estados UnidosRESUMEN
In July 1996, a sheep named Dolly was born in Scotland. What makes Dolly's birth noteworthy is that she is the result of the first successful cloning attempt using the nucleus of an adult cell. The technique that led to Dolly's birth involved transferring the nucleus of a mammary cell from an adult sheep to the enucleated egg cell of an unrelated sheep with gestation occurring in a third sheep. The possibility of applying this technique to human reproduction raised concerns worldwide with several countries moving for an immediate bans on human cloning. In the United States, President Clinton requested that the National Bioethics Advisory Commission ("NBAC"), a multidisciplinary group composed of scientists, lawyers, educators, theologians, and ethicists study the implications of cloning and issue recommendations. The Commission consulted other scientists, ethicists, theologians, lawyers, and citizens with interests in this advancing technology and concluded that, "at this time it is morally unacceptable for anyone in the public or private sector, whether in a research or clinical setting, to attempt to create a child using somatic cell nuclear transfer cloning." This Article was included in a larger work prepared at the request of, and submitted to the Commission by, law professor Lori B. Andrews. Cloning through nuclear transfer will change the way we create and define families. This Article explores how existing law relating to parentage, surrogacy, egg donation, and artificial insemination may apply in the cloning context to clarify the parent-child relationship established through cloning.