RESUMEN
Background: Up to 60% of melanoma patients develop melanoma brain metastases (MBM), which traditionally have a poor diagnosis. Current treatment strategies include immunotherapies (IO), targeted therapies (TT), and stereotactic radiosurgery (SRS), but there is considerable heterogeneity across worldwide consensus guidelines. Objective: To summarize current treatments and compare worldwide guidelines for the treatment of MBM. Methods: Review of global consensus treatment guidelines for MBM patients. Results: Substantial evidence supported that concurrent IO or TT plus SRS improves progression-free survival (PFS) and overall survival (OS). Guidelines are inconsistent with regards to recommendations for surgical resection of MBM, since surgical resection of symptomatic lesions alleviates neurological symptoms but does not improve OS. Whole-brain radiation therapy is not recommended by all guidelines due to negative effects on neurocognition but can be offered in rare palliative scenarios. Conclusion: Worldwide consensus guidelines consistently recommend up-front combination IO or TT with or without SRS for the treatment of MBM.
RESUMEN
Bispecific degraders (PROTACs) of ERα are expected to be advantageous over current inhibitors of ERα signaling (aromatase inhibitors/SERMs/SERDs) used to treat ER+ breast cancer. Information from DNA-encoded chemical library (DECL) screening provides a method to identify novel PROTAC binding features as the linker positioning, and binding elements are determined directly from the screen. After screening â¼120 billion DNA-encoded molecules with ERα WT and 3 gain-of-function (GOF) mutants, with and without estradiol to identify features that enrich ERα competitively, the off-DNA synthesized small molecule exemplar 7 exhibited nanomolar ERα binding, antagonism, and degradation. Click chemistry synthesis on an alkyne E3 ligase engagers panel and an azide variant of 7 rapidly generated bispecific nanomolar degraders of ERα, with PROTACs 18 and 21 inhibiting ER+ MCF7 tumor growth in a mouse xenograft model of breast cancer. This study validates this approach toward identifying novel bispecific degrader leads from DECL screening with minimal optimization.
Asunto(s)
ADN/química , Receptor alfa de Estrógeno/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Animales , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Química Clic , ADN/metabolismo , Antagonistas de Estrógenos/química , Antagonistas de Estrógenos/metabolismo , Antagonistas de Estrógenos/farmacología , Antagonistas de Estrógenos/uso terapéutico , Receptor alfa de Estrógeno/química , Receptor alfa de Estrógeno/genética , Femenino , Semivida , Humanos , Indoles/química , Indoles/metabolismo , Cinética , Ratones , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
There are currently limited published case reports and clinical studies looking at octreotide as a potential therapeutic agent for treating surgery- and malignancy-related chylothorax in adult patients. Few case reports have shown that low-dose subcutaneous octreotide can be used to treat malignant chylothorax. We report the case of a 57-year-old high-grade follicular lymphoma patient with malignant chylothorax which responded rapidly and was successfully treated with octreotide. Significant improvements were noted in her dyspnea, abdominal distention and pain, and chylous output. This case also highlights the importance of understanding the pharmacotherapeutic effects of octreotide when managing malignant chylothorax as it may help to benefit patients by improving symptoms, quality of life, and length of hospital stay. Further prospective studies are warranted to further evaluate the role of octreotide in the management of malignant chylothorax.