Targeting the HuR Oncogenic Role with a New Class of Cytoplasmic Dimerization Inhibitors.

The development of novel therapeutics that exploit alterations in the activation state of key cellular signaling pathways due to mutations in upstream regulators has generated the field of personalized medicine. These first-generation efforts have focused on actionable mutations identified by deep sequencing of large numbers of tumor samples. We propose that a second-generation opportunity exists by exploiting key downstream "nodes of control" that contribute to oncogenesis and are inappropriately activated due to loss of upstream regulation and microenvironmental influences. The RNA-binding protein HuR represents such a node. Because HuR functionality in cancer cells is dependent on HuR dimerization and its nuclear/cytoplasmic shuttling, we developed a new class of molecules targeting HuR protein dimerization. A structure-activity relationship algorithm enabled development of inhibitors of HuR multimer formation that were soluble, had micromolar activity, and penetrated the blood-brain barrier. These inhibitors were evaluated for activity validation and specificity in a robust cell-based assay of HuR dimerization. SRI-42127, a molecule that met these criteria, inhibited HuR multimer formation across primary patient-derived glioblastoma xenolines (PDGx), leading to arrest of proliferation, induction of apoptosis, and inhibition of colony formation. SRI-42127 had favorable attributes with central nervous system penetration and inhibited tumor growth in mouse models. RNA and protein analysis of SRI-42127-treated PDGx xenolines across glioblastoma molecular subtypes confirmed attenuation of targets upregulated by HuR. These results highlight how focusing on key attributes of HuR that contribute to cancer progression, namely cytoplasmic localization and multimerization, has led to the development of a novel, highly effective inhibitor. SIGNIFICANCE: These findings utilize a cell-based mechanism of action assay with a structure-activity relationship compound development pathway to discover inhibitors that target HuR dimerization, a mechanism required for cancer promotion.

Relationship between cognitive functioning, mood, and other patient factors on quality of life in metastatic brain cancer.

OBJECTIVE: Neurocognitive functioning (NCF), mood disturbances, physical functioning, and social support all share a relationship with health-related quality of life (HRQOL). However, investigations into these relationships have not been conducted in persons with brain metastases (BM). PATIENTS AND METHODS: Ninety-three newly diagnosed persons with BM were administered various cognitive batteries. Data were collected across a wide range of categories (ie, cognitive, demographic, disease/treatment, mood, social support, physical functioning). The Functional Assessment of Cancer Treatment (FACT) scale was used to measure HRQOL. RESULTS: Mood and physical function correlated with lower HRQOL in every measured domain. Verbal learning and memory correlated with every FACT subscale except emotional quality of life. Social support also correlated with several HRQOL domains. Stepwise linear regression revealed that mood predicted general well-being and several FACT subscales, including physical, emotional and cognitive well-being. Social support and physical health were predictive of general well-being. Verbal learning and memory predicted cognitive well-being. CONCLUSION: HRQOL is a complex construct affected by numerous variables. In particular, mood, physical functioning, and learning and memory were important predictors of HRQOL, and clinicians are encouraged to obtain information in these areas during baseline assessments in persons with BM.