Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead MSC-4106.

The dysregulated Hippo pathway and, consequently, hyperactivity of the transcriptional YAP/TAZ-TEAD complexes is associated with diseases such as cancer. Prevention of YAP/TAZ-TEAD triggered gene transcription is an attractive strategy for therapeutic intervention. The deeply buried and conserved lipidation pocket (P-site) of the TEAD transcription factors is druggable. The discovery and optimization of a P-site binding fragment (1) are described. Utilizing structure-based design, enhancement in target potency was engineered into the hit, capitalizing on the established X-ray structure of TEAD1. The efforts culminated in the optimized in vivo tool MSC-4106, which exhibited desirable potency, mouse pharmacokinetic properties, and in vivo efficacy. In close correlation to compound exposure, the time- and dose-dependent downregulation of a proximal biomarker could be shown.

Control of Chemo-, Regio-, and Enantioselectivity in Copper Hydride Reductions of Morita-Baylis-Hillman Adducts.

Nonracemically ligated copper hydride can be used to effect tandem SN2'/1,2-reductions of racemic Morita-Baylis-Hillman (MBH) acetates to access enantioenriched chiral allylic alcohols with defined olefin geometry. MBH esters, including those with ß-substitution, can be transformed to stereodefined enoates by taking advantage of a bulky, oligomeric, in situ generated trialkoxysiloxane leaving group. Finally, an atypical conversion of easily arrived at MBH alcohol derivatives to nonracemic allylic alcohols is disclosed.

Radiotherapy for Brain Metastases From Renal Cell Carcinoma in the Targeted Therapy Era: The University of Rochester Experience.

OBJECTIVES: Radiotherapy remains the standard approach for brain metastases from renal cell carcinoma (RCC). Kinase inhibitors (KI) have become standard of care for metastatic RCC. They also increase the radiosensitivity of various tumor types in preclinical models. Data are lacking regarding the effect of KIs among RCC patients undergoing radiotherapy for brain metastases. We report our experience of radiotherapy for brain metastatic RCC in the era of targeted therapy and analyzed effects of concurrent KI therapy. METHODS: We retrospectively analyzed 25 consecutive patients who received radiotherapy for brain metastases from RCC with whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), or both. Kaplan-Meier rates of overall survival (OS) and brain progression-free survival (BPFS) were calculated and univariate analyses performed. RESULTS: Lower diagnosis-specific graded prognostic assessment (DS-GPA) score and multiple intracranial metastases were associated with decreased OS and BPFS on univariate analysis; DS-GPA is also a prognostic factor on multivariate analysis. There was no significant difference in OS or BPFS for SRS compared with WBRT or WBRT and SRS combined. The concurrent use of KI was not associated with any change in OS or BPFS. CONCLUSIONS: This hypothesis-generating analysis suggests among patients with brain metastatic RCC treated with the most current therapies, those selected to undergo SRS did not experience significantly different survival or control outcomes than those selected to undergo WBRT. From our experience to date, limited in patient numbers, there seems to be neither harm nor benefit in using concurrent KI therapy during radiotherapy. Given that most patients progress systemically, we would recommend considering KI use during brain radiotherapy in these patients.

Malignant peripheral nerve sheath tumors (MPNST): a SEER analysis of incidence across the age spectrum and therapeutic interventions in the pediatric population.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNST) are very rare in the general population and challenging to treat. A paucity of data exists regarding the incidence of MPNST across all age groups and treatment outcomes in the pediatric population. We aimed to characterize both using the Survival, Epidemiology, and End Results (SEER) database. PROCEDURE: The SEER-18 database with information on the United States population from 1973 to 2009 was queried for cases of MPNST. For incidence data, 1,182 cases were found among the general population. Of those, 165 cases were in individuals aged 0-19. After exclusions, 139 cases from the SEER-18 database met study criteria for outcomes analysis. For each patient, variables including gender, age, race, stage (localized, regional, or distant), surgical treatment, and radiotherapy were obtained. RESULTS: The overall incidence of MPNST was 1.46 per million person-years, with increased incidence among the elderly. In the pediatric population, the incidence was 0.56 per million person-years, and was higher among post-pubertal children aged 10-19. Median overall survival in the pediatric population was 30 months, with only localized disease and treatment with surgery being positive prognostic factors on multivariate analysis. CONCLUSIONS: MPNST is a rare disease and, among children, is most frequent seen in adolescents. Surgery is crucial as first-line treatment for MPNST, especially if the tumor is localized at diagnosis. In patients with non-localized MPNST, the disease remains extremely difficult to manage, and both surgery and radiotherapy are interventions that should be considered.

Spinal drop metastasis in myxopapillary ependymoma: a case report and a review of treatment options.

Myxopapillary ependymoma (MPE) is a World Health Organization grade I ependymoma that is quite rare and generally thought to be benign. Possible drop metastasis from MPE has been reported three times in the literature; in each case there were cotemporaneous additional MPE lesions. We report the case of a man who had a piecemeal gross total resection of a MPE at L1-L3 followed by adjuvant external beam radiotherapy (EBRT) who presented sixteen months later with a lesion in the thecal sac consistent with drop metastasis. A subtotal resection and adjuvant EBRT were performed. The patient has been disease-free in follow-up 27 months from the second surgery. A review of the literature regarding the treatment for MPE showed that gross total resection is optimal initial management. Several retrospective studies supported the role of adjuvant radiotherapy in enhancing local control and progression-free survival. Chemotherapy has a minimal role in the management of MPE.

Stereoselective silylcupration of conjugated alkynes in water at room temperature.

Micellar catalysis enables copper-catalyzed silylcupration of a variety of electron-deficient alkynes, thereby providing access to isomerically pure E- or Z-ß-silyl-substituted carbonyl derivatives. These reactions take place in minutes, afford high yields and stereoselectivity, and are especially tolerant of functional groups present in the substrates. The aqueous reaction medium has been successfully recycled several times, and a substrate/catalyst ratio of 10,000:1 has been documented for this methodology.

Radiation therapy in the management of patients with limited brain metastases.

Brain metastases are the most common form of intracranial tumor in adults and an increasingly important cause of morbidity and mortality. Rising incidence is attributed to advanced radiographic imaging and prolonged survival due to improvements in cancer therapy (including systemic therapies) that are not as effective in treating intracranial disease. Standard treatment options for brain metastases include resection, whole-brain radiation therapy (WBRT), stereotactic radiosurgery, or a combination of these modalities. Most patients with brain metastases receive some form of radiation therapy during the course of their illness, and for the majority of them, the prognosis is poor and WBRT remains the standard. However, within this very diverse patient population, subgroups exist in which prolonged survival is possible. In recent years, several randomized controlled trials have clearly demonstrated the efficacy of stereotactic radiosurgery in well-selected patients. This, along with an increased recognition of the late neurocognitive effects of WBRT, has led many to question the role of upfront WBRT in patients with limited intracranial metastases. In this review, we summarize the evolving role of radiotherapy in the management of brain metastases and then discuss the issues related to neurotoxicity from radiation and future areas of investigation.

Second primary lung cancer after head and neck squamous cell cancer: population-based study of risk factors.

BACKGROUND: Patients with head and neck squamous cell cancer (HNSCC) are at risk of developing second primary lung cancer (SPLC). METHODS: Among 61,883 patients with HNSCC from the Surveillance, Epidemiology and End Results (SEER) database, 4522 developed SPLC (any histology) ≥2 months after HNSCC. We correlated risk with demographic and tumor-related parameters. RESULTS: The risk of SPLC after HNSCC was 5.8%, 11.4%, and 16.4% at 5, 10, and 15 years, respectively. From Cox regression, significantly adverse (p < .0001) risk factors for SPLC included: regional versus localized HNSCC stage (hazard ratio [HR] = 1.16), hypopharyngeal or supraglottic laryngeal site (HR = 1.57), increased age (HR = 1.26/decade), black race (HR = 1.27), and male sex (HR = 1.26). Glottic (HR = 0.75) and tonsillar or oral cavity sites (HR = 0.80) were associated with significantly (p < .0001) lower risks of SPLC. CONCLUSION: From population-based actuarial analyses, HNSCCs with more aggressive clinicopathologic features were more apt to develop SPLC, suggestive of similar environmental and/or host factors for these cancers.