Functional proteomics of patient derived head and neck squamous cell carcinoma cells reveal novel applications of trametinib.

In this study, we report a differential response of mitogen-activated protein kinase-kinase (MEK) inhibitor trametinib in 20 head and neck squamous cell carcinoma (HNSCC) patients' tumor-derived cell cultures. Relatively sensitive and resistant cases to trametinib were identified using high throughput metabolic assays and validated in extended dose response studies in vitro. High throughput metabolic assays exploring combination therapies with trametinib were subjected to synergy models and maximal synergistic dose analyses. These yielded several candidates, including axtinib, GDC-0032, GSK-690693, and SGX-523. The combination regimen of trametinib and AXL/MET/VEGFR inhibitor glesatinib showed initial efficacy both in vitro and in vivo (92% reduction in tumor volume). Sensitivity was validated in vivo in a patient-derived xenograft (PDX) model in which trametinib as a single agent effected reduction in tumor volume up to 72%. Reverse Phase Protein Arrays (RPPA) demonstrated differentially expressed proteins and phosphoproteins upon trametinib treatment. Furthermore, resistant cell lines showed a compensatory mechanism via increases in MAPK and non-MAPK pathway proteins that may represent targets for future combination regimens. Intrinsic-targeted options have potential to address paucity of medical treatment options for HNSCC cancer patients, enhance response to extrinsic targeted agents, and/or reduce morbidity as neoadjuvant to surgical treatments.

Functional genomic analysis identifies drug targetable pathways in invasive and metastatic cutaneous squamous cell carcinoma.

Although cutaneous squamous cell carcinoma (cSCC) is treatable in the majority of cases, deadly invasive and metastatic cases do occur. To date there are neither reliable predictive biomarkers of disease progression nor FDA-approved targeted therapies as standard of care. To address these issues, we screened patient-derived primary cultured cells from invasive/metastatic cSCC with 107 small-molecule inhibitors. In-house bioinformatics tools were used to cross-analyze drug responses and DNA mutations in tumors detected by whole-exome sequencing (WES). Aberrations in molecular pathways with evidence of potential drug targets were identified, including the Eph-ephrin and neutrophil degranulation signaling pathways. Using a screening panel of siRNAs, we identified EPHA6 and EPHA7 as targets within the Eph-ephrin pathway responsible for mitigating decreased cell viability. These studies form a plausible foundation for detecting biomarkers of high-risk progressive disease applicable in dermatopathology and for patient-specific therapeutic options for invasive/metastatic cSCC.

Do psychological measures predict the ability of lower limb amputees to learn to use a prosthesis?

OBJECTIVE: Can psychological tests predict whether, on admission to a rehabilitation ward post amputation, a lower limb amputee will learn to use a prosthesis during the ensuing inpatient rehabilitation programme? DESIGN: A one-sample design in which psychological variables, and transfemoral/transtibial amputation site were tested as predictors of outcome. SETTING: An inpatient rehabilitation unit in the UK offering prosthetic provision. SUBJECTS: Forty-three consecutive patients with peripheral vascular disease (mean age 66.35 years, standard deviation 14.99) who had received an amputation on average 19 days previously on a surgical ward and were transferred to the unit for rehabilitation including assessment for prosthetic provision. MAIN OUTCOME MEASURE: Whether the patient learnt to use a prosthesis independently during the stay on the rehabilitation unit. RESULTS: During their stay in the rehabilitation unit (mean length of stay = 42 days), 31 patients learnt to use a prosthesis and 12 did not. A forward stepwise logistic regression revealed that the Kendrick Object Learning Test score on admission correctly predicted outcome in 70% of cases. The predictive power rose to 81% correct when the amputation site (transfemoral or transtibial) was included amongst the predictors. Anxiety, depression and recovery locus of control scores were not significant predictors of functional prosthetic use in this study. CONCLUSION: A simple test of learning ability and the amputation site can help to predict the patient's ability to learn to use a prosthesis following amputation and is recommended as part of the assessment process.