Multidimensional biomarker predicts disease control in response to immunotherapy in recurrent or metastatic head and neck squamous-cell carcinoma.

PURPOSE: Anti-PD-1 therapy provides clinical benefit in 40-50% of patients with relapsed and/or metastatic head and neck squamous cell carcinoma (RM-HNSCC). Selection of anti- PD-1 therapy is typically based on patient PD-L1 immunohistochemistry (IHC) which has low specificity for predicting disease control. Therefore, there is a critical need for a clinical biomarker that will predict clinical benefit to anti-PD-1 treatment with high specificity. METHODS: Clinical treatment and outcomes data for 103 RM-HNSCC patients were paired with RNA-sequencing data from formalin-fixed patient samples. Using logistic regression methods, we developed a novel biomarker classifier based on expression patterns in the tumor immune microenvironment to predict disease control with monotherapy PD-1 inhibitors (pembrolizumab and nivolumab). The performance of the biomarker was internally validated using out-of-bag methods. RESULTS: The biomarker significantly predicted disease control (65% in predicted non-progressors vs. 17% in predicted progressors, p < 0.001) and was significantly correlated with overall survival (OS; p = 0.004). In addition, the biomarker outperformed PD-L1 IHC across numerous metrics including sensitivity (0.79 vs 0.64, respectively; p = 0.005) and specificity (0.70 vs 0.61, respectively; p = 0.009). CONCLUSION: This novel assay uses tumor immune microenvironment expression data to predict disease control and OS with high sensitivity and specificity in patients with RM-HNSCC treated with anti-PD-1 monotherapy.

Geriatric assessment and treatment outcomes in older adults with cancer receiving immune checkpoint inhibitors.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer, but outcomes in older adults are not well defined. We evaluated the associations of geriatric assessment (GA) domains with treatment-related outcomes in older adults with solid tumors receiving ICIs. METHODS: We performed a single-center, retrospective study of patients age ≥65 years diagnosed with solid tumors who received ICIs and were evaluated with a GA from January 2011 to April 2017. Using Wilcoxon rank sum test, we examined the associations of GA domains and treatment-related outcomes, including the number of ICI cycles received, best response, immune-related adverse events (irAEs), and hospitalizations during ICI treatment. RESULTS: We identified 28 patients (median age at ICI treatment = 78 years, range 66-93); 60% had Eastern Cooperative Oncology Group (ECOG) Performance Status of ≥2; 39% had lung cancer; 89% had stage IV cancer; and 50% received pembrolizumab. Seventy-five percent had at least one GA domain impairment. Patients with any instrumental activities of daily living (IADL) impairment received fewer cycles of ICI (median: 2.0 vs. 7.0 cycles, p = 0.02). In this small sample, neither age nor GA domain measures were associated with best response, irAEs, or hospitalization during ICI treatment. CONCLUSIONS: Older adults treated with ICIs had a high prevalence of impairments in GA domains, and IADL impairments were associated with shorter duration of ICI treatment. Future prospective studies are needed to evaluate the role of the GA further in this vulnerable patient population in the immunotherapy era.

Follicular Lymphoma: Redefining Prognosis, Current Treatment Options, and Unmet Needs.

Follicular lymphoma is the most common indolent lymphoma in the United States. In this review article, the authors discuss the different prognostic biomarkers available for follicular lymphoma. Treatment options, including observation, immunotherapy versus chemoimmunotherapy, in both the frontline and the relapse setting are also discussed in detail. Patients with follicular lymphoma with unmet needs include those with early relapse, with multiple relapses, and with histologic transformation. The treatment options for these patients are not well defined, and the authors discuss the available data for treating these patients.

Kinomic profiling identifies focal adhesion kinase 1 as a therapeutic target in advanced clear cell renal cell carcinoma.

The introduction of targeted therapies has caused a paradigm shift in the treatment of metastatic clear cell (cc)-renal cell carcinoma (RCC). We hypothesized that determining differential kinase activity between primary and metastatic tumor sites may identify critical drivers of progression and relevant therapeutic targets in metastatic disease. Kinomic profiling was performed on primary tumor and metastatic tumor deposits utilizing a peptide substrate microarray to detect relative tyrosine phosphorylation activity. Pharmacologic and genetic loss of function experiments were used to assess the biologic significance of the top scoring kinase on in vitro and in vivo tumor phenotypes. Kinomics identified 7 peptides with increased tyrosine phosphorylation in metastases that were significantly altered (p<0.005). Based on these peptides, bioinformatics analyses identified several candidate kinases activated in metastases compared to primary tumors. The highest ranked upstream kinase was Focal Adhesion Kinase 1 (FAK1). RCC lines demonstrate evidence of elevated FAK1 activation relative to non-transformed renal epithelial cells. Pharmacologic inhibition of FAK1 with GSK2256098 suppresses in vitro tumor phenotypes. In turn, FAK1 knockdown in RCC cells suppresses both in vitro phenotypes and in vivo tumor growth. Collectively, these data demonstrate functional activation of FAK1 in metastases and provide preclinical rationale for targeting this kinase in the setting of advanced ccRCC.

Correction: Kinomic Profiling of Electromagnetic Navigational Bronchoscopy Specimens: A New Approach for Personalized Medicine.

[This corrects the article DOI: 10.1371/journal.pone.0116388.].

A rare cause of chest pain in a cancer patient.

It is well known that cancer and hypercoagulability go hand in hand. Most thromboembolism is venous in nature although arterial thrombosis can occur. Arterial thrombosis secondary to malignancy is usually seen in the lower extremities; however, it can also be seen elsewhere. This is a case of bronchogenic carcinoma with no history of typical atherosclerotic risk factors including smoking, diabetes mellitus, hypertension, or hyperlipidemia presented with chest pain and was found to have an acute ST segment elevation myocardial infection. Coronary angiography showed a large thrombus in the left anterior descending artery in the absence of any atherosclerotic lesions. Malignancy is considered to be the major contributing factor for this myocardial infarction in the absence of both atherosclerotic risk factors and atherosclerotic lesions in the coronary angiography. We will focus on the relationship between cancer and thrombosis with special emphasis on arterial thromboembolism with subsequent development of myocardial infarction.

High Throughput Kinomic Profiling of Human Clear Cell Renal Cell Carcinoma Identifies Kinase Activity Dependent Molecular Subtypes.

Despite the widespread use of kinase-targeted agents in clear cell renal cell carcinoma (CC-RCC), comprehensive kinase activity evaluation (kinomic profiling) of these tumors is lacking. Thus, kinomic profiling of CC-RCC may assist in devising a classification system associated with clinical outcomes, and help identify potential therapeutic targets. Fresh frozen CC-RCC tumor lysates from 41 clinically annotated patients who had localized disease at diagnosis were kinomically profiled using the PamStation®12 high-content phospho-peptide substrate microarray system (PamGene International). Twelve of these patients also had matched normal kidneys available that were also profiled. Unsupervised hierarchical clustering and supervised comparisons based on tumor vs. normal kidney and clinical outcome (tumor recurrence) were performed and coupled with advanced network modeling and upstream kinase prediction methods. Unsupervised clustering analysis of localized CC-RCC tumors identified 3 major kinomic groups associated with inflammation (A), translation initiation (B), and immune response and cell adhesions (C) processes. Potential driver kinases implicated include PFTAIRE (PFTK1), PKG1, and SRC, which were identified in groups A, B, and C, respectively. Of the 9 patients who had tumor recurrence, only one was found in Group B. Supervised analysis showed decreased kinase activity of CDK1 and RSK1-4 substrates in those which progressed compared to others. Twelve tumors with matching normal renal tissue implicated increased PIM's and MAPKAPK's in tumors compared to adjacent normal renal tissue. As such, comprehensive kinase profiling of CC-RCC tumors could provide a functional classification strategy for patients with localized disease and identify potential therapeutic targets.

Kinomic profiling of electromagnetic navigational bronchoscopy specimens: a new approach for personalized medicine.

PURPOSE: Researchers are currently seeking relevant lung cancer biomarkers in order to make informed decisions regarding therapeutic selection for patients in so-called "precision medicine." However, there are challenges to obtaining adequate lung cancer tissue for molecular analyses. Furthermore, current molecular testing of tumors at the genomic or transcriptomic level are very indirect measures of biological response to a drug, particularly for small molecule inhibitors that target kinases. Kinase activity profiling is therefore theorized to be more reflective of in vivo biology than many current molecular analysis techniques. As a result, this study seeks to prove the feasibility of combining a novel minimally invasive biopsy technique that expands the number of lesions amenable for biopsy with subsequent ex vivo kinase activity analysis. METHODS: Eight patients with lung lesions of varying location and size were biopsied using the novel electromagnetic navigational bronchoscopy (ENB) technique. Basal kinase activity (kinomic) profiles and ex vivo interrogation of samples in combination with tyrosine kinase inhibitors erlotinib, crizotinib, and lapatinib were performed by PamStation 12 microarray analysis. RESULTS: Kinomic profiling qualitatively identified patient specific kinase activity profiles as well as patient and drug specific changes in kinase activity profiles following exposure to inhibitor. Thus, the study has verified the feasibility of ENB as a method for obtaining tissue in adequate quantities for kinomic analysis and has demonstrated the possible use of this tissue acquisition and analysis technique as a method for future study of lung cancer biomarkers. CONCLUSIONS: We demonstrate the feasibility of using ENB-derived biopsies to perform kinase activity assessment in lung cancer patients.

Kinomic exploration of temozolomide and radiation resistance in Glioblastoma multiforme xenolines.

BACKGROUND AND PURPOSE: Glioblastoma multiforme (GBM) represents the most common and deadly primary brain malignancy, particularly due to temozolomide (TMZ) and radiation (RT) resistance. To better understand resistance mechanisms, we examined global kinase activity (kinomic profiling) in both treatment sensitive and resistant human GBM patient-derived xenografts (PDX or "xenolines"). MATERIALS AND METHODS: Thirteen orthotopically-implanted xenolines were examined including 8 with known RT sensitivity/resistance, while 5 TMZ resistant xenolines were generated through serial TMZ treatment in vivo. Tumors were harvested, prepared as total protein lysates, and kinomically analyzed on a PamStation®12 high-throughput microarray platform with subsequent upstream kinase prediction and network modeling. RESULTS: Kinomic profiles indicated elevated tyrosine kinase activity associated with the radiation resistance phenotype, including FAK and FGFR1. Furthermore, network modeling showed VEGFR1/2 and c-Raf hubs could be involved. Analysis of acquired TMZ resistance revealed more kinomic variability among TMZ resistant tumors. Two of the five tumors displayed significantly altered kinase activity in the TMZ resistant xenolines and network modeling indicated PKC, JAK1, PI3K, CDK2, and VEGFR as potential mediators of this resistance. CONCLUSION: GBM xenolines provide a phenotypic model for GBM drug response and resistance that when paired with kinomic profiling identified targetable pathways to inherent (radiation) or acquired (TMZ) resistance.