Retrospective Comparison of Targeted Anticancer Drugs Predicted by the CNS-TAP Tool Versus Those Selected by a Molecularly Driven Tumor Board in Children With DIPG.

The recent trial Pediatric Neuro-Oncology Consortium 003 (PNOC003) utilized a molecular tumor board to recommend personalized treatment regimens based on tumor sequencing results in children with DIPG. We separately developed the Central Nervous System Targeted Agent Prediction (CNS-TAP) tool, which numerically scores targeted anticancer agents using preclinical, clinical, and patient-specific data. We hypothesized that highly scored agents from CNS-TAP would overlap with the PNOC003 tumor board's recommendations.

Molecular-guided therapy for the treatment of patients with relapsed and refractory childhood cancers: a Beat Childhood Cancer Research Consortium trial.

Background: Children with relapsed central nervous system (CNS tumors), neuroblastoma, sarcomas, and other rare solid tumors face poor outcomes. This prospective clinical trial examined the feasibility of combining genomic and transcriptomic profiling of tumor samples with a molecular tumor board (MTB) approach to make real‑time treatment decisions for children with relapsed/refractory solid tumors.

Methods: Subjects were divided into three strata: stratum 1-relapsed/refractory neuroblastoma; stratum 2-relapsed/refractory CNS tumors; and stratum 3-relapsed/refractory rare solid tumors.

Genomic analysis across 53 canine cancer types reveals novel mutations and high clinical actionability potential.

A genomic understanding of the oncogenic processes and individual variability of human cancer has steadily fueled improvement in patient outcomes over the past 20 years. Mutations within tumour tissues are routinely assessed through clinical genomic diagnostic assays by academic and commercial laboratories to facilitate diagnosis, prognosis and effective treatment stratification. The application of genomics has unveiled a wealth of mutation-based biomarkers in canine cancers, suggesting that the transformative principles that have revolutionized human cancer medicine can be brought to bear in veterinary oncology.

Standing in the canine precision medicine knowledge gap: Improving annotation of canine cancer genomic biomarkers through systematic comparative analysis of human cancer mutations in COSMIC.

The accrual of cancer mutation data and related functional and clinical associations have revolutionised human oncology, enabling the advancement of precision medicine and biomarker-guided clinical management. The catalogue of cancer mutations is also growing in canine cancers. However, without direct high-powered functional data in dogs, it remains challenging to interpret and utilise them in research and clinical settings.

A pilot study of genomic-guided induction therapy followed by immunotherapy with difluoromethylornithine maintenance for high-risk neuroblastoma.

Background: Survival for patients with high-risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapies.

Aims: To study the feasibility and safety of incorporating a genomic-based targeted agent to induction therapy for HRNB as well as the feasibility and safety of adding difluoromethylornithine (DFMO) to anti-GD2 immunotherapy.

Methods: Twenty newly diagnosed HRNB patients were treated on this multicenter pilot trial.

Identifying treatment options for BRAFV600 wild-type metastatic melanoma: A SU2C/MRA genomics-enabled clinical trial.

Although combination BRAF and MEK inhibitors are highly effective for the 40-50% of cutaneous metastatic melanomas harboring BRAFV600 mutations, targeted agents have been ineffective for BRAFV600wild-type (wt) metastatic melanomas. The SU2C Genomics-Enabled Medicine for Melanoma Trial utilized a Simon two-stage optimal design to assess whether comprehensive genomic profiling improves selection of molecular-based therapies for BRAFV600wt metastatic melanoma patients who had progressed on standard-of-care therapy, which may include immunotherapy. Of the response-evaluable patients, binimetinib was selected for 20 patients randomized to the genomics-enabled arm, and nine were treated on the alternate treatment arm.

Temporospatial genomic profiling in glioblastoma identifies commonly altered core pathways underlying tumor progression.

Background: Tumor heterogeneity underlies resistance and disease progression in glioblastoma (GBM), and tumors most commonly recur adjacent to the surgical resection margins in contrast non-enhancing (NE) regions. To date, no targeted therapies have meaningfully altered overall patient survival in the up-front setting. The aim of this study was to characterize intratumoral heterogeneity in recurrent GBM using bulk samples from primary resection and recurrent samples taken from contrast-enhancing (EN) and contrast NE regions.

Multiscale, multimodal analysis of tumor heterogeneity in IDH1 mutant vs wild-type diffuse gliomas.

Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition and cellular interactions have not been well characterized. To gain new clinical- and biological-insights into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integrated data from protein, genomic and MR imaging from 20 treatment-naïve glioma cases and 16 recurrent GBM cases. Multiplexed immunofluorescence (MxIF) was used to generate single cell data for 43 protein markers representing all cancer hallmarks, Genomic sequencing (exome and RNA (normal and tumor) and magnetic resonance imaging (MRI) quantitative features (protocols were T1-post, FLAIR and ADC) from whole tumor, peritumoral edema and enhancing core vs equivalent normal region were also collected from patients.

Comparative Tumor RNA Sequencing Analysis for Difficult-to-Treat Pediatric and Young Adult Patients With Cancer.

Importance: Pediatric cancers are epigenetic diseases; therefore, considering tumor gene expression information is necessary for a complete understanding of the tumorigenic processes.

Objective: To evaluate the feasibility and utility of incorporating comparative gene expression information into the precision medicine framework for difficult-to-treat pediatric and young adult patients with cancer.

Design, Setting, And Participants: This cohort study was conducted as a consortium between the University of California, Santa Cruz (UCSC) Treehouse Childhood Cancer Initiative and clinical genomic trials.

Genomics-Enabled Precision Medicine for Cancer.

Genomic information is increasingly being incorporated into clinical cancer care. Large-scale sequencing efforts have deepened our understanding of the genomic landscape of cancer and contributed to the expanding catalog of alterations being leveraged to aid in cancer diagnosis, prognosis, and treatment. Genomic profiling can provide clinically relevant information regarding somatic point mutations, copy number alterations, translocations, and gene fusions.

Leveraging Spatial Variation in Tumor Purity for Improved Somatic Variant Calling of Archival Tumor Only Samples.

Archival tumor samples represent a rich resource of annotated specimens for translational genomics research. However, standard variant calling approaches require a matched normal sample from the same individual, which is often not available in the retrospective setting, making it difficult to distinguish between true somatic variants and individual-specific germline variants. Archival sections often contain adjacent normal tissue, but this tissue can include infiltrating tumor cells.

A pilot precision medicine trial for children with diffuse intrinsic pontine glioma-PNOC003: A report from the Pacific Pediatric Neuro-Oncology Consortium.

This clinical trial evaluated whether whole exome sequencing (WES) and RNA sequencing (RNAseq) of paired normal and tumor tissues could be incorporated into a personalized treatment plan for newly diagnosed patients (<25 years of age) with diffuse intrinsic pontine glioma (DIPG). Additionally, whole genome sequencing (WGS) was compared to WES to determine if WGS would further inform treatment decisions, and whether circulating tumor DNA (ctDNA) could detect the H3K27M mutation to allow assessment of therapy response. Patients were selected across three Pacific Pediatric Neuro-Oncology Consortium member institutions between September 2014 and January 2016.

Bcl-2 inhibitors enhance FGFR inhibitor-induced mitochondrial-dependent cell death in FGFR2-mutant endometrial cancer.

Endometrial cancer is the most commonly diagnosed gynaecological malignancy. Unfortunately, 15-20% of women demonstrate persistent or recurrent tumours that are refractory to current chemotherapies. We previously identified activating mutations in fibroblast growth factor receptor 2 (FGFR2) in 12% (stage I/II) to 17% (stage III/IV) endometrioid ECs and found that these mutations are associated with shorter progression-free and cancer-specific survival.

E6201, an intravenous MEK1 inhibitor, achieves an exceptional response in BRAF V600E-mutated metastatic malignant melanoma with brain metastases.

Malignant melanoma (MM) exhibits a high propensity for central nervous system dissemination with ~50% of metastatic MM patients developing brain metastases (BM). Targeted therapies and immune checkpoint inhibitors have improved overall survival for MM patients with BM. However, responses are usually of short duration and new agents that effectively penetrate the blood brain barrier (BBB) are needed.

Prospective Feasibility Trial for Genomics-Informed Treatment in Recurrent and Progressive Glioblastoma.

Glioblastoma is an aggressive and molecularly heterogeneous cancer with few effective treatment options. We hypothesized that next-generation sequencing can be used to guide treatment recommendations within a clinically acceptable time frame following surgery for patients with recurrent glioblastoma. We conducted a prospective genomics-informed feasibility trial in adults with recurrent and progressive glioblastoma.

A prospective pilot study of genome-wide exome and transcriptome profiling in patients with small cell lung cancer progressing after first-line therapy.

Background: Small cell lung cancer (SCLC) that has progressed after first-line therapy is an aggressive disease with few effective therapeutic strategies. In this prospective study, we employed next-generation sequencing (NGS) to identify therapeutically actionable alterations to guide treatment for advanced SCLC patients.

Methods: Twelve patients with SCLC were enrolled after failing platinum-based chemotherapy.

FGFR2 mutations are associated with poor outcomes in endometrioid endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study.

Purpose: Activating FGFR2 mutations have been identified in ~10% of endometrioid endometrial cancers (ECs). We have previously reported that mutations in FGFR2 are associated with shorter disease free survival (DFS) in stage I/II EC patients. Here we sought to validate the prognostic importance of FGFR2 mutations in a large, multi-institutional patient cohort.

Translating RNA sequencing into clinical diagnostics: opportunities and challenges.

With the emergence of RNA sequencing (RNA-seq) technologies, RNA-based biomolecules hold expanded promise for their diagnostic, prognostic and therapeutic applicability in various diseases, including cancers and infectious diseases. Detection of gene fusions and differential expression of known disease-causing transcripts by RNA-seq represent some of the most immediate opportunities. However, it is the diversity of RNA species detected through RNA-seq that holds new promise for the multi-faceted clinical applicability of RNA-based measures, including the potential of extracellular RNAs as non-invasive diagnostic indicators of disease.

Insulin Receptor Substrate Adaptor Proteins Mediate Prognostic Gene Expression Profiles in Breast Cancer.

Therapies targeting the type I insulin-like growth factor receptor (IGF-1R) have not been developed with predictive biomarkers to identify tumors with receptor activation. We have previously shown that the insulin receptor substrate (IRS) adaptor proteins are necessary for linking IGF1R to downstream signaling pathways and the malignant phenotype in breast cancer cells. The purpose of this study was to identify gene expression profiles downstream of IGF1R and its two adaptor proteins.

Toward precision medicine in glioblastoma: the promise and the challenges.

Integrated sequencing strategies have provided a broader understanding of the genomic landscape and molecular classifications of multiple cancer types and have identified various therapeutic opportunities across cancer subsets. Despite pivotal advances in the characterization of genomic alterations in glioblastoma, targeted agents have shown minimal efficacy in clinical trials to date, and patient survival remains poor. In this review, we highlight potential reasons why targeting single alterations has yielded limited clinical efficacy in glioblastoma, focusing on issues of tumor heterogeneity and pharmacokinetic failure.

An integrated framework for reporting clinically relevant biomarkers from paired tumor/normal genomic and transcriptomic sequencing data in support of clinical trials in personalized medicine.

The ability to rapidly sequence the tumor and germline DNA of an individual holds the eventual promise of revolutionizing our ability to match targeted therapies to tumors harboring the associated genetic biomarkers. Analyzing high throughput genomic data consisting of millions of base pairs and discovering alterations in clinically actionable genes in a structured and real time manner is at the crux of personalized testing. This requires a computational architecture that can monitor and track a system within a regulated environment as terabytes of data are reduced to a small number of therapeutically relevant variants, delivered as a diagnostic laboratory developed test.

The N550K/H mutations in FGFR2 confer differential resistance to PD173074, dovitinib, and ponatinib ATP-competitive inhibitors.

We sought to identify fibroblast growth factor receptor 2 (FGFR2) kinase domain mutations that confer resistance to the pan-FGFR inhibitor, dovitinib, and explore the mechanism of action of the drug-resistant mutations. We cultured BaF3 cells overexpressing FGFR2 in high concentrations of dovitinib and identified 14 dovitinib-resistant mutations, including the N550K mutation observed in 25% of FGFR2(mutant) endometrial cancers (ECs). Structural and biochemical in vitro kinase analyses, together with BaF3 proliferation assays, showed that the resistance mutations elevate the intrinsic kinase activity of FGFR2.

Fibroblast growth factor receptor inhibition synergizes with Paclitaxel and Doxorubicin in endometrial cancer cells.

Objective: The fibroblast growth factor (FGF) family of signaling molecules has been associated with chemoresistance and poor prognosis in a number of cancer types, including lung, breast, ovarian, prostate, and head and neck carcinomas. Given the identification of activating mutations in the FGF receptor 2 (FGFR2) receptor tyrosine kinase in a subset of endometrial tumors, agents with activity against FGFRs are currently being tested in clinical trials for recurrent and progressive endometrial cancer. Here, we evaluated the effect of FGFR inhibition on the in vitro efficacy of chemotherapy in endometrial cancer cell lines.