Publications by authors named "Cynthia D Timmers"

Pancreatic cancer is characterized by abundant desmoplasia, a dense stroma composed of extra-cellular and cellular components, with cancer associated fibroblasts (CAFs) being the major cellular component. However, the tissue(s) of origin for CAFs remains controversial. Here we determine the tissue origin of pancreatic CAFs through comprehensive lineage tracing studies in mice.

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Pancreatic ductal adenocarcinoma (PDAC) is associated with an incredibly dense stroma, which contributes to its recalcitrance to therapy. Cancer-associated fibroblasts (CAFs) are one of the most abundant cell types within the PDAC stroma and have context-dependent regulation of tumor progression in the tumor microenvironment (TME). Therefore, understanding tumor-promoting pathways in CAFs is essential for developing better stromal targeting therapies.

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Oral cavity squamous cell carcinoma (OCSCC) is a prevalent surgically treated subset of head and neck cancer with frequent recurrence and poor survival. Immunotherapy has demonstrated efficacy in recurrent/metastatic head and neck cancer. However, whether antitumor responses could be fostered by neoadjuvant presurgical immunotherapy remains unclear.

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Purpose: This study sought to determine the prognostic significance of the WHO-defined glioma molecular subgroups along with additional alterations, including promoter methylation and mutations in , , , , and , in NRG/RTOG 0424 using long-term follow-up data.

Methods: Mutations were determined using an Ion Torrent sequencing panel. 1p/19q co-deletion and promoter methylation were determined by Affymetrix OncoScan and Illumina 450K arrays.

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Adoptive transfer of tumor-infiltrating lymphocytes (TIL) elicits the regression of metastatic malignancies, yet a low proportion of patients achieve complete durable responses. The high incidence of relapse in these patients highlights the need to better understand mechanisms of tumor escape from T cell control. While melanoma has provided the foundation for developing TIL therapy, much less is known about TIL efficacy and relapse in other malignancies.

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Background: Breast cancer (BC) is the most common cancer in women and the leading cause of cancer-associated mortality in women. In particular, triple-negative BC (TNBC) has the highest rate of mortality due in large part to the lack of targeted treatment options for this subtype. Thus, there is an urgent need to identify new molecular targets for TNBC treatment.

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Purpose: To evaluate the impact of targeted DNA sequencing on selection of cancer therapy for patients with metastatic breast cancer (MBC).

Patients And Methods: In this prospective, single-center, single-arm trial, patients with MBC were enrolled within 10 weeks of starting a new therapy. At enrollment, tumor samples underwent next-generation sequencing for any of 315 cancer-related genes to high depth (> 500×) using FoundationOne CDx.

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Article Synopsis
  • The NRG Oncology/RTOG 9802 study demonstrated that patients with WHO low-grade glioma benefit from adjuvant chemoradiotherapy, showing improved survival compared to radiotherapy alone.
  • A post hoc analysis evaluated the impact of molecular subgroups on patient outcomes, finding significant differences in progression-free survival (PFS) and overall survival (OS) based on molecular mutations.
  • Specifically, treatment with postradiation chemotherapy (PCV) significantly improved PFS and OS for mutant groups, while showing no benefit for patients in the wild-type subgroup, highlighting the importance of molecular profiling in treatment decisions.
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The RNA interference (RNAi) machinery is an essential component of the cell, regulating miRNA biogenesis and function. RNAi complexes were thought to localize either in the nucleus, such as the microprocessor, or in the cytoplasm, such as the RNA-induced silencing complex (RISC). We recently revealed that the core microprocessor components DROSHA and DGCR8, as well as the main components of RISC, including Ago2, also associate with the apical adherens junctions of well-differentiated cultured epithelial cells.

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Cachexia is a wasting syndrome characterized by pronounced skeletal muscle loss. In cancer, cachexia is associated with increased morbidity and mortality and decreased treatment tolerance. Although advances have been made in understanding the mechanisms of cachexia, translating these advances to the clinic has been challenging.

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Aside from their roles in hemostasis and thrombosis, thrombocytes or platelets also promote tumor growth via immune suppression. However, the extent to which platelet activation shapes the immunosuppressive tumor microenvironment (TME) and whether platelet inhibition can be leveraged to improve checkpoint blockade are unknown. We show in this study that platelet function in mice mediates suppression of CD8 T cell function within the TME but not in the draining lymph nodes.

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Objectives: Chemotherapy remains a cornerstone treatment in non-small cell lung cancer either in combination with checkpoint inhibitors or as subsequent therapy. Identifying molecular predictors of response allows for optimal treatment selection. We performed genomic analysis on tumor samples of patients treated with carboplatin and nab-paclitaxel as part of a phase II trial to evaluate the prognostic and predictive value of mutations in DNA repair pathway in patients treated with this regimen.

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BRAF V600E mutations occur in approximately 40% of all patients with papillary thyroid cancer (PTC) and are associated with a worse prognosis in population studies. Treatment with single-agent BRAF inhibitors can result in nondurable partial responses (PRs) in clinical trials, but resistance inevitably develops. The mechanisms of resistance are not completely understood, but in non-thyroid tumors harboring BRAF V600E mutations, resistance has been ascribed to concurrent or acquired mutations in MEK1/2, RAC1, KRAS, and NRAS.

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Background: Dedifferentiated liposarcomas (DDLPS) are mesenchymal tumors associated with universally poor response to treatment. Genomic amplification of murine double minute 2 () is used as a diagnostic biomarker; however, no established biomarkers exist to guide DDLPS treatment. In the largest study of its kind, we report that the extent of amplification, not simply the presence of amplification, may be biologically important to the actions of DDLPS.

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Many breast cancer (BC) patients treated with aromatase inhibitors (AIs) develop aromatase inhibitor-related arthralgia (AIA). Candidate gene studies to identify AIA risk are limited in scope. We evaluated the potential of a novel analytic algorithm (NAA) to predict AIA using germline single nucleotide polymorphisms (SNP) data obtained before treatment initiation.

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LKB1 is a commonly mutated tumor suppressor in non-small cell lung cancer that exerts complex effects on signal transduction and transcriptional regulation. To better understand the downstream impact of loss of functional LKB1, we developed a transcriptional fingerprint assay representing this phenotype. This assay was predictive of LKB1 functional loss in cell lines and clinical specimens, even those without detected sequence alterations in the gene.

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Involuntary weight loss, a part of the cachexia syndrome, is a debilitating comorbidity of cancer and currently has no treatment options. Results from a recent clinical trial at our institution showed that biliary tract cancer patients treated with a MEK inhibitor exhibited poor tumor responses but surprisingly gained weight and increased their skeletal muscle mass. This implied that MEK inhibition might be anticachectic.

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Pelareorep causes oncolysis in tumor cells with activated Ras. We hypothesized that pelareorep would have efficacy and immunomodulatory activity in metastatic pancreatic adenocarcinoma (MPA) when combined with carboplatin and paclitaxel. A randomized phase 2 study (NCT01280058) was conducted in treatment-naive patients with MPA randomized to two treatment arms: paclitaxel/carboplatin + pelareorep (Arm A, n = 36 evaluable patients) versus paclitaxel/carboplatin (Arm B, n = 37 evaluable patients).

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Purpose: Carbonyl reductase (CBR) catalyzes anthracycline metabolism, and single nucleotide polymorphisms (SNPs) in CBR impact metabolic efficiency. In pediatric patients, homozygosity for the major allele (G) in the CBR3 gene was associated with increased risk of anthracycline cardiotoxicity. We hypothesized that CBR SNPs contribute to cardiotoxicity in adults.

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Scope: Tangerine tomatoes (Solanum lycopersicum) are rich in tetra-cis-lycopene resulting from natural variation in carotenoid isomerase. Our objective was to compare the bioavailability of lycopene from tangerine to red tomato juice, and elucidate physical deposition forms of these isomers in tomatoes by light and electron microscopy.

Methods And Results: Following a randomized cross-over design, subjects (n = 11, 6 M/5 F) consumed two meals delivering 10 mg lycopene from tangerine (94% cis) or red tomato juice (10% cis).

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Targeted, capture-based DNA sequencing is a cost-effective method to focus sequencing on a coding region or other customized region of the genome. There are multiple targeted sequencing methods available, but none has been systematically investigated and compared. We evaluated four commercially available custom-targeted DNA technologies for next-generation sequencing with respect to on-target sequencing, uniformity, and ability to detect single-nucleotide variations (SNVs) and copy number variations.

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Bone morphogenetic protein 3B (BMP3B) is a member of the TGF-beta superfamily. The BMP3B promoter sequence was previously identified as a target for aberrant DNA methylation in non-small-cell lung cancer (NSCLC). Aberrant DNA hypermethylation in the BMP3B promoter is associated with downregulation of BMP3B transcription in both primary human lung cancers as well as lung cancer cell lines.

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