Fibroblasts in Pancreatic Ductal Adenocarcinoma: Biological Mechanisms and Therapeutic Targets.

The desmoplastic reaction of pancreas cancer may begin as a wound healing response to the nascent neoplasm, but it soon creates an insidious shelter that can sustain the growing tumor and rebuff therapy. Among the many cell types subverted by transformed epithelial cells, fibroblasts are recruited and activated to lay a foundation of extracellular matrix proteins and glycosaminoglycans that alter tumor biophysics and signaling. Their near-universal presence in pancreas cancer and ostensible support of disease progression make fibroblasts attractive therapeutic targets.

Understanding Disease Biology and Informing the Management of Pancreas Cancer With Preclinical Model Systems.

Recent advances in cytotoxic therapies for pancreatic ductal adenocarcinoma (PDA) are overshadowed by stalled clinical progress of more targeted strategies, the vast majority of which have failed in clinical trials. Inability to translate preclinical promise into clinical efficacy derives, in part, from imperfect disease modeling and mismatches between preclinical and clinical study design and execution. Into these gaps fall our patients who enter the clinical trial landscape expectantly and bear the brunt of its inadequacies.

Runx3 and Cell Fate Decisions in Pancreas Cancer.

The RUNX family transcription factors are critical regulators of development and frequently dysregulated in cancer. RUNX3, the least well characterized of the three family members, has been variously described as a tumor promoter or suppressor, sometimes with conflicting results and opinions in the same cancer and likely reflecting a complex role in oncogenesis. We recently identified RUNX3 expression as a crucial determinant of the predilection for pancreatic ductal adenocarcinoma (PDA) cells to proliferate locally or promulgate throughout the body.

Enhancer Remodeling during Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacologic Targeting of the P-TEFb Complex.

Targeting the dysregulated BRAF-MEK-ERK pathway in cancer has increasingly emerged in clinical trial design. Despite clinical responses in specific cancers using inhibitors targeting BRAF and MEK, resistance develops often involving nongenomic adaptive bypass mechanisms. Inhibition of MEK1/2 by trametinib in patients with triple-negative breast cancer (TNBC) induced dramatic transcriptional responses, including upregulation of receptor tyrosine kinases (RTK) comparing tumor samples before and after one week of treatment.

Mutant p53 Together with TGFβ Signaling Influence Organ-Specific Hematogenous Colonization Patterns of Pancreatic Cancer.

TP53 and the TGFβ pathway are major mediators of pancreatic cancer metastasis. The mechanisms by which they cause hematogenous metastasis have not been fully explored. (;; ) mice were generated, and the frequency and morphology of organ-specific hematogenous metastases compared with that seen in and littermates ().

RUNX3 defines disease behavior in pancreatic ductal adenocarcinoma.

Runt-related transcription factor 3 (RUNX3) functions downstream of transforming growth factor beta (TGFβ) and plays dual roles in pancreas cancer by both suppressing (by inhibiting proliferation) and promoting (by enhancing migratory and metastatic capacity) disease progression. Consideration of the contextual regulation of RUNX3 together with its myriad downstream effects may help improve clinical outcomes for pancreas cancer patients.

RUNX3 Controls a Metastatic Switch in Pancreatic Ductal Adenocarcinoma.

For the majority of patients with pancreas cancer, the high metastatic proclivity is life limiting. Some patients, however, present with and succumb to locally destructive disease. A molecular understanding of these distinct disease manifestations can critically inform patient management.

Application of multiplexed kinase inhibitor beads to study kinome adaptations in drug-resistant leukemia.

Protein kinases play key roles in oncogenic signaling and are a major focus in the development of targeted cancer therapies. Imatinib, a BCR-Abl tyrosine kinase inhibitor, is a successful front-line treatment for chronic myelogenous leukemia (CML). However, resistance to imatinib may be acquired by BCR-Abl mutations or hyperactivation of Src family kinases such as Lyn.

The dynamic nature of the kinome.

Recent advances in proteomics have facilitated the analysis of the kinome 'en masse'. What these studies have revealed is a surprisingly dynamic network of kinase responses to highly selective kinase inhibitors, thereby illustrating the complex biological responses to these small molecules. Moreover these studies have identified key transcription factors, such as c-Myc and FOXO (forkhead box O), that play pivotal roles in kinome reprogramming in cancer cells.

Combined PI3K/mTOR and MEK inhibition provides broad antitumor activity in faithful murine cancer models.

Purpose: Anticancer drug development is inefficient, but genetically engineered murine models (GEMM) and orthotopic, syngeneic transplants (OST) of cancer may offer advantages to in vitro and xenograft systems.

Experimental Design: We assessed the activity of 16 treatment regimens in a RAS-driven, Ink4a/Arf-deficient melanoma GEMM. In addition, we tested a subset of treatment regimens in three breast cancer models representing distinct breast cancer subtypes: claudin-low (T11 OST), basal-like (C3-TAg GEMM), and luminal B (MMTV-Neu GEMM).

Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer.

Kinase inhibitors have limited success in cancer treatment because tumors circumvent their action. Using a quantitative proteomics approach, we assessed kinome activity in response to MEK inhibition in triple-negative breast cancer (TNBC) cells and genetically engineered mice (GEMMs). MEK inhibition caused acute ERK activity loss, resulting in rapid c-Myc degradation that induced expression and activation of several receptor tyrosine kinases (RTKs).