Emerging protein kinase inhibitors for non-small cell lung cancer.

INTRODUCTION: In the current paradigm of precision medicine in non-small cell lung cancer (NSCLC), the therapeutic strategy is determined by the molecular characteristics. The best examples of this approach are the kinase inhibitors that selectively target tumors bearing an epidermal growth factor receptor (EGFR) mutation or an anaplastic lymphoma kinase (ALK) rearrangement. Emerging protein kinase inhibitors may enhance our ability to effectively treat these and other genomic subtypes of NSCLC. AREAS COVERED: This article reviews the next-generation kinase inhibitors targeting EGFR and ALK-positive NSCLC. In addition, targeted kinase inhibitors in clinical development for other specific molecular subtypes of NSCLC are covered, including ROS1, BRAF, RET, HER2, KRAS (upstream of the MEK kinase), MET, PIK3CA, FGFR1, DDR2, VEGFR and AAK. EXPERT OPINION: In EGFR-mutant NSCLC, there are several kinase inhibitors with promising activity, most notably dacomitinib and CO-1686 in tumors with acquired resistance to EGFR-targeted therapy. Next-generation ALK inhibitors appear to have greater potency than crizotinib and several ongoing trials may shed light on their role in both ALK- and ROS1-positive NSCLC. While there is optimism regarding the role of kinase inhibitors in other molecular subtypes, the available evidence is too immature to make recommendations and results from prospective trials are needed.

Loss of transforming growth factor ß adaptor protein ß-2 spectrin leads to delayed liver regeneration in mice.

UNLABELLED: Liver regeneration, following partial hepatectomy (PHx), occurs through precisely controlled and synchronized cell proliferation, in which quiescent hepatocytes undergo one to two rounds of replication, with restoration of liver mass and function. We previously demonstrated that loss of the Smad3/4 adaptor protein ß-2 spectrin (ß2SP) is associated with faster entry into S phase, and hepatocellular cancer formation. These observations led us to further pursue the role of ß2SP in cell cycle progression in vivo. Liver regeneration studies with PHx in ß2SP(+/-) mice reveal a surprising and significant decrease in liver/body weight ratio at 48 hours after PHx in ß2SP(+/-) mice in comparison to wildtype mice. At 48 hours after PHx we also observe decreased levels of cyclin E (2.4-fold, P < 0.05), Cdk1 (7.2-fold, P < 0.05), cyclin A, pRb (Ser249/Thr252), proliferative cell nuclear antigen (PCNA), cyclin D1 with elevated levels of pCdk1 (Thr14) (3.6-fold, P < 0.05). Strikingly, at 24 hours elevated levels of p53 (4-fold, P < 0.05), phospho-p53 (ser15 and ser20), and p21 (200-fold, P < 0.05) persisting to 48 hours after PHx further correlated with raised expression of the DNA damage markers pChk2 (Thr68) and γH2AX (S139). However, compromised cell cycle progression with loss of ß2SP is not rescued by inhibiting p53 function, and that G(2) /M phase arrest observed is independent and upstream of p53. CONCLUSION: ß2SP deficiency results in dysfunctional hepatocyte cell cycle progression and delayed liver regeneration at 48 hours after PHx, which is p53-independent. ß2SP loss may increase susceptibility to DNA damage, impair cell cycle progression, and ultimately lead to hepatocellular cancer.

Non-umbilical cutaneous metastasis of a pancreatic adenocarcinoma.

Pancreatic adenocarcinoma is one of the deadliest human malignancies with the majority of cases diagnosed late in the course of the disease. Cutaneous metastases originating from pancreatic cancer are rare. The most common site reported is the umbilicus. Non-umbilical cutaneous metastases are far less common with only a few cases reported in the literature. Our case involved a 43-year-old man with pancreatic carcinoma who was offered resection and a Whipple procedure was planned. Intraoperatively, the patient was found to have a widely metastatic disease not seen on preoperative imaging. Postoperatively, cutaneous metastasis in the scalp was discovered. Although rare, the recognition of non-umbilical cutaneous metastases of pancreatic adenocarcinoma can be of value because they can not only detect an underlying tumour but also guide management.

Colon cancer stem cells.

Colorectal cancer (CRC) is the second leading cause of death from cancer in the United States. Aggressive research in the last decade has led to a wealth of information about this disease; for example, we now know that more than 80% of sporadic colon tumors contain mutations in the Wnt and TGFß signaling pathways. The latest avenue of research is revealing the existence of and role for the cancer stem cell (CSC) model, which promotes the idea that malignancies originate from a small fraction of cancer cells that show self-renewal and multi- or pluripotency. The model also endorses that CSCs are capable of initiating and sustaining tumor growth. The body of evidence in favor of the CSC model is rapidly growing and includes analyses from flow cytometry of numerous CSC biomarkers, abnormal signaling pathways, symmetric division, dietary augmentation, and analysis of the behavior of these cells in spheroid culture formation. Although the incidence of death from CRC remains high, fervent research, both basic and translational, is beginning to improve patient outcomes. This paper focuses on stem cell biology in the context of CRC to help understand the mechanisms leading to tumor development and therapy resistance, with possible therapeutic indications.

Human tissue-resident stem cells combined with hyaluronic acid gel provide fibrovascular-integrated soft-tissue augmentation in a murine photoaged skin model.

BACKGROUND: Transplantation of adipose tissue-resident mesenchymal stem cells has been found to contribute to the establishment of a supportive fibrovascular network. The authors sought to evaluate the potential of human adipose tissue-derived stem cells to integrate with nonanimal stabilized hyaluronic acid as a novel injectable soft-tissue filler. METHODS: Cell proliferation was measured by bromodeoxyuridine incorporation. Interactions of adipose tissue-derived stem cells with hyaluronic acid were documented by scanning electron microscopy. The effect of this combination on procollagen mRNA was assessed by real-time polymerase chain reaction. The potential therapeutic effects were evaluated in an athymic murine photoaged skin model by histology and by high-resolution magnetic resonance imaging. Angiogenesis was assessed by microvessel density analysis. RESULTS: Under in vitro culture conditions, the authors found an equal proliferation capacity of adipose tissue-derived stem cells grown on hyaluronic acid versus controls. Scanning electron microscopy showed enhanced establishment of complex microvillous networks in adipose tissue-derived stem cells adherent to hyaluronic acid compared with controls. Adipose tissue-derived stem cells and hyaluronic acid induced a significant increase in procollagen 1-alpha-2 mRNA expression compared with controls. In an athymic murine photoaged skin model, injection of this combination ablated photoinduced skin wrinkles. Magnetic resonance imaging revealed a consistent and stable volume fill by adipose tissue-derived stem cells and nonanimal stabilized hyaluronic acid at 3 weeks. Adipose tissue-derived stem cells actively incorporated into the hyaluronic acid fill and showed an organized fibrovascular network at 3 weeks. CONCLUSION: The combination of adipose tissue-derived stem cells and nonanimal stabilized hyaluronic acid holds promise as a tool with which to achieve lasting volume fill in reconstructive surgical soft-tissue augmentation.