Moffitt Researchers Discover Mechanism Leading to Drug Resistance, Metastasis in Melanoma Patients

The gist: New research suggests that some melanoma patients might benefit from a treatment schedule that alternates BRAF inhibitor drugs with MEK inhibitor drugs. The scientists hypothesize that this schedule could help prevent drug resistance and metastasis. The researchers set out to figure out why patients who receive BRAF inhibitors develop more metastases than patients on standard chemotherapy. They found that unusually high activity of a protein called EphA2 on cancer cells may be the culprit. Taking away BRAF inhibitors seemed to lower the aggressiveness of these cells. So, periodically taking away BRAF inhibitors from patients might theoretically help stave off resistance and metastasis.

Moffitt Cancer Center researchers have discovered a mechanism that leads to resistance to targeted therapy in melanoma patients and are investigating strategies to counteract it. Targeted biological therapy can reduce toxicity and improve outcomes for many cancer patients, when compared to the adverse effects of standard chemotherapeutic drugs.  However, patients often develop resistance to these targeted therapies, resulting in more aggressive cells that can spread to other sites or cause regrowth of primary tumors.

“B-Raf is a protein that is frequently mutated in human cancers, leading to increased tumor cell growth, survival and migration.  Drugs that target B-Raf or another protein in the same network called MEK have proved effective in clinical trials. Several B-Raf and MEK inhibitors have been approved with the combination of a B-Raf and a MEK inhibitor being the current standard of care for patients with B-Raf mutant melanoma. However over time many patients become resistant to B-Raf and B-Raf/MEK inhibitor therapy.

“Moffitt researchers found that patients who are on B-Raf inhibitor drugs develop more new metastases than patients who are on standard chemotherapy. The researchers wanted to determine how this acquired resistance develops in order to devise better treatment options for patients. They found that melanoma cells that are resistant to B-Raf inhibitors tend to be more aggressive and invasive, thereby allowing the tumor to spread to a new organ site.  They used a large screening approach and discovered that this resistance and aggressive behavior was due to high activity of a cell surface protein called EphA2, which is also found on glioblastoma stem cells.”


A Retrospective Analysis of VeriStrat Status on Outcome of a Randomized Phase II Trial of First-Line Therapy with Gemcitabine, Erlotinib, or the Combination in Elderly NSCLC Patients

In a multicenter randomized phase II trial of gemcitabine (arm A), erlotinib (arm B), and gemcitabine and erlotinib (arm C), similar progression-free survival (PFS) and overall survival (OS) were observed in all arms. We performed an exploratory, blinded, retrospective analysis of plasma or serum samples collected as part of the trial to investigate the ability of VeriStrat (VS) to predict treatment outcomes.

Gemcitabine is the superior treatment for elderly patients with VS Poor status. First-line erlotinib for elderly patients with VS Good status may warrant further investigation.


Quantitative Chemical Proteomics Profiling Differentiates Erlotinib from Gefitinib in EGFR Wild-type Non-small Cell Lung Carcinoma Cell Lines

Although both erlotinib and gefitinib target the epidermal growth factor receptor (EGFR), erlotinib is effective in patients with EGFR wild-type or mutated tumors, whereas gefitinib is only beneficial for patients with activating mutations. To determine whether these differences in clinical outcomes can be attributed to their respective protein interaction profiles, a label-free, quantitative chemical proteomics study was performed. We propose that, in an EGFR wild-type context, erlotinib may have a complementary mode of action by inhibiting integrin-linked kinase (ILK), -parvin and PINCH (IPP) complex activities, resulting in the slowing down of the metastatic process of epithelial tumors.


Pathobiological Implications of MUC4 in Non-Small-Cell Lung Cancer

Altered expression of MUC4 plays an oncogenic role in various cancers, including pancreatic, ovarian, and breast. This study evaluates the expression and role of MUC4 in non-small-cell lung cancer (NSCLC).

MUC4 plays a tumor-suppressor role in NSCLC by altering p53 expression in NSCLC. Decrease in MUC4 expression in advanced tumor stages also seems to confirm the novel protective function of MUC4 in NSCLC.


A Case Control Study to Assess Impact of Risk Factors on Trends of Lung Cancer

The objective of this research was to identify impact of risk factors on changing trends of lung cancer in a case control study. In the study conducted from 2006 to 2010 the cases included newly diagnosed patients of histological proven lung carcinoma attending the radiotherapy department. Change in trend was observed in patients diagnosed at younger age of 57.48 ± 0.56 years in 2010 with adenocarcinoma unlike 62.89 ± 1.21 years in 2006. Females show increase in incidence of lung cancer in 2010. The “active” smokers and years of smoking were significantly high among cases. The incidence of squamous cell carcinoma declined from 47.4% in 2006 to 15% in 2010 whereas adenocarcinoma increased.


CollabRx Releases Second Generation Lung Cancer Clinical Decision Support Tool for Oncologists

CollabRx, Inc. announced the release of a new version of its Therapy Finder™application (“app”) for lung cancer. The lung cancer Therapy Finder™app is a web-based decision support tool that enables oncologists to take into account the genetics of a patient’s tumor when determining a treatment plan. The newest lung cancer Therapy Finder™ is currently freely available at the company’s website and via distribution partners such as MedPage Today, Everyday Health’s physician portal.


Prognostic Significance of Combinations of RNA-Dependent Protein Kinase and EphA2 Biomarkers for NSCLC

RNA-dependent protein kinase (PKR) is an independent prognostic variable in patients with non-small-cell lung cancer (NSCLC). In the current study, we investigated the correlation between PKR and 25 other biomarkers for NSCLC, identified the markers that could further improve the prognostic significance of PKR and elucidated the mechanisms of interaction between these markers and PKR.

PKR/EphA2 is a significant predictor of prognosis for NSCLC. PKR/EphA2 may be a promising approach to improving screening efficiency and predicting prognosis in patients with NSCLC.