Epithelial to mesenchymal transition is associated with rapamycin resistance

Rapamycin analogues have antitumor efficacy in several tumor types, however few patients demonstrate tumor regression. Thus, there is a pressing need for markers of intrinsic response/resistance and rational combination therapies. We hypothesized that epithelial-to-mesenchymal transition (EMT) confers rapamycin resistance. We found that the epithelial marker E-cadherin protein is higher in rapamycin sensitive (RS) cells and mesenchymal breast cancer cell lines selected by transcriptional EMT signatures are less sensitive to rapamycin. MCF7 cells, transfected with constitutively active mutant Snail, had increased rapamycin resistance (RR) compared to cells transfected with wild-type Snail. Conversely, we transfected two RR mesenchymal cell lines—ACHN and MDA-MB-231—with miR-200b/c or ZEB1 siRNA to promote mesenchymal-to-epithelial transition. This induced E-cadherin expression in both cell lines, and ACHN demonstrated a significant increase in RS. Treatment of ACHN and MDA-MB-231 with trametinib modulated EMT in ACHN cells in vitro. Treatment of MDA-MB-231 and ACHN xenografts with trametinib in combination with rapamycin resulted in significant growth inhibition in both but without an apparent effect on EMT. Future studies are needed to determine whether EMT status is predictive of sensitivity to rapalogs and to determine whether combination therapy with EMT modulating agents can enhance antitumor effects of PI3K/mTOR inhibitors

Combined treatment for at-risk drinking and smoking cessation among Puerto Ricans: A randomized clinical trial

Tobacco and alcohol use are linked behaviors that individually and synergistically increase the risk for negative health consequences. This study was a two-group, randomized clinical trial evaluating the efficacy of a behavioral intervention, “Motivation And Problem Solving Plus” (MAPS+), designed to concurrently address smoking cessation and the reduction of at-risk drinking. Targeted interventions may promote coaction, the likelihood that changing one behavior (smoking) increases the probability of changing another behavior (alcohol use). Puerto Ricans (N=202) who were smokers and at-risk drinkers were randomized to standard MAPS treatment focused exclusively on smoking cessation (S-MAPS), or MAPS+, focused on cessation and at-risk drinking reduction. Drinking outcomes included: number of at-risk drinking behaviors, heavy drinking, binge drinking, and drinking and driving. MAPS+ did not have a significant main effect on reducing at-risk drinking relative to S-MAPS. Among individuals who quit smoking, MAPS+ reduced the number of drinking behaviors, the likelihood of meeting criteria for heavy drinking relative to S-MAPS, and appeared promising for reducing binge drinking. MAPS+ did not improve drinking outcomes among individuals who were unsuccessful at quitting smoking. MAPS+ showed promise in reducing at-risk drinking among Puerto Rican smokers who successfully quit smoking, consistent with treatment enhanced coaction. Integrating an alcohol intervention into cessation treatment did not reduce engagement in treatment, or hinder cessation outcomes, and positively impacted at-risk drinking among individuals who quit smoking. Findings of coaction between smoking and drinking speak to the promise of multiple health behavior change interventions for substance use treatment and chronic disease prevention

Efficacy of a Smoking Cessation Intervention for Survivors of Cervical Intraepithelial Neoplasia or Cervical Cancer: A Randomized Controlled Trial

PURPOSE: Women who smoke and have a history of cervical intraepithelial neoplasia (CIN) or cervical cancer represent a vulnerable subgroup at elevated risk for recurrence, poorer cancer treatment outcomes, and decreased quality of life. The purpose of this study was to evaluate the long-term efficacy of Motivation And Problem Solving (MAPS), a novel treatment well-suited to meeting the smoking cessation needs of this population. METHODS: Women who were with a history of CIN or cervical cancer, age 18 years and older, spoke English or Spanish, and reported current smoking (≥100 lifetime cigarettes plus any smoking in the past 30 days) were eligible. Participants (N = 202) were recruited in clinic in Oklahoma City and online nationally and randomly assigned to (1) standard treatment (ST) or (2) MAPS. ST consisted of repeated referrals to a tobacco cessation quitline, self-help materials, and combination nicotine replacement therapy (patch plus lozenge). MAPS comprised all ST components plus up to six proactive telephone counseling sessions over 12 months. Logistic regression and generalized estimating equations evaluated the intervention. The primary outcome was self-reported 7-day point prevalence abstinence from tobacco at 18 months, with abstinence at 3, 6, and 12 months and biochemically confirmed abstinence as secondary outcomes. RESULTS: There was no significant effect for MAPS over ST at 18 months (14.2% CONCLUSION: MAPS led to a greater than two-fold increase in smoking abstinence among survivors of CIN and cervical cancer at 12 months. At 18 months, abstinence in MAPS declined to match the control condition and the treatment effect was no longer significant