jcru
|
|
Abstract: Lung cancer is the most commonly diagnosed cancer in the world. “Driver” and “passenger” mutations identified in lung cancer indicate that genetics play a major role in the development of the disease, progression, metastasis and response to therapy. Survival rates for lung cancer treatment have remained stagnant at ~15% over the past 40 years in patients with disseminated disease despite advances in surgical techniques, radiotherapy and chemotherapy. Resistance to therapy; either intrinsic or acquired has been a major hindrance to treatment leading to great interest in studies seeking to understand and overcome resistance. Genetic information gained from molecular analyses has been critical in identifying druggable targets and tumor profiles that may be predictors of therapeutic response and mediators of resistance. Mutated or overexpressed epidermal growth factor receptor (EGFR) and translocations in the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) genes (EML4-ALK) are examples of genetic aberrations resulting in targeted therapies for both localized and metastatic disease. Positive clinical responses have been noted in patients harboring these genetic mutations when treated with targeted therapies compared to patients lacking these mutations. Resistance is nonetheless a major factor contributing to the failure of targeted agents and standard cytotoxic agents. In this review, we examine molecular mechanisms that are potential drivers of resistance in non-small cell lung carcinoma, the most frequently diagnosed form of lung cancer. The mechanisms addressed include resistance to molecular targeted therapies as well as conventional chemotherapeutics through the activity of multidrug resistance proteins. Keywords: Non-small cell lung cancer, EGFR, EML4-ALK, tyrosine kinase inhibitors, drug resistance, ABC transporters, ABCB1, ABCC1, ABCC10, ABCG2.Download Full Article |
|
|
Abstract: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine carbonate with a MOA via bis-alkylation of DNA @ N7-guanine and N4-cytosine that has completed adult clinical Phase I and II trials in individuals with malignancies involving the CNS. We report here objective clinical observations seen in a clinical Phase I DM-CHOC-PEN trial with AYA subjects that have cancer (some of which had CNS involvement). Subjects & Methods: DM-CHOC-PEN was administered as a single 3-hr IV infusion once every 21 days in escalating doses from 50 – 98.7 mg/m2 to individuals (aged 15-39 years of age) with advanced malignancies. Results: Twelve (12) AYA individuals have been treated to date (with or without CNS involvement). The drug was well tolerated with fatigue (17%) being the most common adverse effect. No neuro/cognitive, liver dysfunction, hematological, cardiac, renal or GI toxicities were observed. Pharmacokinetic profiling revealed higher AUCs for all dose levels (50-98.7 mg/m2) than had been seen previously in adults. Three (3) AYA individuals treated (1 each with NSCLC, ALL, and astrocytoma involving the CNS) have responded with CR/PR (RECIST 1.1), improved QOL/PFS (Kaplan-Meier) and OS from 8 to 35+ mos. Conclusion: DM-CHOC-PEN is safe in doses of 50-98.7 mg/m2 and produced objective responses with improved OS and manageable toxicities in AYA individuals with malignancies involving the CNS. Complete data on subject responses and observed toxicities will be presented. The data support a 3-stage mechanism for tumor cytotoxicity: entry into the CNS and into the tumor via reversible binding to RBC membranes; then transported into cancer cells with L-glutamine; and bis-alkylation as described above. Keywords: Cancer, central nervous system, metastatic, primary, DM-CHOC-PEN, non-neurotoxicity. Download Full Article |
|
|
Download Full Article |
|
|
Editorial |
|
|
Abstract: Background: Triple Negative Breast Cancer (TNBC) is one of the most aggressive but least understood subtypes of breast cancer. The roles of nodal status and type of surgery while essential in determining the outcomes of patients with TNBC remain controversial and require more examination. Materials and Methods: Clinical and pathological data were retrieved from 1990 until 2001 by retrospective chart review for patients with breast cancer at the American University of Beirut Medical Center. Out of 1455 patients, 524 had complete histological data, of which 138 (26.3%) were diagnosed with TNBC. Median follow up time of patients with TNBC was 3.34 years (Range 0.55 - 10 years). We used the Kaplan-Meier and Cox proportional hazard models to evaluate prognostic effects and estimate hazard ratios (HR). Results: For the 138 patients with TNBC, median age at presentation was 50.91 years (Range 26 - 81). One-year, 5 and 10-year survivals for node-negative patients (N0) were respectively 98.3 %, 91.1% and 74.5 %, compared to 98.5%, 70.3 % and 42.2% for node-positive patients (N1-N3). Numerical nodal staging did not significantly correlate with survival. On multivariate analysis, higher stage (H.R 3.01) and Breast-Conserving Therapy (BCT) had a significant effect on the survival of TNBC patients (H.R 0.195) Conclusion: Lymph node-positivity predicted poorer survival in patients with TNBC. However, within the group of patients with positive LN, the number of positive lymph nodes did not alter survival nor did the tumor size. BCT including radiation therapy had a better effect on survival when compared to mastectomy. Keywords: Triple negative breast cancer, nodal status, breast conservative therapy, modified radical mastectomy, survival.Download Full Article |