Molecular Targeting of the BRAF Proto-Oncogene/Mitogen-Activated Protein Kinase (MAPK) Pathway across Cancers.

The mitogen-activated protein kinase (MAPK) pathway is essential for cellular proliferation, growth, and survival. Constitutive activation of this pathway by BRAF mutations can cause downstream activation of kinases, leading to uncontrolled cellular growth and carcinogenesis. Therefore, inhibition of BRAF and the downstream substrate MEK has been shown to be effective in controlling tumor growth and proliferation. Over the last decade, several BRAF and MEK inhibitors have been investigated, ranging from primarily melanoma to various cancer types with BRAF alterations. This subsequently led to several Food and Drug Administration (FDA) approvals for BRAF/MEK inhibitors for melanoma, non-small cell lung cancer, anaplastic thyroid cancer, colorectal cancer, histiocytosis neoplasms, and finally, tumor-agnostic indications. Here, this comprehensive review will cover the developments of BRAF and MEK inhibitors from melanomas to tumor-agnostic indications, novel drugs, challenges, future directions, and the importance of those drugs in personalized medicine.

Clinical consequences of resistance to ALK inhibitors in non-small cell lung cancer.

Introduction: ALK rearrangements are present in 2-7% of non-small cell lung cancer (NSCLC) cases, where the EML4-ALK fusion is the most frequent. Rearrangement of ALK with other fusion partners occurs only in ≈5% of NSCLC ALK-positive. These patients have benefited from ALK inhibitors, and currently, there are three generations of drugs as the standard of care. The first-generation ALK inhibitor crizotinib is approved in the front-line setting for the treatment of advanced NSCLC; unfortunately, these tumors may eventually develop resistance to this molecule. The Second-generation ALK inhibitors, ceritinib, alectinib, and brigatinib, are approved for patients recently diagnosed or in relapse. The third-generation inhibitor lorlatininb is approved for patients who have developed resistance to any ALK inhibitor.Areas covered: In this review, an unstructured search in Pubmed and SCOPUS was conducted. We summarized the mechanisms of resistance to ALK inhibitors and its consequences in the treatment-decision making in advanced or metastatic NSCLC after failure to a first-line ALK inhibitor.Expert opinion: Currently, there are a growing number of options of therapeutic agents against ALK+ NSCLC (approved and in development); however, adequate selection and sequencing of agents are crucial to deal with the tumor evolution.

Escherichia coli: an important pathogen in patients with hematologic malignancies.

BACKGROUND: Escherichia coli (E. coli) is a pathogen of great concern in immunosuppressed patients. While antimicrobial prophylactic therapy has become the standard, the emergence of resistant pathogens has some questioning its use. This study describes our experience with E.coli as a pathogen in neutropenic patients with a hematologic malignancy, and addresses future directions of treatment for this patient population. METHODS: A retrospective chart review of 245 E.coli bacteremia patients at Moffitt Cancer Center from 05/18/02 - 05/15/12 was conducted. Out of 245 patients, 169 did not meet the criteria due to non-neutropenic status, or not diagnosed with a hematologic malignancy, or due to having insufficient medical records. Thus, they were excluded from the study. As a result, 76 patients were involved in this study. Patients were identified via microbiology laboratory computerized records. RESULTS: The included patients experienced clinically significant E.coli bacteremia resulting in a median hospital stay of 14.7 days. Several patients developed severe sepsis requiring the use of pressor and ventilator therapy. CONCLUSIONS: E.coli is a major pathogen in these patient populations resulting in extended hospital stays and specialized treatment to overcome their E.coli bacteremia. The data supports the use of fluoroquinolone prophylactic therapy, however, earlier detection and treatment of neutropenic infection is needed.

EGF receptor in lung cancer: a successful story of targeted therapy.

Lung cancer research has incorporated molecular medicine into the management of this disease during the last 5 years. Several novel tumorigenesis pathways associated with lung cancer development and proliferation have been discovered and further developed as targets. The idea behind this is to deliver individualized therapy for each patient based on his/her tumor phenotype, which may involve the overexpression or lack of certain proteins, receptors, mutations and other factors. To date, many of these characteristics have been shown to have a potential role as prognostic or predictive biomarkers, with most of the available data being obtained from retrospective analyses, various laboratory platforms, and data sets used for comparison. However, well-designed prospective randomized clinical trials are underway to validate the significance and future role of these novel biomarkers, allowing us to sort out the best personalized management for an individual with lung cancer diagnosis. Nevertheless, one of these features, the EGF receptor (EGFR) gene mutation, has emerged as a prognostic and strongly predictive biomarker when EGFR inhibition is used as a therapy for tumors that harbor the mutation. Our article displays the most recently developed data related to this biomarker and what have we learned based on the analyses of clinical trials that have studied different agents in the clinical arena.

Accelerated second-line or maintenance chemotherapy versus treatment at disease progression in NSCLC.

For many decades, the use of chemotherapy as second-line therapy in non-small-cell lung cancer relied upon disease progression. Several studies have shown that four to six cycles of chemotherapy administered as front-line therapy treatment offers a survival advantage to patients; however, further chemotherapy beyond this initial treatment was more associated with side effects and no benefit in survival. Until 2009, second-line treatment for lung cancer was well established for three therapeutic agents: docetaxel, pemetrexed and erlotinib. Currently, the timeframe to use these agents has been challenged by two large randomized clinical trials in which pemetrexed (JMEN trial) and erlotinib (Sequential Tarceva in Unresectable NSCLC [SATURN] trial) were used as 'maintenance' therapy and shown to impact progression-free survival and overall survival. This review focuses on the actual dilemma that medical oncologists face in clinical practice in terms of when and to whom maintenance therapy should be applied or if the 'watch and wait' approach prior to start second-line therapy is still advisable.