Ryan D. Gentzler

An overview of the mTOR pathway as a target in cancer therapy

Introduction: The mammalian target of rapamycin (mTOR) signaling cascade is a key regulatory pathway controlling initiation of mRNA translation in mammalian cells. The mTOR inhibitor rapamycin and its derivatives have shown potent antineoplastic activities in many preclinical models and clinical trials. First-generation mTOR inhibitors are now FDA-approved for the treatment of renal cell carcinoma. Areas covered: This article reviews the components of the mTOR pathway and their normal functions, highlighting the most common alterations in the pathway, seen in various human malignancies. It also discusses elements and effectors of this signaling cascade and reviews the therapeutic relevance of pharmacological inhibitors of the pathway in several malignancies, including lymphomas, leukemias, sarcomas, renal cell carcinoma, and breast cancer. Expert opinion: mTOR targeting is a highly promising therapeutic approach. First-generation mTOR inhibitors have already shown substantial activity in the treatment of certain tumors, while the emergence of second-generation catalytic mTOR inhibitors provides a better approach to target the pathway in malignant cells and has raised the potential for better clinical outcomes in the future.

F-18 FDG-PET predicts outcomes for patients receiving total lymphoid irradiation and autologous blood stem-cell transplantation for relapsed and refractory Hodgkin lymphoma

Total lymphoid irradiation (TLI) followed by high‐dose chemotherapy and autologous haematopoietic stem cell transplant (aHSCT) is an effective strategy for patients with relapsed/refractory classical Hodgkin lymphoma (HL). We report outcomes for patients with relapsed/refractory HL who received TLI followed by high‐dose chemotherapy and aHSCT. Pre‐transplant fludeoxyglucose positron emission tomography (FDG‐PET) studies were scored on the 5‐point Deauville scale. Of 51 patients treated with TLI and aHSCT, 59% had primary refractory disease and 63% had active disease at aHSCT. The 10‐year progression‐free survival (PFS) and overall survival (OS) for all patients was 56% and 54%, respectively. Patients with complete response (CR) by PET prior to aHSCT had a 5‐year PFS and OS of 85% and 100% compared to 52% and 48% for those without CR (P = 0·09 and P = 0·007, respectively). TLI and aHSCT yields excellent disease control and long‐term survival rates for patients with relapsed/refractory HL, including those with high‐risk disease features. Achievement of CR with salvage therapy is a powerful predictor of outcome.

Maintenance treatment after induction therapy in non-small cell lung cancer: latest evidence and clinical implications

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the industrialized world. Despite significant progress in early stage disease, survival rates for advanced disease remain low. Maintenance therapy is a treatment strategy that has been investigated extensively in NSCLC. Therapies that have been studied in this setting in randomized trials to date include chemotherapy and molecularly targeted agents. Following the development of multiple new agents that show activity in NSCLC and have a tolerable side-effect profile, there has been increasing interest in utilizing them to maintain response to initial therapy after treatment with platinum-based doublets. Two effective strategies have evolved: continuation and switch maintenance. Despite improvements in progression-free survival and often overall survival on multiple clinical trials, there remains considerable controversy around this treatment paradigm. Here, we briefly outline the evolution of this treatment strategy and examine the available data, including recently updated data from the PARAMOUNT, AVAPERL, and PointBreak maintenance trials. Ultimately, the decision to use maintenance chemotherapy requires a nuanced discussion between the patient and physician that adequately assesses benefits of prolonged therapy and impact in terms of toxicity, quality of life, and financial cost.

The changing landscape of phase II/III metastatic NSCLC clinical trials and the importance of biomarker selection criteria

Over the last decade, new cytotoxic treatments and targeted therapies have altered treatment paradigms for patients with metastatic non‐small cell lung cancer (NSCLC). We sought to analyze the impact of histology and biomarker selection criteria on outcomes of clinical trials in metastatic NSCLC reported over the last decade at the American Society of Clinical Oncology (ASCO) Annual Meeting. Data were collected from ASCO abstracts of Phase II–IV clinical trials for patients with metastatic NSCLC from 2004–2014. 770 of 2,989 identified metastatic NSCLC category abstracts met selection criteria. Despite a decline in the number of abstracts from 107 to 46 abstracts annually over this period, the proportion of trials with positive progression free survival (PFS) and overall survival (OS) outcomes has increased significantly. Trials with histology selection (6%) or molecular biomarker (15%) criteria were more likely to result in an improvement in PFS than those without selection criteria (21% vs. 8%, p = 0.0001 and 31% vs. 10%, p < 0.0001, respectively). These data demonstrate profound changes in the clinical trial landscape over the last 10 years with significantly increasing proportion of trials with positive outcomes. These changes are likely attributed to the use of histology and biomarker selection criteria in clinical trial design. Cancer 2014;120:3853–3858.

Bevacizumab in advanced NSCLC: Chemotherapy partners and duration of use

Opinion statementBevacizumab is an effective targeted therapy with demonstrated survival benefits for many patients with advanced nonsquamous non-small cell lung cancer (NSCLC). Some patient populations are at higher risk for bleeding complications and bevacizumab should be avoided, but advanced age should not be used as the sole exclusion criterion for use. Bevacizumab is generally a well-tolerated therapy that can be safely given in combination with multiple chemotherapy agents in the induction and maintenance phases of therapy. The optimal maintenance strategy is yet to be determined and is the focus of ongoing trials, such as ECOG 5508. Early use of bevacizumab in the adjuvant setting and continued use in the second-line setting are being investigated in current clinical trials.

Complex hypereosinophilia arising from post-polycythemia vera myelofibrosis: A case of imatinib-responsiveness.

The classical myeloproliferative neoplasms (MPNs) feature an overproduction of mature blood elements. Phenotypic conversion, including transformation to myelofibrosis (MF) in those with antecedent ET and PV is a feared complication. Hypereosinophilic syndromes (HESs), especially those with myeloproliferative variants, can display similar features, including organomegaly, marrow fibrosis, clonality, thrombotic tendencies, and acute myeloid leukemia (AML) transformation. However, this group of illnesses is typically clinically and molecularly distinct from the classical MPNs. We report a case of a 59-yr-old woman with complex hypereosinophilia in the setting of post-polycythemic myelofibrosis (post-PVMF), with multi-system end-organ damage characteristic of HES.