Jason Kaplan

Repurposing metformin for cancer treatment: current clinical studies

In recent years, several studies have presented evidence suggesting a potential role for metformin in anti-cancer therapy. Preclinical studies have demonstrated several anticancer molecular mechanisms of metformin including mTOR inhibition, cytotoxic effects, and immunomodulation. Epidemiologic data have demonstrated decreased cancer incidence and mortality in patients taking metformin. Several clinical trials, focused on evaluation of metformin as an anti-cancer agent are presently underway. Data published from a small number of completed trials has put forth intriguing results. Clinical trials in pre-surgical endometrial cancer patients exhibited a significant decrease in Ki67 with metformin monotherapy. Another interesting observation was made in patients with breast cancer, wherein a trend towards improvement in cancer proliferation markers was noted in patients without insulin resistance. Data on survival outcomes with the use of metformin as an anti-cancer agent is awaited. This manuscript will critically review the role of metformin as a potential cancer treatment.

Wnt/beta-catenin pathway: modulating anticancer immune response

Wnt/β-catenin signaling, a highly conserved pathway through evolution, regulates key cellular functions including proliferation, differentiation, migration, genetic stability, apoptosis, and stem cell renewal. The Wnt pathway mediates biological processes by a canonical or noncanonical pathway, depending on the involvement of β-catenin in signal transduction. β-catenin is a core component of the cadherin protein complex, whose stabilization is essential for the activation of Wnt/β-catenin signaling. As multiple aberrations in this pathway occur in numerous cancers, WNT-directed therapy represents an area of significant developmental therapeutics focus. The recently described role of Wnt/β-catenin pathway in regulating immune cell infiltration of the tumor microenvironment renewed the interest, given its potential impact on responses to immunotherapy treatments. This article summarizes the role of Wnt/β-catenin pathway in cancer and ongoing therapeutic strategies involving this pathway.

Concordance between genomic alterations assessed by next-generation sequencing in tumor tissue or circulating cell-free DNA

Genomic analysis of tumor tissue is the standard technique for identifying DNA alterations in malignancies. Genomic analysis of circulating tumor cell-free DNA (cfDNA) represents a relatively non-invasive method of assessing genomic alterations using peripheral blood. We compared the concordance of genomic alterations between cfDNA and tissue biopsies in this retrospective study. Twenty-eight patients with advanced solid tumors with paired next-generation sequencing tissue and cfDNA biopsies were identified. Sixty-five genes were common to both assays. Concordance was defined as the presence or absence of the identical genomic alteration(s) in a single gene on both molecular platforms. Including all aberrations, the average number of alterations per patient for tissue and cfDNA analysis was 4.82 and 2.96, respectively. When eliminating alterations not detectable in the cfDNA assay, mean number of alterations for tissue and cfDNA was 3.21 and 2.96, respectively. Overall, concordance was 91.9–93.9%. However, the concordance rate decreased to 11.8–17.1% when considering only genes with reported genomic alterations in either assay. Over 50% of mutations detected in either technique were not detected using the other biopsy technique, indicating a potential complementary role of each assay. Across 5 genes (TP53, EGFR, KRAS, APC, CDKN2A), sensitivity and specificity were 59.1% and 94.8%, respectively. Potential explanations for the lack of concordance include differences in assay platform, spatial and temporal factors, tumor heterogeneity, interval treatment, subclones, and potential germline DNA contamination. These results highlight the importance of prospective studies to evaluate concordance of genomic findings between distinct platforms that ultimately may inform treatment decisions.

Adenoid cystic carcinoma: current therapy and potential therapeutic advances based on genomic profiling

Adenoid cystic carcinoma (ACC) is a rare cancer with high potential for recurrence and metastasis. Efficacy of current treatment options, particularly for advanced disease, is very limited. Recent whole genome and exome sequencing has dramatically improved our understanding of ACC pathogenesis. A balanced translocation resulting in the MYB-NFIB fusion gene appears to be a fundamental signature of ACC. In addition, sequencing has identified a number of other driver genes mutated in downstream pathways common to other well-studied cancers. Overexpression of oncogenic proteins involved in cell growth, adhesion, cell cycle regulation, and angiogenesis are also present in ACC. Collectively, studies have identified genes and proteins for targeted, mechanism-based, therapies based on tumor phenotypes, as opposed to nonspecific cytotoxic agents. In addition, although few studies in ACC currently exist, immunotherapy may also hold promise. Better genetic understanding will enable treatment with novel targeted agents and initial exploration of immune-based therapies with the goal of improving outcomes for patients with ACC.

Outcomes of Patients With Double-Hit Lymphoma Who Achieve First Complete Remission

Purpose Patients with double-hit lymphoma (DHL) rarely achieve long-term survival following disease relapse. Some patients with DHL undergo consolidative autologous stem-cell transplantation (autoSCT) to reduce the risk of relapse, although the benefit of this treatment strategy is unclear. Methods Patients with DHL who achieved first complete remission following completion of front-line therapy with either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or intensive front-line therapy, and deemed fit for autoSCT, were included. A landmark analysis was performed, with time zero defined as 3 months after completion of front-line therapy. Patients who experienced relapse before or who were not followed until that time were excluded. Results Relapse-free survival (RFS) and overall survival (OS) rates at 3 years were 80% and 87%, respectively, for all patients (n = 159). Three-year RFS and OS rates did not differ significantly for autoSCT (n = 62) versus non-autoSCT patients (n = 97), but 3-year RFS was inferior in patients who received R-CHOP compared with intensive therapy (56% v 88%; P = .002). Three-year RFS and OS did not differ significantly for patients in the R-CHOP or intensive therapy cohorts when analyzed by receipt of autoSCT. The median OS following relapse was 8.6 months. Conclusion In the largest reported series, to our knowledge, of patients with DHL to achieve first complete remission, consolidative autoSCT was not associated with improved 3-year RFS or OS. In addition, patients treated with R-CHOP experienced inferior 3-year RFS compared with those who received intensive front-line therapy. When considered in conjunction with reports of patients with newly diagnosed DHL, which demonstrate lower rates of disease response to R-CHOP compared with intensive front-line therapy, our findings further support the use of intensive front-line therapy for this patient population.

Genomic landscape of DNA repair genes in cancer

DNA repair genes are frequently mutated in cancer, yet limited data exist regarding the overall genomic landscape and functional implications of these alterations in their entirety. We created comprehensive lists of DNA repair genes and indirect caretakers. Mutation, copy number variation (CNV), and expression frequencies of these genes were analyzed in COSMIC. Mutation co-occurrence, clinical outcomes, and mutation burden were analyzed in TCGA. We report the 20 genes most frequently with mutations (n > 19,689 tumor samples for each gene), CNVs (n > 1,556), or up- or down-regulated (n = 7,998). Mutual exclusivity was observed as no genes displayed both high CNV gain and loss or high up- and down-regulation, and CNV gain and loss positively correlated with up- and down-regulation, respectively. Co-occurrence of mutations differed between cancers, and mutations in many DNA repair genes were associated with higher total mutation burden. Mutation and CNV frequencies offer insights into which genes may play tumor suppressive or oncogenic roles, such as NEIL2 and RRM2B, respectively. Mutual exclusivities within CNV and expression frequencies, and correlations between CNV and expression, support the functionality of these genomic alterations. This study provides comprehensive lists of candidate genes as potential biomarkers for genomic instability, novel therapeutic targets, or predictors of immunotherapy efficacy.

Blinatumomab for the treatment of acute lymphoblastic leukemia.

SummaryBackgroundAcute lymphoblastic leukemia (ALL) is a potentially fatal disease that involves clonal expansion of early lymphoid progenitor cells. Much of drug development for ALL treatment involves targeting antigens of the clonal cell surface. Blinatumomab belongs to an emerging class of anti-cancer therapeutics referred to as bispecific T-cell engaging antibodies. The Food and Drug Administration approved its use in relapsed or refractory adult Philadelphia chromosome-negative B-cell precursor ALL in December of 2014.Mechanism of action and pharmacodynamicsBlinatumomab contains both an anti-CD3 and anti-CD19 arm, allowing for the juxtaposition of CD3+ T-cells to malignant CD19+ B-cells, thereby resulting in granzyme- and perforin-mediated B-cell apoptosis.Preclinical pharmacologyPreclinical studies suggest that blinatumomab’s efficacy is related to the effector-to-target ratio and to the difference between its affinity for CD19 and CD3.Pharmacokinetics and metabolismPreclinical and early phase clinical studies have allowed for the characterization of the pharmacokinetics of blinatumomab, including the determination of its short half-life. The metabolic pathway has not been fully characterized but is thought to be similar to that of other antibodies.Clinical studiesPhase I and II studies led to the identification of an ideal stepwise dose, involving long-term continuous intravenous infusion (CIVI), to optimize its efficacy and reduce the risk of certain toxicities. A high remission rate and duration were noted among a relapsed/refractory population of patients.SafetyThe results of clinical trials have identified cytokine release syndrome and neurotoxicity, among others, as serious drug-related toxicities, leading to the institution of a Risk Evaluation and Mitigation Strategy.Discussion and conclusionsBlinatumomab represents a significant addition to the treatment options for ALL, but it is not without its limitations, of which are its short-half life, necessitating long-term CIVI, and the eventual emergence of CD19-negative clones. Continual development of the agent involves assessing its role in the frontline setting and in combination with chemotherapy.

Targeting mTOR signaling pathways and related negative feedback loops for the treatment of acute myeloid leukemia

An accumulating understanding of the complex pathogenesis of acute myeloid leukemia (AML) continues to lead to promising therapeutic approaches. Among the key aberrant intracellular signaling pathways involved in AML, the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) axis is of major interest. This axis modulates a wide array of critical cellular functions, including proliferation, metabolism, and survival. Pharmacologic inhibitors of components of this pathway have been developed over the past decade, but none has an established role in the treatment of AML. This review will discuss the preclinical data and clinical results driving ongoing attempts to exploit the PI3K/AKT/mTOR pathway in patients with AML and address issues related to negative feedback loops that account for leukemic cell survival. Targeting the PI3K/AKT/mTOR pathway is of high interest for the treatment of AML, but combination therapies with other targeted agents may be needed to block negative feedback loops in leukemia cells.

Tyrosine kinase inhibitor therapy in chronic myeloid leukemia: update on key adverse events

Current treatment recommendations for chronic myeloid leukemia (CML) are guided by results from multiple clinical trials involving tyrosine kinase inhibitors that target BCR-ABL1. Consideration of the unique clinical benefits and potential risks associated with each tyrosine kinase inhibitor approved for the treatment of CML is crucial for physicians when recommending the most appropriate therapy for each patient. Monitoring for and prompt management of adverse events may increase adherence to therapy and optimize patient outcomes. Here we provide an overview of the efficacy and safety of tyrosine kinase inhibitors approved for the treatment of CML, as well as recommendations for the management of key adverse events reported with these agents in clinical trials involving patients with CML.

Spotlight on lenvatinib in the treatment of thyroid cancer: patient selection and perspectives

Thyroid cancer is the most common endocrine malignancy, with over 60,000 cases reported per year in the US alone. The incidence of thyroid cancer has increased in the last several years. Patients with metastatic differentiated thyroid cancer (DTC) generally have a good prognosis. Metastatic DTC can often be treated in a targeted manner with radioactive iodine, but the ability to accumulate iodine is lost with decreasing differentiation. Until recently, chemotherapy was the only treatment in patients with advanced thyroid cancer, which is no longer amenable to therapy with radioactive iodine. The modest efficacy and significant toxicity of chemotherapy necessitated the need for urgent advances in the medical field. New insights in thyroid cancer biology propelled the development of targeted therapies for this disease, including the tyrosine kinase inhibitor sorafenib as salvage treatment for DTC. In 2015, the US Food and Drug Administration approved a second tyrosine kinase inhibitor, lenvatinib, for the treatment of radioiodine-refractory thyroid cancer. Although associated with a significant progression-free survival improvement as compared to placebo in a large Phase III study (median progression-free survival 18.2 vs 3.6 months; hazard ratio 0.21; 99% confidence interval 0.14–0.31; P<0.001), the benefit of lenvatinib needs to be proved in the context of associated moderate to severe toxicities that require frequent dose reduction and delays. This article reviews the evidence supporting the use of lenvatinib as salvage therapy for radioactive iodine-refractory thyroid cancer, with a focus on the toxicity profile of this new therapy.