A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN®), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-naïve patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥ 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that pelareorep complements single agent gemcitabine in PDAC

Kinetics in signal transduction pathways involving promiscuous oligomerizing receptors can be determined by receptor specificity: Apoptosis induction by TRAIL

Here we show by computer modeling that kinetics and outcome of signal transduction in case of hetero-oligomerizing receptors of a promiscuous ligand largely depend on the relative amounts of its receptors. Promiscuous ligands can trigger the formation of non-productive receptor complexes, which slows down the formation of active receptor complexes and thus can block signal transduction. Our model predicts that increasing the receptor-specificity of the ligand without changing its binding parameters should result in faster receptor activation and enhanced signaling. We experimentally validated this hypothesis using the cytokine Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) and its four membrane-bound receptors as an example. Bypassing ligand-induced receptor hetero-oligomerization by receptor-selective TRAIL variants enhanced the kinetics of receptor activation and augmented apoptosis. Our results suggest that control of signaling pathways by promiscuous ligands could result in apparent slow biological kinetics and blocking signal transmission. By modulating the relative amount of the different receptors for the ligand, signaling processes like apoptosis can be accelerated or decelerated and even inhibited. It also implies that more effective treatments using proteins therapeutics could be achieved simply by altering specificity.Here we show by computer modeling that kinetics and outcome of signal transduction in case of hetero-oligomerizing receptors of a promiscuous ligand largely depend on the relative amounts of its receptors. Promiscuous ligands can trigger the formation of non-productive receptor complexes, which slows down the formation of active receptor complexes and thus can block signal transduction. Our model predicts that increasing the receptor-specificity of the ligand without changing its binding parameters should result in faster receptor activation and enhanced signaling. We experimentally validated this hypothesis using the cytokine Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) and its four membrane-bound receptors as an example. Bypassing ligand-induced receptor hetero-oligomerization by receptor-selective TRAIL variants enhanced the kinetics of receptor activation and augmented apoptosis. Our results suggest that control of signaling pathways by promiscuous ligands could result in apparent slow biological kinetics and blocking signal transmission. By modulating the relative amount of the different receptors for the ligand, signaling processes like apoptosis can be accelerated or decelerated and even inhibited. It also implies that more effective treatments using proteins therapeutics could be achieved simply by altering specificity

The Landscape of Targeted Therapies in TNBC

Triple negative breast cancer (TNBC) constitutes the most aggressive molecular subtype among breast tumors. Despite progress on the underlying tumor biology, clinical outcomes for TNBC unfortunately remain poor. The median overall survival for patients with metastatic TNBC is approximately eighteen months. Chemotherapy is the mainstay of treatment while there is a growing body of evidence that targeted therapies may be on the horizon with poly-ADP-ribose polymerase (PARP) and immune check-point inhibitors already established in the treatment paradigm of TNBC. A large number of novel therapeutic agents are being evaluated for their efficacy in TNBC. As novel therapeutics are now incorporated into clinical practice, it is clear that tumor heterogeneity and clonal evolution can result to de novo or acquired treatment resistance. As precision medicine and next generation sequencing is part of cancer diagnostics, tailored treatment approaches based on the expression of molecular markers are currently being implemented in clinical practice and clinical trial design. The scope of this review is to highlight the most relevant current knowledge regarding underlying molecular profile of TNBC and its potential application in clinical practice

Treatment of proliferative disorders with a death receptor agonist

A method of treating a proliferative disorder, and a pharmaceutical composition for use in such a method, comprises administering to the patient a combination of an agonist of a death receptor and an antagonist of Egr-1. The death receptor agonist and the Egr-1 antagonist may be administered sequentially, separately or in combinatio

Current State of Liver-Directed Therapies and Combinatory Approaches with Systemic Therapy in Hepatocellular Carcinoma (HCC)

The increasing set of liver-directed therapies (LDT) have become an integral part of hepatocellular carcinoma (HCC) treatment. These range from percutaneous ablative techniques to arterial embolization, and varied radiotherapy strategies. They are now used for local disease control, symptom palliation, and bold curative strategies. The big challenge in the face of these innovative and sometimes overlapping technologies is to identify the best opportunity of use. In real practice, many patients may take benefit from LDT used as a bridge to curative treatment such as resection and liver transplantation. Varying trans-arterial embolization strategies are used, and comparison between established and developing technologies is scarce. Also, radioembolization utilizing yttrium-90 (Y-90) for locally advanced or intermediate-stage HCC needs further evidence of clinical efficacy. There is increasing interest on LDT-led changes in tumor biology that could have implications in systemic therapy efficacy. Foremost, additional to its apoptotic and necrotic properties, LDT could warrant changes in vascular endothelial growth factor (VEGF) expression and release. However, trans-arterial chemoembolization (TACE) used alongside tyrosine-kinase inhibitor (TKI) sorafenib has had its efficacy contested. Most recently, interest in associating Y-90 and TKI has emerged. Furthermore, LDT-led differences in tumor immune microenvironment and immune cell infiltration could be an opportunity to enhance immunotherapy efficacy for HCC patients. Early attempts to coordinate LDT and immunotherapy are being made. We here review LDT techniques exposing current evidence to understand its extant reach and future applications alongside systemic therapy development for HCC

Optimizing outcomes in patients with chronic myeloid leukemia in chronic phase: comparative safety profiles of newer agents

Imatinib is broadly used in the frontline treatment of chronic myeloid leukemia (CML). Although long-term safety and efficacy have been established, some patients will not respond to imatinib. Nilotinib and dasatinib successfully recapture responses for most patients with imatinib-refractory or -intolerant disease. These drugs have different safety profiles, which are likely associated with their divergent inhibitory targets. The presence of Bcr-Abl mutations and safety profiles of available therapies in relation to patient history should be considered when choosing a second-line agent. This review evaluates the safety and tolerability of agents approved for CML treatment and briefly discusses newer third-line agents

Nilotinib: optimal therapy for patients with chronic myeloid leukemia and resistance or intolerance to imatinib

Ronan Swords, Devalingam Mahalingam, Swaminathan Padmanabhan, Jennifer Carew, Francis GilesInstitute for Drug Development, Cancer Therapy and Research Centre, University of Texas Health Science Centre at San Antonio, USAAbstract: Chronic myeloid leukemia (CML) is the consequence of a single balanced translocation that produces the BCR-ABL fusion oncogene which is detectable in over 90% of patients at presentation. The BCR-ABL inhibitor imatinib mesylate (IM) has improved survival in all phases of CML and is the standard of care for newly diagnosed patients in chronic phase. Despite the very significant therapeutic benefits of IM, a small minority of patients with early stage disease do not benefit optimally while IM therapy in patients with advanced disease is of modest benefit in many. Diverse mechanisms may be responsible for IM failures, with point mutations within the Bcr-Abl kinase domain being amongst the most common resistance mechanisms described in patients with advanced CML. The development of novel agents designed to overcome IM resistance, while still primarily targeted on BCR-ABL, led to the creation of the high affinity aminopyrimidine inhibitor, nilotinib. Nilotinib is much more potent as a BCR-ABL inhibitor than IM and inhibits both wild type and IM-resistant BCR-ABL with significant clinical activity across the entire spectrum of BCR-ABL mutants with the exception of T315I. The selection of a second generation tyrosine kinase inhibitor to rescue patients with imatinib failure will be based on several factors including age, co-morbid medical problems and ABL kinase mutational profile. It should be noted that while the use of targeted BCR-ABL kinase inhibitors in CML represents a paradigm shift in CML management these agents are not likely to have activity against the quiescent CML stem cell pool. The purpose of this review is to summarize the pre-clinical and clinical data on nilotinib in patients with CML who have failed prior therapy with IM or dasatinib.Keywords: nilotinib, chronic myeloid leukemia, imatini

Serosal inflammation (pleural and pericardial effusions) related to tyrosine kinase inhibitors

Tyrosine kinase inhibitors (TKIs) have dramatically changed the treatment of chronic myeloid leukemia (CML) and are increasingly used in other malignancies. Despite the apparent selectivity of these agents significant side effects can occur mainly due to off target kinase inhibition. Clinical consequences of serosal inflammation, including pleural and pericardial effusions, have emerged as a frequent adverse event associated with dasatinib while occurring much less frequently during imatinib and nilotinib therapy. The pathogenesis is uncertain but may involve inhibition of platelet derived growth factor or expansion of cytotoxic T and natural killer cells. The development of serosal inflammation with dasatinib poses a significant challenge to physicians, as it cannot be predicted, the time of onset is variable, and management frequently requires repeat invasive procedures

TRAIL receptor signalling and modulation: Are we on the right TRAIL?

Tumour necrosis factor-related apoptosis-inducing ligand or Apo2 ligand (TRAIL/Apo2L) is a member of the turnout necrosis factor (TNF) superfamily of cytokines that induces apoptosis upon binding to its death domain-containing transmembrane receptors, death receptors 4 and 5 (DR4, DR5). Importantly, TRAIL preferentially induces apoptosis in cancer cells while exhibiting little or no toxicity in normal cells. To date, research has focused on the mechanism of apoptosis induced by TRAIL and the processes involved in the development of TRAIL resistance. TRAIL-resistant tumours can be re-sensitized to TRAIL by a combination of TRAIL with chemotherapeutics or irradiation. Studies suggest that in many cancer cells only one of the two death-inducing TRAIL receptors is functional. These findings as well as the aim to avoid decoy receptor-mediated neutralization of TRAIL led to the development of receptor-specific TRAIL variants and agonistic antibodies. These molecules are predicted to be more potent than native TRAIL in vivo and may be suitable for targeted treatment of particular tumours. This review focuses on the current status of TRAIL receptor-targeting for cancer therapy, the apoptotic signalling pathway induced by TRAIL receptors, the prognostic implications of TRAIL receptor expression and modulation of TRAIL sensitivity of turnout cells by combination therapies. The mechanisms of TRAIL resistance and the potential measures that can be taken to overcome them are also addressed. Finally, the status of clinical trials of recombinant TRAIL and DR4-/DR5-specific agonistic antibodies as well as the pre-clinical studies of receptor-selective TRAIL variants is discussed including the obstacles facing the use of these molecules as anti-cancer therapeutics. (C) 2008 Elsevier Ltd. All rights reserved

Cdc7 kinase – A new target for drug development

The cell division cycle 7 (Cdc7) is a serine threonine kinase that is of critical importance in the regulation of normal cell cycle progression. Cdc7 kinase is highly conserved during evolution and much has been learned about its biological roles in humans through the study of lower eukaryotes, particularly yeasts. Two important regulator proteins, Dbf4 and Drf1, bind to and modulate the kinase activity of human Cdc7 which phosphorylates several sites on Mcm2 (minichromosome maintenance protein 2), one of the six subunits of the replicative DNA helicase needed for duplication of the genome. Through regulation of both DNA synthesis and DNA damage response, both key functions in the survival of tumour cells, Cdc7 becomes an attractive target for pharmacological inhibition. There are much data available on the pre-clinical anti-cancer effects of Cdc7 depletion and although there are no available Cdc7 inhibitors in clinical trials as yet, several lead compounds are being optimised for this purpose. In this review, we will address the current status of Cdc7 as an important target for new drug development