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First cancer patient in Europe scanned in Cambridge using new technique showing whether drugs work

On April 11, 2016, Cancer Research UK reported that the first cancer patient in Europe has been scanned with a revolutionary imaging technique that could enable doctors to see whether a drug is working within a day or two of starting treatment (Press release, Cancer Research UK, APR 10, 2016, View Source [SID:1234510639]).

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The patient is the first to take part in a new metabolic imaging trial* of patients across a wide range of cancer types to be carried out by Cancer Research UK-funded scientists at Addenbrooke’s Hospital, part of Cambridge University Hospitals. The study, which is funded by a Wellcome Trust Strategic Award, could show whether patients can stop taking drugs that aren’t working for them, try different ones and receive the best treatment for their cancer as quickly as possible.

The rapid scan will allow doctors to map out molecular changes in patients, opening up potential new ways to detect cancer and monitor the effects of treatment.

The technique uses a breakdown product of glucose called pyruvate. The pyruvate is labelled with a non-radioactive form of carbon, called carbon 13 (C-13) which makes it 10,000 times more likely to be detected in a magnetic resonance imaging (MRI) scan. Pyruvate is injected into the patient and tracked as the molecule moves around the body and enters cells. The scan monitors how quickly cancer cells break pyruvate down – a measure of how active the cells are that tells doctors whether or not a drug has been effective at killing them.

Professor Kevin Brindle, co-lead based at the Cancer Research UK Cambridge Institute, said: "We’re very excited to be the first group outside North America, and the third group world-wide, to test this with patients and we hope that it will soon help improve treatment by putting to an end patients being given treatments that aren’t working for them. Each person’s cancer is different and this technique could help us tailor a patient’s treatment more quickly than before."

Dr Ferdia Gallagher, co-lead also funded by Cancer Research UK and based at the Department of Radiology at the University of Cambridge**, said: "It’s fantastic that we can now try this technique in patients. We hope this will progress the way cancer treatment is given and make therapy more effective for patients in the future. This new technique could potentially mean that doctors will find out much more quickly if a treatment is working for their patient instead of waiting to see if a tumour shrinks."

Dr Emma Smith, Cancer Research UK’s science information manager, said: "Finding out early on whether cancer is responding to therapy could save patients months of treatment that isn’t working for them. The next steps for this study will be collecting and analysing the results to find out if this imaging technology provides an accurate early snapshot of how well drugs destroy tumours."

Trial Watch-Oncolytic viruses and cancer therapy.

Oncolytic virotherapy relies on the administration of non-pathogenic viral strains that selectively infect and kill malignant cells while favoring the elicitation of a therapeutically relevant tumor-targeting immune response. During the past few years, great efforts have been dedicated to the development of oncolytic viruses with improved specificity and potency. Such an intense wave of investigation has culminated this year in the regulatory approval by the US Food and Drug Administration (FDA) of a genetically engineered oncolytic viral strain for use in melanoma patients. Here, we summarize recent preclinical and clinical advances in oncolytic virotherapy.

Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine model of breast cancer.

Monoclonal antibodies (mAbs) targeting coinhibitory molecules such as PD-1, PD-L1 and CTLA-4 are increasingly used as targets of therapeutic intervention against cancer. While these targets have led to a critical paradigm shift in treatments for cancer, these approaches are also plagued with limitations owing to cancer immune evasion mechanisms and adverse toxicities associated with continuous treatment. It has been difficult to reproduce and develop interventions to these limitations preclinically due to poor reagent efficacy and reagent xenogenecity not seen in human trials. In this study, we investigated adverse effects of repeated administration of PD-1 and PD-L1 mAbs in the murine 4T1 mammary carcinoma model. We observed rapid and fatal hypersensitivity reactions in tumor bearing mice within 30-60 min after 4-5 administrations of PD-L1 or PD-1 mAb but not CTLA-4 antibody treatment. These events occurred only in mice bearing the highly inflammatory 4T1 tumor and did not occur in mice bearing non-inflammatory tumors. We observed that mortality was associated with systemic accumulation of IgG1 antibodies, antibodies specific to the PD-1 mAb, and accumulation of Gr-1(high) neutrophils in lungs which have been implicated in the IgG mediated pathway of anaphylaxis. Anti-PD-1 associated toxicities were alleviated when PD-1 blockade was combined with the therapeutic HSP90 inhibitor, ganetespib, which impaired immune responses toward the xenogeneic PD-1 mAb. This study highlights a previously uncharacterized fatal hypersensitivity exacerbated by the PD-1/PD-L1 axis in the broadly used 4T1 tumor model as well as an interesting relationship between this particular class of checkpoint blockade and tumor-dependent immunomodulation.

Heparanase: a rainbow pharmacological target associated to multiple pathologies including rare diseases.

In recent years, heparanase has attracted considerable attention as a promising target for innovative pharmacological applications. Heparanase is a multifaceted protein endowed with enzymatic activity, as an endo-β-D-glucuronidase, and nonenzymatic functions. It is responsible for the cleavage of heparan sulfate side chains of proteoglycans, resulting in structural alterations of the extracellular matrix. Heparanase appears to be involved in major human diseases, from the most studied tumors to chronic inflammation, diabetic nephropathy, bone osteolysis, thrombosis and atherosclerosis, in addition to more recent investigation in various rare diseases. The present review provides an overview on heparanase, its biological role, inhibitors and possible clinical applications, covering the latest findings in these areas.

Investigation of the teratogenic potential of VLA-4 antagonist derivatives in rats.

Very late antigen-4 (VLA-4), which is concerned with cell-cell adhesion, plays important roles in development of the heart, and some VLA-4 antagonists cause cardiac anomalies. In this study, we evaluated the teratogenic potential of VLA-4 antagonist derivatives as screening, and investigated the conditions that induce cardiac anomalies. Seventeen compounds were orally administered to pregnant rats throughout the organogenesis period, and fetal examinations were performed. In addition, drug concentrations in the embryos were assayed. As a result, the incidence of ventricular septal defect (VSD) ranged from 0 to 100% depending on the compound. Plasma drug concentrations in the dams were related to increased incidence of VSD; however, these incidences were not increased when the concentration of the compound in the embryos at 24h after dosing was low. It is considered that continuous pharmacological activity in the embryo for more than 24h might disrupt closure of the ventricular septum.
Copyright © 2014. Published by Elsevier Inc.