CANCER: Therapeutic

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Thursday, June 13, 2013

Novel Therapeutic Approach To Treating Inflammation In Cardiovascular Disease

Main Category: Heart Disease
Also Included In: Immune System / Vaccines;??Cancer / Oncology
Article Date: 07 May 2013 - 1:00 PDT Current ratings for:
Novel Therapeutic Approach To Treating Inflammation In Cardiovascular Disease
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Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs, an established treatment for cancer patients, could offer a novel therapeutic approach to decrease levels of inflammation in the atherosclerotic plaques of patients with cardiovascular disease (CVD), reported an abstract1 study at the International Conference on Nuclear Cardiology and Cardiac CT, May 5 to 8 in Berlin, Germany.

"Our results should act as a stimulus for further exploration of radionuclide based interventions in atherosclerosis. Ultimately such therapies might be used to lower the degree of inflammation in atherosclerosis which has the potential to reduce the occurrence of heart attacks," said Imke Schatka, the first author of the study from the Department of Nuclear Medicine at Hannover Medical School, Germany.

PRRT is a technique currently used to treat patients with metastatic neuroendocrine tumours (NETS), a diverse group of malignancies deriving from the neuroendocrine cell system (the most frequent locations being pancreas, small intestine and lung).

The discovery of over expression of somatostatin receptors (SSTR) on NET tumours first opened the way for development of radiolabelled somatostatin analogs to image tumours during PET/CT scans. DOTATATE is a somatostatin receptor (SSTR) ligand targeting SSTR-2, a receptor known to be expressed on 70% of NET tumours. Once tumours have been visualized, it is possible to target therapy by attaching the beta-emitter 1?? Lutetium (1??Lu) to the ligand.

Active inflammation has been widely implicated in the initiation, progression and disruption of vulnerable plaques, and consequently offers an emerging target for the imaging and treatment of atherosclerosis. "Since SSTR-2 receptors are also expressed on macrophages we speculated that DOTATATE-PET/CT might be used to detect vulnerable plaques and that a PRRT procedure could reduce inflammation in the arterial wall," explained Schatka.

For the current study, 11 patients (from a group of 165 undergoing PRRT for NET tumours) were retrospectively identified because they met the criteria of only receiving the beta emitter1??Lu treatment after undergoing two consecutive scans, with a third scan following treatment.

For each of the three scans, vessel wall uptake of the DOTATATE ligand was measured in six arterial segments of PET images (carotid, aortic arch, ascending, descending, abdominal aorta, and iliac arteries) and then the overall vessel uptake was determined for each individual patient.

Results showed that for the first scan the overall vessel uptake of the ligand correlated with the age of the patient (P<0.01), the number of calcified plaques (P<0.001) and furthermore was higher in subjects with hypercholesterolemia (p=0.04). No significant differences in overall vessel uptakes were found between scans 1 and 2, confirming reproducibility in the absence of treatment.

However, when treatment with the beta-emitter 1?? Lu-DOTATATE was delivered following scan 2, scan 3 showed significant reductions in the overall vessel uptake of the ligand when compared with both scan 1 (p=0.001) and scan 2 (p=0.004).

"Uptake of the ligand can be considered to be a measure of the quantity of SSTR receptors, which in turn is likely to correlate with the number of activated macrophages and the extent of the inflammatory process," explained Schatka. "Our results suggest that treatment has had a beneficial effect in reducing inflammation."

The next step, said Schatka, would be to get histological proof that reductions in inflammation really had been imaged with DOTATATE-PET/CT by looking at carotid artery samples removed from patients during routine surgery.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our heart disease section for the latest news on this subject. 1. I Schatka, T Wollenweber, C Haense, et al. Peptide receptor radionuclide therapy decreases inflammation in atherosclerotic plaques, as quantified by 68Ga-DOTATATE PET/CT. Abstract no 70100.
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Sunday, June 2, 2013

Potential Therapeutic Target Discovered For Cushing's Disease

Main Category: Cancer / Oncology
Also Included In: Neurology / Neuroscience;??Endocrinology
Article Date: 10 May 2013 - 0:00 PDT Current ratings for:
Potential Therapeutic Target Discovered For Cushing's Disease
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Scientists at the Salk Institute for Biological Studies have identified a protein that drives the formation of pituitary tumors in Cushing's disease, a development that may give clinicians a therapeutic target to treat this potentially life-threatening disorder.

The protein, called TR4 (testicular orphan nuclear receptor 4), is one of the human body's 48 nuclear receptors, a class of proteins found in cells that are responsible for sensing hormones and, in response, regulating the expression of specific genes. Using a genome scan, the Salk team discovered that TR4 regulates a gene that produces adrenocorticotropic hormone (ACTH), which is overproduced by pituitary tumors in Cushing's disease (CD). The findings were published in the early online edition of Proceedings of the National Academy of Sciences.

"We were surprised by the scan, as TR4 and ACTH were not known to be functionally linked," says senior author Ronald M. Evans, a professor in Salk's Gene Expression Laboratory and a lead researcher in the Institute's Helmsley Center for Genomic Medicine. "TR4 is driving the growth and overexpression of ACTH. Targeting this pathway could therapeutically benefit treatment of CD."

In their study, Evans and his colleagues discovered that forced overexpression of TR4 in both human and mouse cells increased production of ACTH, cellular proliferation and tumor invasion rates. All of these events were reversed when TR4 expression was reduced.

First described more than 80 years ago, Cushing's disease is a rare disorder that is caused by pituitary tumors or excess growth of the pituitary gland located at the base of the brain. People with CD have too much ACTH, which stimulates the production and release of cortisol, a hormone that is normally produced during stressful situations.

While these pituitary tumors are almost always benign, they result in excess ACTH and cortisol secretion, which can result in various disabling symptoms, including diabetes, hypertension, osteoporosis, obesity and psychological disturbances. Surgical removal of the tumors is the first-line therapy, with remission rates of approximately 80 percent; however, the disease recurs in up to 25 percent of cases.

Drugs such as cabergoline, which is used to treat certain pituitary tumors, alone or in combination with ketoconazole, a drug normally used to treat fungal infections, have been shown to be effective in some patients with Cushing's disease. More recently, mefipristone-best known as the abortion pill RU-486-was approved by the FDA to treat CD. Despite these advances in medical therapy, the Salk scientists say additional therapeutic approaches are needed for CD.

"Pituitary tumors are extremely difficult to control," says Michael Downes, a senior staff scientist in the Gene Expression Laboratory and a co-author of the study. "To control them, you have to kill cells in the pituitary gland that are proliferating, which could prevent the production of a vital hormone."

Previous studies have found that, by itself, TR4 is a natural target for other signaling molecules in the pituitary. Small-molecule inhibitors that have been developed for other cancers could be potentially applied to disrupt this signaling cascade. "Our discovery," says Evans, a Howard Hughes Medical Institute investigator and holder of the March of Dimes Chair in Molecular and Developmental Biology, "might lead clinicians to an existing drug that could be used to treat Cushing's disease."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject. Other researchers on the study were Li Du, Marvin Bergsneider, Leili Mirsadraei, Stephen H. Young, William H. Yong and Anthony P. Heaney of the David A. Geffen School of Medicine at the University of California, Los Angeles, and Johan W. Jonker of the University of Groningen.
The study was supported by the National Institutes of Health, the Leona M. and Harry B. Helmsley Charitable Trust, the Samuel Waxman Cancer Research Foundation, the Jonsson Comprehensive Cancer Center at UCLA, and Ipsen/Biomeasure.
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