Agents Targeting Prostate Cancer Bone Metastasis
UroToday.com – Advanced prostate cancers regularly metastasize to the skeleton, and better treatments are needed to decrease morbidity and increase survival in men with end-stage disease. Metastatic prostate cancer cells alter the bone microenvironment in two ways:
1) they stimulate formation of disorganized new bone with poor biomechanical quality;
2) they stimulate bone remodeling by activating osteoclasts.
These two steps offer unique adjuvant targets to supplement conventional anti-tumor therapies. Drugs against osteoclasts include classes of anti-resorptive agents developed against osteoporosis. In addition to the approved bisphophonates, inhibitors are in Phase III trials against osteoclast-selective targets cathepsin K and RANK ligand. Pathological bone in osteoblastic lesions may be caused by prostate-secreted endothelin-1, whose actions are blocked by endothelin receptor antagonists in Phase III trials. The status of these drugs is reviewed in the linked title article. Bone metastases provide a novel paradigm for cancer treatment: adjuvant therapy aimed at the metastatic microenvironment (rather than the tumor itself) can reduce tumor burden and decrease morbidity and mortality. Such therapy can increase the efficacy of conventional cytotoxic agents to kill tumor within bone (1,2), where it is otherwise resistant to treatment. The next step beyond the abstract is to develop more adjuvant therapies that target the microenvironment. The agents described above were developed for non-cancer indications: anti-resorptives for osteoporosis and endothelin antagonists for pulmonary hypertension. They were easily tested in animal models and rapidly brought to clinical trials, since their pharmacokinetics and safety profiles were known. How will we go about testing new mechanisms? For example, the authors have preliminary data that the tumor-secreted peptide adrenomedullin might be a good target for adjuvant therapy, but there are no drugs ready to test in laboratory animals, which is also a slow and expensive approach. Direct anti-tumor drugs are first tested against growth of tumor cells in vitro, but bone metastases do not form in vitro. It would be risky to develop drugs in vitro to find out that the drug target was not important in vivo. Read more
‘Junk DNA’ Could Spotlight Breast And Bowel Cancer
Cancer Research UK funded scientists have found that a group of rogue genetic messengers, produced by DNA sequences commonly known as ‘junk DNA’, could help diagnose breast and bowel cancer. Their research is published in the journal Genomics.
The researchers, led by Dr Cristina Tufarelli at the University of Nottingham, discovered that seven of these faulty genetic messengers – known as chimeric transcripts – are more common in breast cancer cells. Five were only present in breast cancer cells while two were found in both normal and breast cancer cells.
These rogue messengers are produced by DNA sequences called LINE-1 (L1). Despite being labelled as ‘junk DNA’ it is clear that some of these sequences have important roles in the genome, such as influencing when genes are switched on.
L1s carry a switch that is able to randomly turn on nearby genes. When genes are inappropriately switched on in this way, they make the rogue genetic messengers that can sabotage the normal functioning of cells. To prevent the potentially damaging effects of these rogue elements, normal cells silence L1s with a chemical ‘off switch’. Read more