Feb 24 2016
Osteosarcoma is a cancer present in the bones of adolescents and children. Considered an aggressive cancer, Osteosarcoma has only a 15 per cent, five-year survival rate when detected in an advanced metastatic stage. Every year in the US there are about 800 new cases of osteosarcoma with no suitable treatment.
A new study conducted by Tel Aviv University provides substantial hope of restricting the spread of this disease using a therapeutic pathway. The study also provides the fundamental basic-science for unique nanomedicines, customized to monitor cancer cells in an asymptomatic state.
The proof of concept was initiated by Prof. Ronit Satchi-Fainaro, Chair of the Department of Physiology and Pharmacology at TAU's Sackler Faculty of Medicine and Head of TAU's Cancer Angiogenesis and Nanomedicine Laboratory. This new study is the outcome of a five-year collaboration between Prof. Satchi-Fainaro's team, headed by TAU PhD student Galia Tiram, and the laboratories of Rainer Haag and Marcelo Calderón of Berlin's Frei University. The study was recently featured in ACS Nano.
Finding the switch for cancer cells
We want to keep the cancer 'switch' turned off. Once osteosarcoma metastasizes away from the primary tumor site, there is no effective treatment, just different ways of prolonging life. A 1993 article in the New England Journal of Medicine by William C. Black and H. Gilbert Welch about dormant tumor lesions discovered in the autopsies of people who were considered healthy until their accident-related deaths provided the basis for our research. We decided to investigate osteosarcoma recurrence, with an eye toward the potentially therapeutic value of dormancy.
Professor Satchi-Fainaro, Chair of the Department of Physiology and Pharmacology, TAU
There is the possibility of the reoccurrence of osteosarcoma tumors, even if the tumors are detected and removed from the primary site in the very early stages. In the case of "minimal residual disease," cancerous cells that were removed after surgery in a localized area suddenly reappeared, causing recurrence of the disease. In the other case of "dormant micrometastatic lesions," mini-tumors that were not detected by the existing imaging technologies suddenly reappeared as very big macro-metastases, present primarily in the lungs.
We wanted to understand what causes the cancer cells to 'switch on' in these cases. As long as cancer cells remain asymptomatic and dormant, cancer is a manageable disease. Many people live with thyroid lesions without their knowledge, for example. Ours is a very optimistic approach, and we believe it could apply to other cancers as well.
Professor Satchi-Fainaro, Chair of the Department of Physiology and Pharmacology, TAU
A circuit-breaker for cancer cells?
Prof. Satchi-Fainaro and her research team used mice to develop model pairs of osteosarcoma tumor tissues (part "progressive" cancer, part "silent" cancer) and examined their varied characteristics.
We wanted to examine what was different, because we knew that if we could understand their genesis, then we could understand what kept the tumor tissue dormant. If we could inhibit the growth of cancer, we could target it and keep it dormant.
Professor Satchi-Fainaro, Chair of the Department of Physiology and Pharmacology, TAU
The team arranged microRNAs in the tissue and identified three microRNAs that were expressed in low levels in the aggressive tumor tissue, and in high levels in the dormant tumor tissue. The researchers then placed the microRNA into the tumor tissues in a petri dish and detected a reduced malignant potential, indicated by the cancer cells lack of ability to interact with the normal cells existing in the microenvironment.
We saw that the osteosarcoma cells treated with the selected microRNAs were unable to recruit blood vessels to feed their growth. In order to keep these microRNAs stable in the blood, we needed to encapsulate them in a nanoparticle that circulates in healthy blood vessels, but that disembark and deliver the drug therapy at the leaky blood vessels that exist at tumor sites. We designed a nanomedicine that would have a special activation method at the tumor site in the target cell. The mice treated with the nanomedicine lived for six months, which is the equivalent of 25-odd human years," she reported. "This makes us very optimistic. If we cannot teach tumor cells to be normal, we can teach them to be dormant.
Professor Satchi-Fainaro, Chair of the Department of Physiology and Pharmacology, TAU
Prof. Satchi-Fainaro stated that there is significant potential for this therapeutic approach. Currently she and her team of researchers are examining other tumor types and also planning to shift the current work into clinical trials.
This has huge potential, because the insertion of microRNA affects many, many genes — making it that much more difficult for cancer to avoid them and compensate for their loss with an alternative pathway. I hope our findings will apply to other tumor types as a universal approach to treating cancer.
Professor Satchi-Fainaro, Chair of the Department of Physiology and Pharmacology, TAU