Many researchers are studying effects of treatment and injury on the molecular level. SARRP allows the researcher to target specific organs or regions with a collimator as small as 0.5mm.
When a tumor is in a region, the normal tissue changes its microenvironment. The tumor causes certain pathways to be inhibited and others to work more effectively. This allows the normal tissue to work for the tumor. When these pathways are studied they can be manipulated by researchers and the effects may change the tumor microenvironment to the detriment of the tumor. Radiation therapy is used in many types of tumors that are hard to treat. Using these pathways plus radiation added benefits can be available. SARRP allows the researcher to target specific organs or regions with a collimator as small as 0.5mm.
With the different tumor mechanisms, these multi-modality approaches may offer curative outcomes in preclinical studies. The SARRP can be used to target specific areas to cause an immune response that immunological agents may react to.
These preclinical immunotherapy plus radiation treatments offer compelling evidence to further these types of studies
Using an orthotopic GBM model, Anti-PD-1 was studied alone and in combination with stereotactic radiotherapy. A 3mm x 3mm nozzle was used to surround the tumor based on CBCT guidance. There were four arms in this study: Control, Anti-PD-1 only, Radiation only, Radiation plus Anti-PD-1. The radiation was given in one fraction of 10Gy 10 days after implantation of GBM. The SARRP was able to identify on CBCT and target only the brain of the mouse allowing for high dose escalation. Anti-PD-1 was given on day 10, 12, and 14 after implantation. Survival with immunotherapy alone was 27 days, radiotherapy alone was 28 days and combination therapy was 53 days.
Interestingly enough, the mice with no visible tumor were re-challenged on day 90 by the addition of a flank tumor. None of the mice showed visible tumor after 3 weeks as compared to the control which did show tumor in the same timeline.
SARRP was featured in the 2014 ASTRO Annual Meeting – Plenary Session http://www.softconference.com/astro/SessionDetail.asp?SID=367995. The session was titled: Radiotherapy combined with anti-PD-1 Checkpoint Blockade Immunotherapy: A Promising Future Direction. Andrew Sharabi, M.D./Ph.D. Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins
These change as the cell changes (ex. tumor volumes). Following these pathways in normal and cancerous tissue can help aid in treatment. Some pathways are able to inhibit tumor growth or aid in regrowth of the tumor. Some pathways allow the tumor to be more susceptible to radiation called radiosensitizers. In cases where radiation is a common course of treatment but not very effective, radiosensitizers can increase the benefit from this treatment in a great way.
SARRP offers ways to specifically target organs or regional areas to study radiosensitizers plus radiation for specific purposes. The target can be as small as 0.5mm.
Heat Shock Protein 90 (Hsp90) is overexpressed in prostate cancer compared to surrounding normal tissue. This protein affects many pathways that allow for Radiosensitization. Hsp90 was found to only affect tumor cells. AUY922 is a HSP90 inhibitor. It is implicated in Radiosensitization in immunocompromised and immunocompetent and androgen-dependent and AR-null. Using the SARRP machine the researchers were able to target the prostate while avoiding nearby organs that would be affected by Radiation. Radiation Therapy plus AUY922 produced tumor growth delay compared to radiation alone or AUY922 alone. These researchers are the first to study AUY922 in prostate cancer and want to focus on the importance of adding radiation to the treatment for added benefit.
The vasculature, signaling molecules, extracellular matrix and immune cells all have an effect on how the tumor will grow and change. Depending on how the tumor microenvironment changes the tumor one may be able to predict how the tumor will react to specific treatments.
A study of the effects of radiation induced injury on a specific part of the bone. Utilizing SARRP, researchers were able to irradiate the distal half of a mouse left femur to 4Gy once a day for 5 days. They looked at the bone changes and the bone cell changes. They found that there were changes in the distal left femur after a week but no changes in the proximal left femur. Then they looked at mesenchymal stem cells (MSC) to evaluate the bone microenvironment. MSC were not observed at any part of the left femur but where were found in the right femur. Four weeks later, MSCs were beginning to form in the left proximal femur but not the distal portion. Mesenchymal stem cells survival was affected the addition of free radicals created during irradiation of the bone only affecting the irradiated side.
As a tumor grows the vasculature cannot handle the burden. This gives varied levels of oxygenation through the cells in the tumor. This can have dramatic effects in treatment options and therefore is a popular area of study.
Current descriptions of hypoxia characterize it as small isolated foci interspersed with oxic tissue. On a larger level these foci of hypoxia are disorganized due to an unknown distance of oxygen diffusion. This group is studying hypoxia in regional areas based on the hypoxia marker EF5. The information they found suggests that oxic sources spread to poorly oxygenated sources larger that than originally believed. This distance is called longitudinal arteriole gradients. This novel concept allows the blood flow to become organized on a macroscopic level. This may have effects in the temporal and spatial distribution of tumor hypoxia. Using the SARRP, these researchers irradiated a portion of the tumor and used gH2AX stain to show the DNA damage. This damaged area correlated to higher levels of oxygen therefore using this to show oxic and hypoxic areas.