Abstract 127P
Background
Bone-resident cancer types such as multiple myeloma, osteosarcoma and metastatic prostate cancer are frequently not amiable to surgery when occupying the bone. For small molecule therapeutics for these cancer types, specific-targeting of the cancer also allows for reduced peripheral toxicity. We know that for bone-resident cancers, their number one characteristic is the recruitment of bone-remodeling cells such as osteoclasts and osteoblasts as they breakdown existing bone and form new bone around the tumor. Another of their characteristics is the acidification of the bone-compartment that they occupy. For these cancer types, the metabolic pathway of mTORC1 is also frequently and constitutively upregulated.
Methods
Small molecule mTORC1 inhibitor, sirolimus, was chemically conjugated to alendronate, a bisphosphanate. The linkage was covalent and acid-cleavable. The molecule was tested for potency in being able to inhibit mTORC1 and being able to bind to the bone-matrix, hydroxyapatite, and being released when exposed to the low pH of a tumor microenvironment. A NOG (NOD/Shi-scid/IL-2Rγnull) mouse model of ectopic bone-resident multiple myeloma (RPMI8226) was established, and the injected molecule was tested for reaching the bone-tumor site (anti-sirolimus detection of the small molecule) and blocking its target (anti-S6 kinase staining of the mouse bone-tumor samples). Blood samples were analyzed for liver and kidney markers of toxicity and mouse weights were monitored.
Results
The conjugated and modified sirolimus was able to reach the tumor site via tail-vein injection and block the activity of its target mTORC1. There was also a sizable decrease in tumor size. In addition, there were no adverse effects in terms of weight loss. There were also no adverse changes in the liver or kidney function from a two-week monitoring of the repeatedly-injected compound.
Conclusions
The modified mTORC1 inhibitor was able to effectively target the bone-resident tumor and reach its target and block it with no overt toxicity. This inhibitor also showed utility in targeting a bone-resident cancer, releasing a specific therapeutic to the remodeled bone in the tumor periphery.
Editorial acknowledgement
Clinical trial identification
Legal entity responsible for the study
Hallym University (S. Korea) Ewha Womans University (S. Korea).
Funding
National Research Foundation of Korea (NRF) funded by the Ministry of Science (S. Korea).
Disclosure
The author has declared no conflicts of interest.
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