Research Projects

In about 85% breast cancer (BC) patients, it metastasizes to the bones, disrupting normal bone physiology and causing bone resorption. In severe cases, surgery to remove metastatic tissue and replace damaged bone with prostheses or bioimplants is performed, but it can lead to critical sized bone defects. However, a small fraction of the lesion can remain at the excision site after surgery, thus increasing the risk for recurrence. To promote bone regeneration and prevent recurrent tumor growth in tandem, it is imperative to develop bifunctional biomaterials that combine tumor therapy and tissue engineering. In this attempt, we believe that drug eluting biomaterials is superior and aids in in-situ bone regeneration and modulates tumor-bone microenvironment. Agents with both anti-tumor and bone-anabolic actions have been tested separately but not in bone defects arising from BC metastasis. To address this, we hypothesize to propose statins, especially simvastatin (SIM), a well-tolerated drug could be the right candidate which is known for its anti-tumor potential and play key roles in bone regeneration. Despite accumulating evidence supporting SIM use, there is no report deciphering its osteogenic role under tumor microenvironment (TME). Another question that puzzles us is, how does SIM modulate the interaction of BC cells with osteoblasts, osteoclasts, mesenchymal stem cells (MSCs) under normal and TME? BC cells can stimulate osteoblasts to produce factors that promote survival of the tumor cells. They can also alter MSCs behavior and functions. Deciphering the answer to this lacuna will enable use of SIM for bone regeneration in BC patients. We will assess the anti-tumor capacity of SIM on proliferation, invasion and metastatic ability of breast cancer cells isolated from patients under invitro and using CAM model. We were also interested to assess its potential to be used as a bifunctional agent to promote bone regeneration and inhibit further tumor progression in BC mediated bone metastasis. To improve the pharmacological effects and minimize off targeting, we intend for in-situ sustained delivery of SIM from a biomaterial with excellent bone regeneration ability. We therefore propose to load, and deliver simvastatin from mesoporous calcium silicate particles (already known for its bone regenerative ability). The biomaterial system will be characterized for its physico-chemical and biological properties. We will also study the osteogenic role of wollastonite loaded with SIM under normal and tumor microenvironment (co-culture) under in vitro. Finally, we will unravel its bone formation ability in critical sized bone defects in rat models and in-house developed zebrafish models with BC mediated bone metastasis. The outcome is expected to unravel the osteogenic mechanisms mediated by SIM under TME.