Engineered stem cells could help treat metastatic cancers in bone without killing normal surrounding bone, according to new research.
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Many cancers originating in other parts of the body produce bone metastases. Breast cancer is notorious for forming tumor deposits in far-away bones in up to 70% of cases. These are difficult to treat and cause severe pain and disability in cancer patients. In the US alone, more than 350,.000 cancer patients die each year with bone metastases.
The problem with bone metastases is that the cancer cells release factors that promote the formation of bone-destroying cells called osteoclasts around the tumor. This causes increased bone resorption, which in turn results in the release of compensatory growth factors to promote bone repair. These, however, stimulate tumor growth.
This vicious cycle between the bone microenvironment (the “soil”) and the breast cancer cells (the “seed”) is responsible for the increased rate of cancer growth and rapid destruction of bone.
No existing therapeutic strategy including surgery, chemotherapy, radiation or hormonal manipulation, can selectively target the tumor without adversely affecting surrounding normal bone. This makes these therapies both less effective and highly toxic.
Doctors till do not understand how drugs which are intended to prevent bone resorption, like bisphosphonates and RANKI antibodies, act on tumor growth. Combinations of these therapies have proved ineffective, highly toxic, and associated with new metastases, cancer relapse, and drug resistance.
Nanoparticle-based targeting systems are still in their infancy. All this means the five-year survival rate for metastatic breast cancer is only about 20% even with modern advances in treatment.
Treating metastases with stem cells
The current approach involved using anti-tumor and anti-bone resorptive agents to treat both the seed and the soil. It was developed by researchers at the University of California, Irskine.
They introduced specific messenger RNA (mRNA) into mesenchymal stem cells to drive the transcription and production of specific proteins that enable them to home in on the sites of cancer metastases in the bones. These molecules include P-selectin glycoprotein ligand-1 (PSGL-1)/Sialyl-Lewis X (SLEX), which target the selectin molecules that are abundant on the tumor cells.
Once the stem cells reach the bone metastatic site, they dump their payload of therapeutic factors. These are altered versions of a tumor-killing factor, cytosine deaminase (CD) complexed with a chemotherapeutic drug precursor(5-fluorocytosine), and osteoprotegerin (OPG), a natural RANKI receptor that suppresses osteoclast production. These then act to destroy the tumor cells while simultaneously inhibiting bone resorption.
This was tested out in several different models of bone metastasis. The study is published in the journal EBioMedicine.
Mesenchymal stem cells are ideal for this technique as they target the bone marrow and tumor sites very selectively. The scientists used their mRNA engineering technology to introduce a combination of factors that select the site for the cells to home on to and destroy the tumor while preserving the bone from tumor-mediated resorption. This makes these engineered stem cells a powerful platform to deliver combination therapy that inhibits the vicious cycle of tumor growth leading to bone resorption.
This technology is simple, safe to use as it avoids genetic engineering, allows for rapid production of CD and OPG proteins after transfecting the cancer cells, and can be used to deliver multiple factors to the tumor site at the same time for optimal effect. Moreover, the stem cells are typically killed with the cancer cells soon after the prodrug is converted to its active form, avoiding their persistence in the body.
The outstanding benefit of the new technique is that it produces no ill effects on the bone surrounding the tumor metastasis compared to other therapies.
What's powerful about this strategy is that we deliver a combination of both anti-tumor and anti-bone resorption agents so we can effectively block the vicious circle between cancers and their bone niche. This is a safe and almost nontoxic treatment compared to chemotherapy.”
Weian Zhao, Lead Author
This treatment platform is capable of being personalized to treat patients according to their disease characteristics, type of tumor and stage. This could be adapted to use for other non-malignant bone diseases which resist traditional management, such as osteoporosis and multiple myeloma.
The stem cell used is already approved for clinical use, and thus a clinical trial of the novel therapy can be carried out in short order. The researchers want to treat patients who have bone metastases in the trial.
They also expect that the technique, being of modular design, can be modified to treat many other cancers and diseases by using different types of cells and payloads.
Eurekalert.org. (2019). UCI team pioneers cancer treatment that targets bone metastases while sparing bone.
Segaliny A. L., et al., (2019). Combinatorial targeting of cancer bone metastasis using mRNA engineered stem cells. EBioMedicine. doi.org/10.1016/j.ebiom.2019.06.047