Bone marrow vascular microenvironment combination RNAi-bortezomib nanotherapy for multiple myeloma

Why is multiple myeloma incurable and such a tricky cancer to treat? Many think that this is due to the ability of multiple myeloma to rapidly mutate, and thus researchers tirelessly work on new therapies to target those mutations. While great advancements have been made in this area of research, multiple myeloma remains incurable. So how else can we improve upon these therapies? What we also know about multiple myeloma is that it has the ability to move across the body very quickly, and invade and hide in bone tissues, which makes the disease very hard to treat. Through recent advancements in multiple myeloma research, we now know that blood vessels in bone marrow release a molecule that 'lure' multiple myeloma from one tissue to another. We also know that these vessels express another molecule that 'latch' onto multiple myeloma cells, allowing them to 'stick' to the new tissues that they are invading. So what if, instead of just targeting the mutations of multiple myeloma with drugs, we also 'shut off' these molecules and thus the ability of multiple myeloma to move and hide in different tissues across the body? Can we make these therapies better for patients by doing this? We can do this with a technology called RNA interference (RNAi), a Nobel-Prize winning discovery that has the potential to silence undraggable targets such as these. However, it very difficult to get RNA molecules inside cells that comprise blood vessels within the body, and requires the development of a 'carrier' to deliver them within these cells. The focus of this research is to develop a nanoparticle carrier, similar to the ones used for the COVID-19 mRNA vaccines, to deliver RNA to these blood vessels in combination with FDA-approved multiple myeloma drugs as an entirely new way to treat this incurable disease. The first part of this grant will focus on developing this nanoparticle carrier, specifically so that it can reach deep into blood vessels of bone marrow where multiple myeloma lies. The second part of the grant will focus on encapsulating the RNA molecules of interest within nanoparticles, to see if they can 'shut' off these molecules of interest in a model of these blood vessel cells in a dish. The last part of the grant with combine the nanoparticle carriers, RNA molecules, and the FDA approved multiple myeloma therapeutic bortezomib, to assess whether this new combination therapy enhances the therapeutic response in a mouse model of multiple myeloma compared to conventional drugs alone. We anticipate that positive results of this research will lead to work with our clinical collaborators at Penn Medicine to rapidly translate this into a novel therapeutic for multiple myeloma patients who sorely need it, particularly for those who are unresponsive to all therapies and survive on the order of only 3-6 months upon diagnosis. But it doesn't end there - since leukemia and lymphoma also spread throughout the body in a similar way, our new technology may have broader implications and can also be used as an entirely new means to treat blood cancers broadly.