Combination Therapy to Improve the Efficacy of Multiple Myeloma-Targeted Nanotherapeutics:
Overview:
The objective of this basic/discovery research project is to develop combination therapies that enhance the efficacy of multiple myeloma killing by the nanotherapeutics being developed in Projects 1 and 2. These combination therapies may lead to the cure of some multiple myeloma patients who relapse or are resistant to the nanotherapeutics being developed in Projects 1 and 2.
Similar to normal hematopoietic stem cells, multiple myeloma cells interact both anatomically and functionally with several components of the bone marrow microenvironment. These microenvironmental components consist of an extracellular matrix rich in fibronectin, collagens, and various proteoglycans as well as several cellular constituents including mesenchymal stromal cells, endothelial cells, osteoblasts, osteoclasts, macrophages, and autonomic neurons. The interactions between these components determine the proliferation, migration and survival of multiple myeloma cells as well as their acquisition of drug resistance and the development of a progressive behavior. We have previously shown that disruption of the CXCL12/CXCR4 axis with small molecule CXCR4 inhibitors renders acute myeloid leukemia and multiple myeloma cells more sensitive to chemotherapy in both preclinical and clinical studies. In Project 3, we are testing if CXCR4, VLA-4 and proteasome inhibitors promote multiple myeloma cell mobilization to the peripheral blood and sensitizes them to the Project 1 and 2 nanotherapeutics.
Malignant cells, including multiple myeloma, have evolved to overcome the phagocytic properties of macrophages via up-regulation of the cell surface molecule CD47. Increased CD47 expression is thought to protect cancer cells from phagocytic clearance by sending a “don’t eat me” signal to macrophages via SIRPα, an inhibitory receptor that prevents phagocytosis of CD47-bearing cells. Anti-CD47 monoclonal antibodies (CD47mAbs) that block the CD47/SIRPα interaction enhance phagocytosis of cancer cells (including multiple myeloma) in vitro and contribute to control of tumor burden in xenograft tumor models. In Project 3, we are testing if CD47mAbs enhance multiple myeloma cell killing by the Project 1 and 2 nanotherapeutics via elicitation of macrophage-mediated tumor regression and tumor toxicity.
Major Accomplishments:
LLP2A is a high-affinity peptidomimetic ligand for VLA-4, and bioconjugates of LLP2A have shown promise as imaging and therapeutic agents. We demonstrated the sensitive and specific molecular imaging of activated VLA-4 on multiple myeloma cells in mice using the PET radiopharmaceutical64 Cu-LLP2A (Soodgupta et al. J. Nucl. Med. 2016;57:640-645). 64 Cu-LLP2A displayed favorable dosimetry for human studies and is a potential imaging candidate for overexpressed and/or activated VLA-4 in multiple myeloma and other malignancies.
We reported at the 2016 American Society of Hematology meeting that activated VLA-4 can be detected on primary human multiple myeloma cells using an optical analog of LLP2A (https://www.bloodjournal.org/content/128/22/2056). These data support the continued development of LLP2A as a molecular diagnostic imaging reagent for multiple myeloma and as a potential therapeutic target of VLA-4 in multiple myeloma.
We established, characterized and compared a myeloma-derived stromal cell line (Myeloma Stromal Puente-1, MSP-1) with two normal stromal cell lines (HS-5 and HS- 27A). MSP-1 was found to affect multiple myeloma proliferation, adhesion, migration and drug resistance in a more profound manner than HS-5 and HS-27A. These results demonstrated the importance of malignant versusnormal BM microenvironment on several key multiple myeloma processes, providing a new myeloma-derived stromal cell line to study the effect of tumor microenvironment on multiple myeloma (De la Puente et al. Haematologica. July 2016;101:e307-e311).