Critical role of bone marrow pH as a determinant of multiple myeloma progression and treatment

About This Grant

Significance to VA healthcare mission: Myeloma is an incurable disease of malignant plasma cells that engrafts in the bone marrow (BM). VA patient-related risk factors for MM include age, sex, race (African Americans are twice as likely to develop MM), smoking, and substance abuse. MM is also correlated with exposure to Agent Orange, radiation, and toxic agents, including solvents used in the 1991 Gulf War, a Veteran healthcare priority research area (“Military Service/Deployment Related Occupational Exposures”). MM is often detected at the MGUS stage, which is less malignant but progresses to more aggressive disease at a rate of 12% per year. Since 10% of all MM cases are treated in the VA, and with an aging population, it remains a significant concern to the VA healthcare mission. Innovation and Impact: MM therapies, like proteasome inhibitors, immunomodulatory (IMiDs) drugs, monoclonal antibodies, and steroids, have improved outcomes, but no cure exists. NK- and CAR-T-based immunotherapy are promising, but it is unclear how durable the remissions will be over the long run. The reason(s) for relapse are diverse but may be due to activation of pro-survival pathways induced by the BM niche. While the physiology of the TME plays an essential role in MM pathology, it is poorly understood. Low pO2 conditions result in acidification of the intracellular pH (pHi). The acidic pH activates regulatory survival pathways to remove acidic byproducts, since failure to regulate the pH within a narrow, basic range results in cell death. The process of pumping acidic byproducts from the intracellular compartment into the TME establishes a “pH gradient” that correlates with advanced disease, bone lesions, and treatment-resistant and metastatic MM phenotypes. This provides a therapeutic window for treating MM. To assess this, we will: Aim 1: Determine the role of pH regulation in engrafted MM tumors and test if inhibiting acid/base regulation (alone or in combination with other anti-MM drugs) induces cell death and reduces MM pathology. Aim 2: Test whether the alkalization of the TME reduces or mediates the formation of osteolytic bone lesions in the skeleton and elucidate the mechanisms involved. Aim 3: Define how pH and hypoxia correlate with MM stage using patient BM aspirates, focusing on CD138+ metabolic activity and pH regulation. Methodology: Male and female NSG mice will be challenged with a single IV tail injection of luciferasetransfected human MM cell lines. These cells engraft into the skeleton and can be treated with various inhibitors of acid/base- regulating pathways. We will use MRI and PET/CT to study the development and extent of changes in MM cells (cell death, pH and pO2 levels, formation of bone lesions) in vivo. MRI and PET/CT are non-invasive, so multiple readings can be made of the same mouse, giving us a powerful tool to study MM in situ. We will also confirm the role of pH-regulating pathways using archived MM patient samples. Path to Translation/Implementation: Clinical Trials and Research Directions: Our research will be directed toward developing future clinical trials to assess the efficacy of targeting pH in patients with relapsed/refractory disease. First, combining traditional anti-MM and bone reabsorption treatments with drugs that modulate pH in vivo could enhance treatment outcomes and improve the clinic’s efficacy. Second, we can exploit metabolic pathways involved in acid production (such as glycolysis) that would reduce lactic acid accumulation and alter the tumor’s pH balance, making it less favorable for the survival and progression of MM. Third, we propose developing buffering agents that neutralize acidity and restore normal pH levels within the TME. Finally, we can use pH-sensitive drug delivery systems that release their active components in response to acidic TME.