The common and typical induction of osteolytic bone disease in multiple myeloma (MM) led to the notion that bone disease is both a consequence and a necessity of MM progression and metastasis. Our reported and preliminary data suggest that osteoclasts support myeloma cell survival and metastasis through production of certain serine proteases known as dipeptidyl peptidase-IV activity and/or structure homolog (DASH) proteins and that inhibiting activity of osteoclasts or DASH proteases suppresses growth of medullary MM. Conversely, we found that osteoblasts reduce growth of myeloma cells through production of certain small leucine-rich proteoglycans and that increased osteoblast activity in myelomatous bones (from treating with osteoblast-activating agents [parathyroid hormone or anti-DKKI] or with cytotherapy [osteoprogenitor cells]) increases bone formation, creating an inhospitable microenvironment that attenuates MM progression in vivo. Based on these findings, we hypothesize that the microenvironment in existing focal lesions is a critical determinant of long-term survival and dissemination of myeloma cells;therefore, simultaneously inhibiting osteoclast activity and stimulating bone formation is critical for sustaining a patient's response to treatment and for preventing metastasis.
In Specific Aim 1, we will determine whether increased bone formation by bone-anabolic agents (e.g., PTH, anti-DKKI), with or without exogenous osteoblast precursors, will sustain remission induced by clinical agents (e.g., melphalan, dexamethasone, bortezomib, lenalidomide), and/or prevent tumor metastasis upon relapse. We will also investigate molecular mechanisms associated with these effects.
In Specific Aim 2, we will determine whether osteoclast-produced DASH proteases contribute to MM-induced bone disease, support survival of MM in osteolytic lesions, and stimulate metastasis directly by signaling through caveolae and indirectly through reduced retention of myeloma cells by inactivating the central chemokine SDF-1.
In Specific Aim 3, we will determine whether combining treatments to increase activity of osteoblasts and inhibit activity of DASH proteases has superior effects on controlling MM growth and dissemination and on preventing relapse than either individual therapeutic approach. Through interactions with all projects and cores, using our SCID-hu model and coculture systems with primary samples and myeloma cell lines, we will unravel antitumor and antimetastatic effects of factors associated with bone anabolism, as well as molecular mechanisms of DASH proteases in MM using gain-and-loss approaches, specific inhibitors, and recombinant proteins.
Achieving sustained remission and preventing new osteolytic lesions upon relapse are critical goals for improving survival and quality of life of patients with myeloma. Osteoclasts and osteoblasts play critical roles in behavior of myeloma cells during the disease's active and inactive states. Therefore, unraveling the consequences of altered activities of osteoclasts and osteoblasts on tumor dissemination, and understating molecular mechanisms involved, will help in developing novel interventions for myeloma.
|Johnson, Sarah K; Stewart, James P; Bam, Rakesh et al. (2014) CYR61/CCN1 overexpression in the myeloma microenvironment is associated with superior survival and reduced bone disease. Blood 124:2051-60|
|Dhodapkar, Madhav V; Sexton, Rachael; Waheed, Sarah et al. (2014) Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120). Blood 123:78-85|
|Lapteva, Natalia; Szmania, Susann M; van Rhee, Frits et al. (2014) Clinical grade purification and expansion of natural killer cells. Crit Rev Oncog 19:121-32|
|Bam, R; Venkateshaiah, S U; Khan, S et al. (2014) Role of Bruton's tyrosine kinase (BTK) in growth and metastasis of INA6 myeloma cells. Blood Cancer J 4:e234|
|Papanikolaou, X; Rosenbaum, E R; Tyler, L N et al. (2014) Hematopoietic progenitor cell collection after autologous transplant for multiple myeloma: low platelet count predicts for poor collection and sole use of resulting graft enhances risk of myelodysplasia. Leukemia 28:888-93|
|Sawyer, Jeffrey R; Tian, Erming; Heuck, Christoph J et al. (2014) Jumping translocations of 1q12 in multiple myeloma: a novel mechanism for deletion of 17p in cytogenetically defined high-risk disease. Blood 123:2504-12|
|Tian, Erming; Sawyer, Jeffrey R; Heuck, Christoph J et al. (2014) In multiple myeloma, 14q32 translocations are nonrandom chromosomal fusions driving high expression levels of the respective partner genes. Genes Chromosomes Cancer 53:549-57|
|Waheed, Sarah; Mitchell, Alan; Usmani, Saad et al. (2013) Standard and novel imaging methods for multiple myeloma: correlates with prognostic laboratory variables including gene expression profiling data. Haematologica 98:71-8|
|Lamy, Laurence; Ngo, Vu N; Emre, N C Tolga et al. (2013) Control of autophagic cell death by caspase-10 in multiple myeloma. Cancer Cell 23:435-49|
|Sousa, Mirta M L; Zub, Kamila Anna; Aas, Per Arne et al. (2013) An inverse switch in DNA base excision and strand break repair contributes to melphalan resistance in multiple myeloma cells. PLoS One 8:e55493|
Showing the most recent 10 out of 227 publications