Multiple myeloma (MM) is a neoplasm of bone marrow (BM) resident long-lived plasma cells (LLPC) that comprises 20% of all hematologic malignancies - second only to non-Hodgkin?s lymphoma. Despite new chemotherapeutic agents, MM remains incurable. Although initially sensitive to chemotherapy, the primary cause of treatment failure is the development of progressively more chemo-refractory disease whose resistance is due to upregulation of pro-survival mechanisms. Thus defining the specific mechanisms of myeloma cell survival/drug resistance is essential for the development of curative treatment approaches in MM. It is now clear that myeloma cells are critically dependent on interactions with BM microenvironment (ME) for their survival, just like their normal LLPC counterparts, and these interactions play a major role in MM resistance to chemotherapy. Despite their central importance in myeloma survival however, the specific molecular and cellular components involved in these interactions remain poorly characterized. In our original proposal, we hypothesized that CD28 was playing significant pro-survival role in myeloma. Although it has been primarily characterized as the prototype T cell costimulatory receptor involved in T cell activation and survival, CD28 is also expressed on normal PC and MM. Work accomplished during the last funding cycle has demonstrated that CD28 activation through two downstream signaling pathways plays an essential role in the survival of both normal LLPC and MM cells, and that therapeutically blocking CD28 activation leads to MM cell death/resensitization to chemotherapy in preclinical in vivo models. Based on these findings and initial evidence for clinical efficacy, we have just opened a phase II clinical trial of blocking CD28 activation in refractory/relapsed MM (NCT02334865) More recently, we have found that CD28 activation substantially enhances the metabolic fitness of MM cells, which plays a major role in its pro-survival effect. In addition to directly supporting MM survival, we have found that MM CD28 also modulates the MM ME. CD28 engagement of its ligands CD80 and CD86 on stromal dendritic cells (DC) initiates CD80/CD86 ?backsignaling? that induces DC production of the pro-MM survival cytokine IL-6 and the immunosuppressive tryptophan (Trp)-catabolizing enzyme indoleamine 2, 3 dioxygenase (IDO). We have also shown that CD86 expressed on MM cells has independent pro-survival function. More recently we have determined that kynurenine (Kyn, produced by IDO degradation of Trp) is an endogenous ligand for the aryl-hydrocarbon receptor (AhR), and AhR activation has a significant but previously unrecognized pro-survival role in MM.
The Specific Aims of this proposal are: 1). Characterize the effect of blocking CD28 activation on myeloma chemoresistance in a Phase 2 clinical trial in MM patients, 2). Define how CD28 activation enhances the metabolic fitness of myeloma cells, and 3). Determine the role of MM CD28-mediated modulation of DC in the BM ME in supporting MM survival.

Public Health Relevance

The primary cause of disease relapse and patient death in multiple myeloma is the development of chemotherapy resistant disease. We have found that a key mediator of this resistance is activation of the CD28 receptor in myeloma cells. The overall goal of this proposal is to define the molecular mechanisms involved in CD28-augmented myeloma resistance and survival, and develop novel therapeutic strategies to target them.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA121044-14
Application #
10085205
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Howcroft, Thomas K
Project Start
2007-09-12
Project End
2024-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
14
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Nair, J R; Caserta, J; Belko, K et al. (2017) Novel inhibition of PIM2 kinase has significant anti-tumor efficacy in multiple myeloma. Leukemia 31:1715-1726
Gavile, Catherine M; Barwick, Benjamin G; Newman, Scott et al. (2017) CD86 regulates myeloma cell survival. Blood Adv 1:2307-2319
Fink, E E; Mannava, S; Bagati, A et al. (2016) Mitochondrial thioredoxin reductase regulates major cytotoxicity pathways of proteasome inhibitors in multiple myeloma cells. Leukemia 30:104-11
Rozanski, Cheryl H; Utley, Adam; Carlson, Louise M et al. (2015) CD28 Promotes Plasma Cell Survival, Sustained Antibody Responses, and BLIMP-1 Upregulation through Its Distal PYAP Proline Motif. J Immunol 194:4717-28
Farren, Matthew R; Carlson, Louise M; Netherby, Colleen S et al. (2014) Tumor-induced STAT3 signaling in myeloid cells impairs dendritic cell generation by decreasing PKC?II abundance. Sci Signal 7:ra16
Koorella, Chandana; Nair, Jayakumar R; Murray, Megan E et al. (2014) Novel regulation of CD80/CD86-induced phosphatidylinositol 3-kinase signaling by NOTCH1 protein in interleukin-6 and indoleamine 2,3-dioxygenase production by dendritic cells. J Biol Chem 289:7747-62
Murray, Megan E; Gavile, Catherine M; Nair, Jayakumar R et al. (2014) CD28-mediated pro-survival signaling induces chemotherapeutic resistance in multiple myeloma. Blood 123:3770-9
Boise, Lawrence H; Kaufman, Jonathan L; Bahlis, Nizar J et al. (2014) The Tao of myeloma. Blood 124:1873-9
Chitta, Kasyapa S; Paulus, Aneel; Ailawadhi, Sikander et al. (2013) Development and characterization of a novel human Waldenström macroglobulinemia cell line: RPCI-WM1, Roswell Park Cancer Institute - Waldenström Macroglobulinemia 1. Leuk Lymphoma 54:387-96
Mannava, Sudha; Zhuang, DaZhong; Nair, Jayakumar R et al. (2012) KLF9 is a novel transcriptional regulator of bortezomib- and LBH589-induced apoptosis in multiple myeloma cells. Blood 119:1450-8

Showing the most recent 10 out of 18 publications