2018 Brian D. Novis Grant Recipients

In this project, we wish to find novel ways to treat Multiple Myeloma (MM) by examining how MM cells “digest” nutrients to produce energy. MM develops in the bone marrow which provides these nutrients in a symbiotic fashion. In this project, we wish to recreate this environment by either placing MM cells in a co-culture with bone marrow cells or by examining these interactions in a mouse model. We will analyze metabolic changes on a broad-scale using the latest analytical equipment. To determine whether these targets provide therapeutic benefits, we will block them and evaluate tumor development in the murine model. 

Despite a century of medical advances multiple myeloma (MM) remains incurable because current therapy is limited in its ability to target all members of malignant cells. The efficacy of current therapies (standard high-dose chemotherapy and stem cell transplantation) for MM may be limited by treatment-related morbidity and mortality. We have a desperate need to identify more selective druggable targets that capture the hierarchy of MM malignant cells. This is possible through identification of causes and consequences of epigenetic alterations (mRNA splicing) in MM cells, which is a goal of the proposed study.

The role of metabolic alterations in the pathophysiology of multiple myeloma (MM) bone disease will be investigated. Manipulating glutamine (Gln) metabolism of myeloma cells we hypothesize to block bone destruction. Moreover, we will check the effect of the anti-MM drugs on the enzymes of Gln metabolism in the bone microenvironment and the possible relationship between the bone marrow levels of Gln and its metabolites and the presence of bone lesions in MM patients. This study could identify new metabolic markers of bone disease and provide novel approaches to the treatment of MM bone disease.

Multiple myeloma (MM) is the second most common haematological cancer and remains incurable, causing 2.1% of the cancer-related deaths in the US. Despite the numerous efforts to find a treatment for this disease, current studies are limited by the lack of mouse models which are able to mimic all the clinically relevant characteristics of MM. It has been reported that over 80% of drugs that enter clinical studies fail to get the approval, despite having successful preclinical trials, mainly due to the lack of clinically predictable animal models. To circumvent this, here we proposed the development of a humanised animal model to increase the knowledge and find new therapeutic strategies.

Cancer genomic efforts are providing to the scientific community a myriad of putative cancer genes. The challenge of the scientists is now to rigorously define the molecular mechanism underlying the oncogenic potential of these mutated genes. DIS3 is one of such genes. Frequently mutated in hematological cancers, in up to 18 % in multiple myeloma, little if anything is known about its mechanistic role in this disease. The goal of this project is to increase the knowledge of the DIS3 oncogenic mechanisms providing the framework for the development of individualized, molecularly based therapies that may improve outcomes, with reduced toxicity.

Multiple myeloma (MM) is an incurable blood cancer located in the bone marrow. A main feature of MM is genomic instability, leading to drug resistance and disease progression. However, mechanisms driving this genomic instability can also form the Achilles heel of the MM cells and offer unique therapeutic opportunities. Currently, mechanisms driving genomic instability remain mostly unknown. Here, we will investigate the role of PRMT5 in genomic instability, drug resistance and MM progression using cell lines, patient samples and a mouse model. This project will improve our understanding of MM progression and help to develop new, personalized treatments.