2019 Brian D. Novis Grant Recipients

Chemoresistance in MM is inevitable and alternative strategies at that stage are desperately needed. Current treatment involves proteasome inhibition, but we found that proteasome enhancement also translates into potent anti-MM efficacy, but without apparent toxicity. Before 20S enhancement can be considered as a new therapeutic strategy, its rationale (how it disrupts MM pathogenesis) and efficacy (as an adjuvant with standard treatments) needs to be demonstrated. The data obtained from this work will provide the missing link between the efficacy of 20S proteasome enhancement and MM pathogenesis, which in turn provides a rationale for designing combination therapy with classical MM therapeutics.

MGUS is an asymptomatic condition affecting 4% of adults over age 50. Every year, 1% of these patients will develop the incurable blood cancer multiple myeloma. While the factors that drive myeloma development are currently unclear, our data suggest that changes in the bone marrow environment, rather than the tumor itself, play a key role in this process. We will perform state-of-the-art single cell sequencing to identify the individual cell types that make up the myeloma environment to determine how these cells, and the factors they produce, support myeloma development. These studies will ultimately identify new therapeutic targets for multiple myeloma.

Systemic light chain (AL) amyloidosis is a life-threatening plasma cell (PC) disease caused by clonal production of an aggregation-prone immunoglobulin light chain, which deposits in tissues resulting in fatal organ dysfunction. Antibody production results in abundant misfolded byproducts causing a critical dependence of normal and pathological PCs on pathways that maintain protein homeostasis. This addiction has relevant therapeutic implications: indeed, proteasome inhibitors have showed extraordinary efficacy against AL and the PC malignancy, multiple myeloma. Dissecting how PCs regulate the secretory capacity, in efficient coordination with protein degradative pathways, may be fundamental to disclose new therapeutic targets against AL.

Cancer cells are known for their ability to evade the immune system. Important in this process is the ability of cancer cells to prevent the activation of the immune system which has been insufficiently studied in multiple myeloma. In this project, we will investigate how multiple myeloma cells prevent the stimulation of two important immune cell types that should ‘eat’ myeloma cells or part of myeloma cells in order to stimulate the immune system. The obtained results should be helpful to develop new treatments to stimulate these immune cells and improve well being of patients.

Development of novel therapies for multiple myeloma (MM) and other neoplasias has historically focused on blocking the function of key proteins (“oncoproteins”) driving malignant cell behavior. We and others observed though that more potent anti-MM effect can be achieved by compounds causing the breakdown of these oncoproteins; and identified molecular mechanisms that can allow MM cells to escape the activity of these “degraders”. Our studies will explore new therapeutic approaches to enhance the anti-MM activity of such "degraders" of key MM oncoproteins and facilitate future clinical studies of these compounds to overcome MM cell resistance to established therapies.

A type of T cells named terminal effector CD8+T cells are responsible for keeping Myeloma in an asymptomatic pre-cancerous stage for many years, and when they fail the disease progresses. In this study we will use cutting edge technologies to discover changes in genes and proteins in these cells during disease progression. These changes will describe structural and functional disturbances in these T cells caused by the malignant cells, potentially identify therapeutic targets and suggesting ways to improve their capacity to eliminate myeloma.