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What’s Next in Blood Cancer: Looking Ahead to 2023

The most important blood cancer scientific meeting, the American Society of Hematology (ASH), is held every December.

Development of LILRB1-based immunotherapy for multiple myeloma treatment

LILRB1 is a human immune inhibitory receptor expressed on a variety of immune cells. Based on preliminary data, we hypothesize that blocking LILRB1 signaling in immune effector cells of myeloma patients will lead to increased anti-cancer activities of immune cells. We will identify subsets of myeloma patients with higher LILRB1 expression on immune cells, and determine whether anti-LILRB1 antagonizing antibodies can improve the function of immune cells for multiple myeloma treatment.

Daratumumab and hyaluronidase-fihj

Darzalex Faspro® is a combination of daratumumab, a CD38-directed cytolytic antibody, and hyaluronidase, an endoglycosidase, and is indicated for the treatment of adult patients with:

Targeting the Osteogenic Lineage as a Therapeutic Strategy in Multiple Myeloma

Multiple myeloma causes devastating bone disease characterised by focal bone lesions and generalise bone loss, which leads to an increase in bone fractures. Current therapies only stop bones from getting worse so patients continue to suffer fractures. We discovered that inhibiting a molecule called sclerostin in mice increases bone and is much better than current treatments. In this program we will investigate whether inhibiting sclerostin is able to restore lost bone and reduce fractures in patients with myeloma.

Anti-Sox2 immunotherapy to prevent multiple myeloma relapse

Advances in multiple myeloma (MM) therapy have improved survival, but serial cycles of response and relapse still lead to treatment-refractory and fatal disease in nearly all patients. To specifically target mechanisms of MM relapse, we propose to develop an immunotherapy targeting Sox2, a stem-cell transcription factor implicated in clonogenic MM growth that enables relapse.

Carfilzomib

Carfilzomib is indicated in combination with

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Immunotherapies on a Roll at #ASH20

More than three years after the first chimeric antigen receptor (CAR) T-cell therapy achieved U.S. Food and Drug Administration (FDA) approval, the revolutionary approach that has upended blood cancer treatment continues to generate excitement.

Elotuzumab

Elotuzumab is FDA approved for the treatment of multiple myeloma

  • In combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received one to three prior therapies.
  • In combination with pomalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. 

Novel targeted therapies for acute myeloid leukaemia and multiple myeloma

Outcomes for acute myeloid leukemia (AML) and multiple myeloma (MM) patients remain inadequate and new treatment options to combat resistance against existing agents are urgently needed. My research aims to identify and target selective vulnerabilities of AML and MM cells. I am particularly interested in epigenetic and metabolic pathways that control self-renewal and differentiation of hematopoietic cells and that can be leveraged to modulate cell fate for therapeutic benefit.

Adenylate Kinase 2-A Novel Therapeutic Target in Multiple Myeloma

We identified the adenine nucleotide regulator AK2 as a selective dependency in multiple myeloma (MM) that is more essential for survival of MM cells overexpressing the histone methyltransferase NSD2. Here, we propose a series of experiments to understand the role of AK2 in MM cell fitness and response to existing therapies and elucidate the molecular basis of the increased dependence on AK2 driven by NSD2 overexpression. This study will elucidate the effects of AK2 inhibition in MM and will credential the enzyme as a therapeutic target.

Investigating anti-neoplastic effects of beta blockers in multiple myeloma

Multiple myeloma (MM) relies on the bone marrow (BM) niche to progress to refractory disease. We found that beta blockers alter BM niche elements fostering MM growth and also reduce MM cell survival. Our objective is to elucidate the cellular and metabolic basis of how beta adrenergic signals impact the BM niche and MM progression. Knowledge of the prophylactic and therapeutic utility of beta blockers in MM will unravel new means to target neural niche remodeling fueling this fatal malignancy.

Selinexor

Selinexor is FDA approved

Stem cell features and Notch signaling in p53 deleted multiple myeloma

We have investigated the consequences of p53 loss on stem cell properties, namely clonogenic growth, self-renewal, and drug resistance in multiple myeloma. We have found that both the level of Notch signaling and BCMA impact these properties, and we will explore novel strategies to improve outcomes in p53 mutant multiple myeloma.

Designed biosensor to enhance CAR T cell therapy for multiple myeloma

We will develop a novel T cell therapy strategy for multiple myeloma (MM) that will combine existing chimeric antigen receptors (CARs) with a novel designed biosensor responding to soluble factors abundantly present in the MM bone marrow environment in patients. The biosensor will be expressed as novel type of chimeric receptor in T cells concomitantly with the CAR and signal the T cells to persist longer and keep eliminating cancer cells from the body. We will deeply characterize the effects of our novel biosensor in CAR T cells to precisely understand how the treatment works.

Denosumab

Denosumab is FDA approved for  the prevention of skeletal-related events in patients with multiple myeloma.


 

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Highlights from ASH 2021

The American Society of Hematology (ASH) annual meeting is the premier scientific forum on blood cancers. More than 5,000 potentially game-changing research abstracts were presented at this year’s meeting. Every year, I come away with a strengthened sense of hope about new treatments on the horizon and renewed pride in The Leukemia & Lymphoma Society’s (LLS) role in supporting so many of them.

Targeting DCAF1 as a novel treatment strategy for therapy resistant multiple myeloma

We have identified the multi-domain protein DCAF1 as a genetic dependency in multiple myeloma and developed a series of potent on-target DCAF1 inhibitors that have a unique mode of action compared with existing therapies. In this proposal we will continue the detailed molecular characterization of our lead compound Vpr8. In parallel, using Vpr8 as the scaffold, we will develop a new series of PROTAC drugs that engage the ubiquitin ligase activity of DCAF1-containing E3 complexes.

Inflammation-responsive mechanisms of malignant stem cell generation and eradication in multiple myeloma

The focus of my research is to elucidate the core molecular regulators of malignant stem cell generation in multiple myeloma. My approach addresses the tumor cell-intrinsic versus niche-dependent mechanisms of myeloma regeneration by exploring transcription factor expression and stemness profiles within single cells from primary samples and patient-derived models. The central goal of my research is to uncover novel therapeutic strategies and translate these into new myeloma treatments.