Showing 2 ideas for tag "leukemia"

Goal 3: Advance Translational Research

How can we develop more selective immunosuppression for allogeneic hematopoietic cell transplantation?

Graft versus host disease (GVHD) remains the most significant complication of allogeneic hematopoietic stem cell transplantation (HCT). While the use of HCT has grown significantly safer and has demonstrated broad efficacy in the setting of a broad range of blood diseases, immunosuppressive therapy has not dramatically evolved since the introduction of calcineurin inhibitor-based approaches decades ago. The availability... more »

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? Compelling Question (CQ)

Details on the impact of addressing this CQ or CC

GVHD remains a critical problem and major barrier to the more widespread utilization of HCT, especially for nonmalignant diseases, where tolerance of treatment-related mortality is understandably low.

There is a compelling need for novel immunosuppressive agents that can effectively limit alloreactivity mediated by donor T and B cells, while relatively sparing pathogen-specific T cells, including those mediating antiviral T cell responses important in the post-HCT interval.

In the past decade, drug development has facilitated the introduction into preclinical and clinical trials of a broad range of agents that in addition to targeting pathways of interest in target cells (e.g., aberrant signaling in cancer cells) may also effectively inhibit T and/or B cell responses. Examples include hypomethylating agents (e.g., azacitidine), HDAC inhibitors (e.g., vorinostat), MEK inhibitors (e.g., trametinib) and BTK inhibitors (e.g., ibrutinib). Each of these classes of agents has been demonstrated in preclinical and/or clinical studies to also limit alloreactive T cells, and/or augment regulatory T cell responses, leading to a net reduction of alloreactivity. Unlike traditional agents (e.g., the calcineurin inhibitors) these agents appear to be more selective, and in some cases may have dual benefit in reducing relapse.

The NHLBI can facilitate the identification and translation to clinical practice in the setting of HCT trials of novel immunosuppressive agents.

Feasibility and challenges of addressing this CQ or CC

Research funding targeted to improving the pipeline of novel immunosuppressive agents could have immediate and dramatic impact in the field of HCT, especially impacting its application for nonmalignant diseases. Patients lacking optimal registry donors, especially those from underrepresented minority groups, will particularly benefit from improvements in immunosuppression, as patients receiving less than optimally matched donors are at much higher risk of GVHD.

The NHLBI can encourage and facilitate research that tests compounds that have already passed through the drug development process, but in many cases were not intended to function as immunosuppressive agents. Compelling preclinical studies have suggested that targeted inhibition of T and B cells, and/or epigenetic modifiers can lessen alloreactivity while preserving beneficial cellular immune responses and facilitating immune reconstitution.

It will be far easier to appropriate therapeutic agents already developed for another purpose than to do novel drug development from scratch. In many cases, preclinical studies have highlighted the therapeutic potential in immunosuppression for agents that have been developed to treat malignancies, but yielded suboptimal success. Research that encourages the development of these drugs as part of a combined immunosuppressive/immunomodulation approach may rescue such compounds, while yielding potential dramatic advances in clinical HCT.

Name of idea submitter and other team members who worked on this idea Krishna Komanduri, M.D.


106 net votes
129 up votes
23 down votes

Goal 2: Reduce Human Disease

Kinetic analysis of transcriptional regulation by aberrant transcription factors in vivo

Aberrant transcription factors, such as leukemia fusion proteins, promote diseases by deregulating transcription of target genes. Recent genome-wide studies have provided new insight into transcriptional deregulation by aberrant transcription factors. Most of these studies have not used cells with synchronized transcriptional activities at specific repression/activation steps and, therefore, may have limited value in... more »

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? Critical Challenge (CC)

Feasibility and challenges of addressing this CQ or CC

These studies are feasible. Transcriptional regulation of a population of cells may be synchronized by epigenetic drugs, or by using inducible expression/knockdown approaches. Alternatively, it may be possible to overcome the heterogeneity issue by single-cell-based analysis. Next, time-dependent genome-wide studies may be applied to the cells to reconstruct dynamic transcriptional pathways associated with aberrant transcription factors. These approaches may be generally applicable to the study of other disease-related transcriptional and signaling molecules.

Name of idea submitter and other team members who worked on this idea Jinsong Zhang


1 net vote
1 up votes
0 down votes