A team from Columbia University Irving Medical Center and NewYork-Presbyterian Hospital have been awarded a Translational Grant by the V Foundation for Cancer Research for their research into a new signaling pathway as a precision medicine approach to myelodysplasia (MDS) and acute myeloid leukemia (AML).

Members from Dr. Kousteni's lab

The project is led by Dr. Stavroula Kousteni and collaborators Drs. Azra Raza, Joseph Jurcic, and Jianhua Hu, all members of the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian/Columbia.

 The V Foundation is a charitable organization founded by ESPN and legendary basketball coach Jim Valvano that has awarded over $225 million in cancer research grants since its formation in 1993. V Foundation translational grants support ‘bench-to-bedside’ research whose end goal is to bring the new therapy to the patient via a new clinical trial.

The Need

Despite decades of research, MDS and AML are still mainly treated with the same toxic agents of the last 30 years.

While effective treatments have advanced for other cancers, particularly with the advent of personalized or precision treatments, myelodysplasia (MDS) and acute myeloid leukemia (AML) have been left behind.

Because MDS and AML patients are generally older, less than 10% are candidates for a bone marrow transplant. Only half of MDS patients respond to existing FDA-approved chemotherapy drugs, and their response is temporary at best.

Dr. Kousteni and her co-PIs have been researching a new pathway of communication between cells in the bone marrow and MDS or AML cells for nearly a decade, continuously building on their research in the laboratory to unlock the potential to bring more effective treatments to patients in the clinic.

The Research

The newly-discovered pathway involves overexpression of JAGGED1, a ligand that stimulates the Notch signaling pathway, which is involved with cell proliferation, differentiation, and survival, and one of the most commonly activated pathways in cancer. Blocking this pathway, the researchers hypothesized, could stop the cancer from progressing.

Using a sample of 320 patients, they found that JAGGED1 is overexpressed in approximately 35% MDS and AML patients, representing one of the most unifying pathways for these very diverse cancers.

The team then demonstrated that this pathway can be blocked by inhibiting JAGGED1 signaling and  developed an anti-JAGGED1 antibody effective in blocking the signal in mice models with no observed toxicity. The researchers then generarated human antibodies  to test for use  in clinical trials.

With the support of the V Foundation award, the team will build on this research, identifying the most effective antibody out of the three created by testing it on human cells from patinets with different types of MDS and AML in the lab. They will also use xenografts, or mouse models, to hone in on the best design for a clinical trial using this new therapy.

 “The goal is to bring this antibody to the bedside. We’ve already developed a robust and simple screening test for identifying patients in which this  pathway in active  using cells from their bone marrow,” notes Dr. Kousteni. “By targeting these specific patients, our precision medicine approach will increase the success and efficacy of treatment.”

The Clinical Application

The potential therapeutic application for the JAGGED1 antibody is far-reaching.  First, the potential population who could benefit from this therapy is broad, with nearly 35% of MDS/AML patients exhibiting the overexpression of JAGGED1. As these are very diverse cancers, this pathway is the singlemost unifying cellular expression that has been identified across this population.

Additionally, by targeting a nearby bone cell rather than the leukemic cell itself, the researchers think that they could alleviate the pitfall of many other targeted therapies – that the cancer mutates and finds a way around the mechanism of the therapy. Since the JAGGED1 antibody targets a more stable cell, a bone cell, it is potentially a more lasting treatment that can overcome the type of resistance that can emerge when the cancer clones exapand and adapt.

In their studies, the researchers did not observe any toxicities, or side effects, associated with the JAGGED1 antibody in the mouse models. While immunotherapies provide new and often more effective treatments options for patients with cancer, they are not without the risk of side effects, sometimes severe. The JAGGED1 antibody could offer patients an therapy option with limited or no side effects.

Toxicities will be further evaluated in clinical trials, which the researchers hope to launch within three years after the research has been completed.

--Kristina F. Mesoznik