Searching for Molecular Targets in Myeloid Malignancies and Beyond – OncLive

Significant headway has been made in recent years to develop novel therapeutics that can eliminate entire mutant subclones in patients with myeloid malignancies, some of which include immunotherapy, dual MDMX and MDM2 inhibition, and STAT3 inhibition, according to Ulrich Steidl, MD, PhD.

In lymphoid malignancies, we have very good immunotherapy targets, including CD19 and a few others. [However,] in myeloid malignancies, more specific targets have been lacking, Steidl said. We are hopeful that with immunotherapy, [we] will [see] some significant activity very soon in myelodysplastic syndromes [MDS] and acute myeloid leukemia [AML]. It would be very exciting to take these concepts further beyond lymphoid malignancies.

In an interview with OncLive during an Institutional Perspectives in Cancer webinar on hematologic malignancies, Steidl, leader of the Stem Cells Differentiation and Cancer Program at Albert Einstein Cancer Center and director of the Stem Cell Isolation and Xenotransplantation Facility of the Ruth L. and David S. Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, discussed translational research efforts that have been made with targeting leukemia stem cells and ongoing clinical trials that are examining novel therapeutic targets in myeloid malignancies and beyond.

Steidl: The diseases that were talking about are not only driven by whats detectable in the bulk tumor population at any given time. Whats actually really difficult to target and eradicate with therapies are cancer stem cells or leukemia stem cells. We have directed many of our research efforts in the past 10 years or so to better understand these leukemia stem cells and to identify therapeutic targets in these disease-driving stem cell populations. This would, in conjunction with conventional therapies, lead to not only a transient debulking, but really to a more lasting disease control. A lot of progress has been made in that area.

This is a very exciting direction for research and one thats really starting to gain traction. Several early-phase clinical trials have been launched based on some of these strategies that we, or others, have developed. A lot of that basic research that was done 10 to 15 years ago is finally being translated into the clinical space and early trials.

One concept that has come out of those studies is that there is more heterogeneity in those leukemia stem cells within individual patients than we had previously anticipated. The idea is that you can detect a certain bulk tumor population and you can molecularly characterize that [by noting whether the] patient has [a certain] mutation or chromosomal rearrangement; that leads to clinical classification. However, it turns out that underneath the surface of this bulk tumor population, there are a lot of smaller hidden subclones. If you hit the bulk hard and eradicate it, or even push back hard on the dominant population, then the smaller subclones that are hidden underneath the surface come out.

This recognition has led [us to believe] that its not necessarily the most promising idea to go after individual clones or genetic aberrations. Rather, we have to think about these leukemia stem cells and where the disease is coming from as a whole. Weve tried to and have been successful in identifying targets that are actually shared among these different populations.

A great example of this is [some of] the immunotherapy approaches that [have been explored. There,] we are not actually interested in a single clone, but we want to train the immune system to recognize and fight the entirety of the subclones that are present. Some of these chimeric antigen receptor T-cell approaches are really trying to do thatnot just eliminate 1 subclone, but to sharpen the immune system to fight the problem more broadly. We have identified other surface markers in the lab that are shared among different subclones that could be good future targets for immunotherapy in myeloid malignancies, where this concept is still a little bit underdeveloped compared with lymphoid malignancies.

Another concept is that certain molecular mechanisms are responsible for this heterogeneity. Mutations happen all the time in normal cells and also in tumor cells. However, normally, what happens is that the body has mechanisms to recognize these mutant cells or the cells themselves have sensors that tell them, OK, theres a mutation or too many mutations in my DNA. Then, the cells are sent into programmed cell death. Thats a very important pathway thats regulated, for instance, by tumor suppressors, such as the TP53 protein. A lot of data have shown that this pathway is generally inactivated in myeloid malignancies, such as AML. As such, we have developed strategies to reactivate TP53.

The idea is simple: If you reactivate TP53 globally, then the cells would eliminate mutant subclones at a higher rate across the boardnot just 1 specific mutant subclone that you target with a drug. [This can] sharpen the bodys own mechanisms, specifically how it usually fights the initiation of cancer.

To this end, we have identified 1 of these targets that mediate the p53 pathway: a protein called MDMX. [In a collaborative effort,] we have also helped to develop a drug that targets this protein and [inhibits] p53. This work originated in the lab 5 to 8 years ago and has since led to a clinical trial, where this strategy is now actively being tested in patients. We dont yet know how successful this approach will be in the long term, but its just a very good example of how translational research can lead to very innovative clinical trials down the road. Thats something were very excited about.

One example is the MDMX protein, which is an endogenous inhibitor of the TP53 tumor suppressor. Clinical trials [are examining] the first drug [developed to target] this MDMX protein together with a closely related protein called MDM2. We have had a trial on this strategy of dual MDMX and MDM2 inhibition in MDS and AML. This [approach] is even being evaluated in several other tumors.

Another good example is targeting a transcription factor, a molecule that regulates gene activity. In our labs, Amit Verma, MD, and colleagues discovered STAT3 almost 8 years ago [and found it] to be overexpressed and overactivated in leukemia or in the malignant stem cells of patients with MDS. Aditi Shastri, MD, also of Albert Einstein College of Medicine, has really taken this fundamental discovery all the way to a planned clinical trial. Now, shes also working with a company to develop an agent that can inhibit STAT3; thats a new strategy that is moving forward. Its a team effort, from the discovery in the lab to clinical testing.

A number of years ago, we identified a molecule called IL1RAP, which is an IL-1 coreceptor that is drastically overexpressed on leukemia stem cells. We believe that its a very promising target for leukemia stem cells in MDS and AML. Many ongoing efforts are being made, and not all of them are in-house efforts. Quite a few pharmaceutical companies read our papers, and then they jump on it and develop molecules.

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Searching for Molecular Targets in Myeloid Malignancies and Beyond - OncLive