Leukemia Program: Genetic Targets Driving Drug Development Success

Richard Stone, MD

Richard Stone, MD

“It has been an exciting time to be involved in leukemia,” said DF/HCC Leukemia Program Clinical Leader Richard Stone, MD (DFCI), referring especially to the availability of four new FDA-approved drugs for acute myeloid leukemia (AML) in 2017 and one for acute lymphocytic leukemia (ALL). “And DF/HCC researchers had a role in all of these from identifying therapeutic targets and conducting preclinical work to participating in clinical trials that lead to drug approvals.”

Researchers with the DF/HCC Leukemia program continue to push for new strategies to help more patients faced with new or relapsed leukemia diagnoses achieve remission and cure. Currently, the program hosts more than 70 open clinical studies.

“Our program has made enormous contributions towards understanding the mutations that lead to leukemia and other hematologic malignancies,” said DF/HCC Leukemia Program Leader Benjamin Ebert, MD, (DFCI). “We are also making rapid progress in understanding how to use that information to predict prognosis, to improve diagnostics, and to predict which patients are most likely to respond to particular treatments.”

Avalanche of New AML Therapies

“In AML we are gradually picking off subsets of the disease by developing targeted therapies,” said Dr. Stone, who is also a member of DF/HCC’s Developmental Therapeutics Program. “It is a relatively rare disease but there is also a lot of heterogeneity within it which we are trying to exploit with these various therapies.”

DF/HCC researchers have played key roles in the development of nearly all of these new AML targeted therapies, including Rydapt, Vyxeos, Mylotarg, and Idhifa. 

Benjamin Ebert, MD, PhD

Benjamin Ebert, MD, PhD

In one of many examples of new drugs in development, Dr. Ebert is researching the mechanism of action of lenalidomide, a thalidomide derivative with proven efficacy in MDS. Earlier research showed that lenalidomide and related compounds act by modulating the function of an E3 ubiquitin ligase. The goal is to develop new novel modulators of E3 ubiquitin ligases that will be useful in leukemia and other blood cancers.

Looking forward, the Leukemia Program is building on the translational success of these genetic and molecular heterogeneities in AML and other leukemias to develop a portfolio of clinical research and trials to discover new drugs. “I am particularly enthused that there are targeted therapies showing significant clinical efficacy. I am hopeful that our research will provide the evidence for new therapeutic targets, and for using new drugs in combination with chemotherapy and bone marrow transplantation to improve long-term outcomes for people with leukemia and other blood cancers,” said Dr. Ebert.

Molecular and Genetic Analyses Inform Treatment

As the 2017 AML drug approvals highlight, an understanding of the genetics influencing leukemia development has been at the heart of the progress made in identifying several new therapeutic targets. Dr. Ebert’s laboratory recently defined the genetics of the pre-malignant state for leukemia and other blood cancers known as CHIP (clonal hematopoiesis of indeterminate potential), a discovery which may help identify individuals who are at a high risk of developing these diseases. “This premalignant state increases the risk of other diseases as well, most notably cardiovascular disease,” Dr. Ebert noted. This work is opening up a new line of leukemia research, particularly in understanding premalignant states and how they may influence not just the development of cancer, but other non-malignant diseases as well.

Anthony Letai, MD, PhD

Anthony Letai, MD, PhD

In the laboratory of Leukemia Program member Anthony Letai, MD, PhD(DFCI), molecular analysis has led to development of a new tool to help predict which leukemia cells will respond to a particular therapy. Dr. Letai developed a BH3 profiling assay that measures how close a cancer cell is to the threshold of programmed cell death, or apoptosis. “By using that we can identify cells that are closer to the threshold, meaning they are more chemosensitive,” he explains.

Dr. Letai also uses the assay to test short-term drug exposures to determine which drugs move cancer cells toward the apoptotic threshold. “We use only fresh patient samples in our studies,” Dr. Letai explained, “which gives us a whole new dimension of study because we can evaluate actual function in real tissue.” He used this technology to predict that venetoclax, a drug already approved for chronic lymphocytic leukemia (CLL), may also be useful with AML, ALL, and a rare blood cancer known as BPDCN. Thus far, Dr. Letai has evaluated 100 patient samples with BH3 profiling and he hopes to bring the technology into clinical use within the year to help clinicians make treatment decisions personalized to each patient’s individual cancer.

NCI Myeloid Malignancies SPORE

In October 2017, leukemia research at DF/HCC was given a boost when the NCI’s Translational Research Program awarded the Cancer Center one of only three nationwide SPORE’s (Specialized Program of Research Excellence) focused on leukemia. The SPORE’ goal is to further unravel the genetic and molecular basis of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) that will translate directly into new treatments.

The 5-year SPORE grant in Myeloid Malignancies includes $11 million for investment in four projects, four cores, a developmental research program, and a career enhancement program. “It provides us with funding not only for a number of promising therapeutic projects but also provides funding for infrastructure and professional development,” says Dr. Ebert. “It will inject energy into our ability to do great translational leukemia research and work on projects where the science is going to lead to new developments that will enter clinical trials or already have.”

The SPORE projects highlight the programs’ already translational nature, and encompass diverse methods and strategies for improving outcomes in this disease.

Project 1 – “Targeting MLL/Menin in AML
Basic Research Co-Leader: 
Scott Armstrong, MD, PhD (DFCI)
Clinical Research Co-Leader: 
Richard Stone, MD (DFCI)
Mutations that drive leukemia development frequently lead to over expression or rearrangement of genes’ encoding proteins that control gene expression. As a result, gene expression programs that direct normal hematopoietic development are corrupted leading to leukemia. Reversal of these aberrant gene expression programs and expression of transcription factors such as HOXA9/MEIS1, MYB, and MYC leads to leukemia cell differentiation and apoptosis suggesting that these approaches should be therapeutically beneficial. However, the mutations that drive aberrant expression rarely lead to direct activation of an enzyme, and thus targeting with small molecules has been challenging.

Recent studies have shown that disrupting critical interactions of multiprotein complexes that control gene expression frequently through chromatin-based mechanisms can modulate expression of these critical genes. This has prompted a wave of small molecule development. Inhibitors of histone modifying complex components such as BET-Bromodomain inhibitors, DOT1L inhibitors, and LSD1 inhibitors have all entered phase I trials for patients with relapsed leukemia. Furthermore, inhibitors of the MLL1/Menin interaction (which is also critical for the maintenance of HOXA gene expression) are being developed and will likely enter clinical assessment in the next year.

Dr. Armstrong and Dr. Stone propose studies that will provide a broader understanding of the importance of the MLL-Menin interaction and identify biomarker strategies that will be employed in early phase clinical trials that this group will initiate. They will assess which types of leukemia might benefit from these newly developed approaches, and which combinations of small molecules should move forward to clinical assessment.

Project 2 – “Targeting SYK Kinase in AML”
Basic Research Co-Leader: 
Kimberly Stegmaier, MD (DFCI)
Clinical Research Co-Leader: 
Daniel DeAngelo, MD, PhD (DFCI)
While much progress has been made in understanding the pathogenesis of acute myeloid leukemia (AML) through the application of genetic and genomic approaches, clinical progress in treating this disease has lagged far behind. The backbone of treatment for most patients with AML still relies on the use of cytotoxic drugs that are several decades old. Through the application of integrative chemical and functional genomic approaches, Dr. Stegmaier and Dr. DeAngelo have identified the target spleen tyrosine kinase (SYK) as a new dependency in AML. SYK is a cytoplasmic tyrosine kinase widely expressed in hematopoietic cells and critical in B cell differentiation and signal transduction pathways. They have determined that SYK is a new target for promoting AML differentiation, is a critical regulator of FLT3, and that FLT3-ITD, one of the most common genetic abnormalities in AML, is a candidate biomarker of response to SYK inhibition.

In this project, they will build upon their prior work to now translate SYK inhibitors to the clinic for patients with AML with the goals of identifying synergistic combinations of drugs with SYK inhibitors, both chemotherapy and targeted agents, and testing SYK inhibitors alone and in combination in patients with AML.


Project 3 – “Targeting SF3B1 for the treatment of MDS”
Basic Research Co-Leader: 
Benjamin Ebert, MD, PhD (DFCI)
Clinical Research Co-Leader: David Steensma, MD (DFCI)
Somatic mutations in the core components of the pre-mRNA splicing complex, the spliceosome, are the most common genetic lesions in patients with myelodysplastic syndromes (MDS). Specifically, recurrent missense mutations in the SF3B1 gene are present in 10-20% of all MDS cases. Inhibitors of SF3B1 have been developed and represent a promising new frontier for MDS therapy.

In this project, Dr. Ebert and Dr. Steensma propose to develop pre-clinical models of SF3B1 mutant protein, to test a novel SF3B1 inhibitor in these models, alone or in combination with azacitidine, and to perform correlative studies in the context of a Phase I/II clinical trial of an SF3B1 inhibitor in collaboration with H3 Biomedicine. H3 Biomedicine has generated a compound, H3B 8800, that shows promising mutant-selective activity in cell lines and that is poised for clinical trials. The Ebert laboratory has developed a conditional knock-in mouse model that expresses the SF3B1 K700E mutation, the most common mutation in MDS patients. Since SF3B1 mutations commonly co-occur with mutations in DNMT3A in MDS, the co-Leaders will create a model with both conditional SF3B1 knock-in mutation and conditional DNMT3Ainactivation. They will test H3B 8800 in this model and will test the combination of H3B 8800 with azacitidine, a drug with efficacy in MDS and in TET2-mutated cases in particular. They will identify mechanisms of resistance to H3B 8800 using a genome-wide CRISPR-Cas9 screen, and finally, they will examine the safety and efficacy of H3B 8800 in MDS patients in a phase I/II clinical trial. This first-in-class agent has the potential for major clinical impact in a large fraction of MDS cases with aberrant spliceosome function due to somatic mutations. The studies proposed in this project will define the activity of the drug in different genetic backgrounds, examine the activity of the drug in hematopoietic stem and progenitor cells, identify mechanisms of therapy resistance as well as insights into the mode of action of the drug, and examine therapeutic efficacy in patients.

Project 4 – “DC AML Fusion Cell Vaccination with Immune checkpoint Blockade”
Basic Research Co-Leader: 
Gordon Freeman, PhD (DFCI)
Clinical Research Co-Leader: 
David Avigan, MD (BIDMC)
Dr. Avigan and Dr. Freeman are pursuing an immunotherapy approach to treating AML through a personalized tumor vaccine. The pair has already shown that when AML patients are given a vaccine made from a fusion of their own AML and dendritic cells, their incidence of relapse was lower. Results of that study showed that at five years of follow-up, over 70% of patients were still in remission, including patients who were in a second complete remission. On average, progression of disease-free survival in that patient population is only 10-20%.

With this approach, a patient’s leukemia cells are harvested at diagnosis. They receive chemotherapy and once in remission, the patient’s dendritic cells are harvested and fused chemically with leukemic cells. The fused leukemic cells act as antigen-presenting cells which help the immune system recognize the leukemia cells. “The idea is to take the patient’s tumor population with all the different antigens presented on that tumor and put them together with the immune-stimulating machinery of the dendritic cells so you have effective antigen presentation,” said Dr. Avigan.

In a twist on the typical approach, Dr. Freeman and Dr. Avigan’s SPORE project will include patients undergoing allogeneic stem cell transplants. “Relapse is still a big problem after allogeneic stem cell transplants,” said Dr. Avigan. In the SPORE vaccine project, a fusion product will be made from the donor’s dendritic cells and the patient’s leukemia cells and delivered after allogeneic stem cell transplant. “We hope it can help to decrease the relapse rate by teaching the immune system to recognize the leukemia antigen that might be present,” he said.

Career Enhancement Program
Working in parallel with the scientific projects, the SPORE’s Career Enhancement Program (CEP) seeks to recruit and train new investigators in translational research leukemia. CEP Director and Leukemia Program member Timothy Graubert, MD (MGH) explains, “We are now in the process of identifying promising candidates in the early stage of their careers and provide this additional support so they have some protected time and effort to devote to a translational research project and also other activities that will enhance their career development.” The SPORE will fund up to two junior faculty or advanced trainees per year with grants up to $50,000 each.

The SPORE’s projects are supported by 4 cores: an Administrative Core directed by SPORE PIs Benjamin Ebert, MD, PhD (DFCI) and Richard Stone, MD (DFCI), a Biostatistics Core directed by Donna Neuberg, ScD (DFCI), a Biospecimens and Xenograft Core directed by Jerome Ritz, MD (DFCI) and David Weinstock, MD (DFCI), and a Correlative Science Core directed by Jon Aster, MD, PhD (BWH) and David A. Williams, MD (BCH).

Impact on Outcomes

“Clinical investigators in the DF/HCC leukemia program have made fundamental contributions to the development of new therapies for the treatment of leukemia, including studies that led to FDA approval of Rydapt and multiple other studies that have altered the standard of care for leukemia,” said Dr. Ebert. Members of the DF/HCC Leukemia Program have also made major discoveries regarding the genetic mutations that cause leukemia, and determining the clinical significance of these mutations. “This has improved our ability to predict prognosis and select optimal therapies for patients,” he says. “With new drugs, the potential to combine them together for greater efficacy, and the ability to use genetic testing to target the use of these drugs to patients who are most likely to benefit, the DF/HCC Leukemia Program is poised to make significant progress in improving outcomes for patients with this challenging cancer.”

-Alice McCarthy