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Q&A with Kimberly Stegmaier

Q&A with Kimberly Stegmaier

There is much that excites U.S. physician/scientist, Kimberly Stegmaier, about advances in AML research. The Professor of Pediatrics at Harvard Medical School, Boston, was one of the international speakers at the Leukaemia Foundation-hosted New Directions in Leukaemia Research conference, in Brisbane in 2018. We spoke to her following her presentation, ‘Clinical translation of AML genomics’.

Kimberly Stegmaier
Kimberly Stegmaier focuses on finding new therapeutic targets for children with cancer.

How did you become interested in leukaemia?

As a child I was always interested in cancer. When I was 12 and in a gifted program at school, I did a research project on paediatric leukaemia and wrote a fictional story about a child with leukaemia. In college, on a pre-med track, I vividly remember my excitement in figuring out the answer to a Cell Biology test question about receptor tyrosine kinase signaling in cancer. Moreover, when I secured a research fellowship at Harvard Medical School, I had an amazing year in the lab of a well-known leukaemia researcher and became hooked on science. I started a paediatrics residency and did an oncology rotation as early as I could. I absolutely loved it. It was then that I knew I would pursue a career in paediatric oncology with a focus on leukaemia.

What is it about AML that particularly interests you?

In medical school I worked on acute lymphoblastic leukaemia (ALL). However, when I did my clinical training in paediatric haematology/oncology, I was very struck by how toxic the therapy was for children with AML and how poorly we were doing treating these children. It was horrible. When I went back to the lab later in my fellowship training, I decided to work on AML. I felt it was a very strong unmet need, both for children and adults, and felt the work had potential for a broad impact on both paediatric and adult patients.

What’s the focus of research at the lab you direct at the Dana-Farber Cancer Institute?

Our primary focus is finding new therapeutic targets and ultimately new drugs for children with cancer. Half of my laboratory works on leukaemia while the other half works on paediatric solid tumors. We have been using both chemical screening and functional genomic approaches to identify new therapeutic targets in these cancers. Most recently, we have been using a

powerful new technology called CRISPR-Cas9 to systematically delete every gene in the human genome in leukaemia and other cancer cells to identify the Achilles heels of these cells. Our hope is that these Achilles heels will inform new drug targets for these cancers.

Have you found anything in particular that you are excited about?

We are excited about a number of new targets that we have discovered in the lab. The project that’s gone deepest is our work on SYK (an enzyme), which has been translated to clinical trials. This work has benefitted from the pharmaceutical industry’s interest in the enzyme as a target for autoimmune disorders and cancer. Two drugs are being actively tested in adults with AML, with some complete responses observed in patients, including with the SYK inhibitor entospletinib. Published data indicates that the mixed lineage leukaemia (MLL) rearranged AML group may be particularly sensitive to these molecules. That is very exciting because the MLL gene is involved in both AML and ALL in children and adults. Infants (children less than one) is one particularly high-risk patient group with MLL rearrangements. MLL rearrangements are particularly common in infants with leukaemia, and this leukaemia subset is particularly resistant to standard chemotherapy, so new therapeutic approaches are very much needed for these children. Our own data also suggests that patients with FLT3 mutations, another poor prognostic group, may also be sensitive to SYK inhibitors. It is exciting that these molecules may have potential for patients most in need of new therapies.

What technologies are you excited about?

Cutting-edge technologies, such as CRISPR and shRNA screening, enable us to find new drug targets more rapidly by systematically deleting or repressing genes in order to figure out the Achilles heels in these cancer cells. We couldn’t do that 10 years ago. The ability to incorporate information about AML mutations and functionally perturb every gene in a cell is very powerful. It gives me a lot of optimism that by combining these different technologies with new approaches in chemistry, we will make inroads into novel AML therapies more rapidly than before. There was a long gap in any FDA approvals for AML, but now three targeted therapies awere recently approved – that’s exciting. There’s still a ton of work to do. Rather than extending survival by a few months, we’re looking to cure patients; that’s our goal.

Are mutations the problem with AML?

If we take all cancers, rank order them by how many mutations are present in any one cancer, AML has amongst the least! Cancers such as melanoma or lung cancer tend to have a high mutational burden. AML, however, tends to have shockingly few mutations. What we do see, however, is heterogeneity (a great diversity) from patient-to-patient and even within an individual patient’s leukaemia. Not all of the leukaemia cells have the same mutations. There are cell-to-cell differences which can be a challenge. For example, in the case of FLT3-mutated AML, we know that not every leukaemia cell within a person’s AML has a FLT3 mutation. The acquisition of FLT3 mutations is a later event in the evolution of the leukaemia. So, you can potentially eliminate those FLT3-mutated AML cells with a FLT3 inhibitor drug, but there are frequently AML cells that lack the mutation. That’s a problem.

Another challenge is that many of the mutational events that occur in AML don’t make for easy drug targets. For example, a common event in AML is the presence of a cancer-promoting fusion oncoprotein. These fusions occur when there are breaks in chromosomes and then the chromosomes fuse together to generate abnormal genes encoding cancer-promoting proteins. Often these fusion oncoproteins involve a class of proteins called transcription factors. These DNA binding proteins have been notoriously difficult to make drugs against. In other cases, the mutations lead to an absence of the protein, such as is the case of cohesin complex mutations. It is really difficult to replace missing proteins.

What is also quite puzzling is that while many patients with AML will go into remission, the majority of adults with AML will relapse. Why? These patients don’t typically have new mutations in the AML cells at the time of relapse. There are hypotheses about the stem cell and how these cells may be more immune to the effects of chemotherapy because they are not dividing as much as the bulk of the leukaemia cells. Arguably, the answer to this question is still largely unknown. Our lab has been thinking about the right types of studies to understand the differences in those cells that lead to relapse for those that are effectively killed by chemotherapy drugs.

What is GSK-3 alpha?

A fundamental problem in AML is that the cells stay in a very immature state. One of our research goals is to figure out how to trigger the cells to mature. One of the targets that I discussed during the NDLR conference was glycogen synthase kinase 3 alpha (GSK-3 alpha). This is an enzyme involved in a number of important activities within cells. We were excited to discover this target several years ago as a candidate for promoting AML differentiation. However, we were limited in our studies because we didn’t have selective molecules to distinguish between the GSK-3 alpha and GSK-3 beta isoforms. By targeting both at the same time, you unfortunately also stabilise a protein called beta-catenin, which can promote leukaemic stem cells. Thus, we needed molecules to specifically only target GSK-3 alpha because selective targeting of only the alpha isoform does not stabilise beta-catenin. In order to accomplish this goal, our laboratory joined forces with a chemistry team at the Broad Institute to develop some important molecules that inhibit GSK-3 alpha. We have found that these compounds promote AML cell differentiation and also impair the leukaemia-initiating cells preventing the establishment of the leukaemia in models of AML tested in the lab.

Can you tell us more about the new GSK-3 alpha inhibitors?

The molecule that we have validated, BRD0705, is still a tool compound; it’s not a drug yet. The big goal of the project, which we have recently published in Science Translational Medicine, was to find chemicals (small molecules) that target the alpha and not the beta isoforms of GSK-3. In my opinion, BRD0705 is the best molecule we have today that does just that. The next step is to use medicinal chemistry to make that molecule a proper drug. Academic groups are good at finding lead molecules but many millions of dollars and a lot of effort is necessary to optimise a lead compound for delivery to human patients. BRD0705 has been licensed to a company, and that work is underway. The information we published included the compound structures so that chemists can synthesise the molecule themselves and study them too. That’s one of the beauties of sharing and having data in the public domain; it gives that information to the community broadly to expedite progress for the patients we treat.

How does your clinical patient care as a paediatric oncologist inform your discoveries in the lab?

In addition to running my laboratory, I take care of children with cancer, most typically leukaemia, at the Dana-Farber Cancer Institute and Boston Children’s Hospital. My clinical work is a constant reminder of why I’m doing what I’m doing in the laboratory. The bedside care is an inspiration like no other to work harder in the lab. These children are in urgent need of better therapies. Right now, I’m involved in leading a multi-institution study that’s right at the edge of the clinic and the lab. We are sequencing samples from patients across the U.S. with relapsed or refractory leukaemia or very high-risk subsets of newly diagnosed leukaemia. The goal of the study is to determine the feasibility of rapidly sequencing leukaemia promoting genes in individual patient samples and matching these mutations to targeted drugs. For a number of the children in the study, this type of sequencing has informed a change in their therapy.

In your own lab, what are you working on now that’s new, different and promising?

I am very excited about using the new and very powerful CRISPER technology to systematically define the Achilles heels in AML cells. Our lab is now aggressively validating candidate drug targets that have emerged from these genome-wide CRISPR screens.

What’s the one thing you’d like to achieve in your research career?

For me the Holy Grail would be that a discovery made in our lab has a strong impact on curing patients with cancer.

Anything else?

For me, there is nothing more gratifying than working with children with cancer. It is a real honour. It is truly remarkable now that I have been in this profession for many years, to see them grown up – adults, married with their own children and pursuing exciting careers. These are moments to treasure.

I am very excited about new opportunities in cancer discovery. It has been an amazing time in terms of advancements in technologies. From sequencing genomes to deleting genes one by one with CRISPR, I believe that these advances will enable discoveries that change how we treat patients with leukaemia. I am also excited about new classes of drugs that perturb the epigenome. And, of course, while not a focus of my own work, there is a lot of excitement about the promise of other new therapeutic approaches such as the application of immunotherapy.

Leukaemia Foundation and HSANZ Jointly Funds Three PhD Investigators

Leukaemia Foundation and HSANZ Jointly Funds Three PhD Investigators

The Leukaemia Foundation and the Haematology Society of Australia and New Zealand (HSANZ) are proud to announce the co-funding of three Australian Clinical and Science PhD investigators, whose work will focus on understanding blood cancer biology and the development of new diagnostics and precision medicines.

“It is paramount that we continue to invest in Australian blood cancer research and support the next generation of medical and science investigators whose work examines emerging and cutting edge therapies with the aim to lead us closer to better treatments, care and ultimately a cure for blood cancer,” Leukaemia Foundation’s CEO Bill Petch said.

The funding is the latest from the Leukaemia Foundation’s National Research Program which has seen more than $47 million invested into blood cancer research since 2002.

Over the past 16 years, the Leukaemia Foundation’s National Research Program has supported 355 researchers and co-investigators to undertake 260 research projects through PhD scholarships, clinical and post-doctoral fellowships and research grants.

The Leukaemia Foundation’s investment into research has contributed to development of new techniques and therapies many of which are now undergoing either clinical trial or are currently being used in the clinic including Venetoclax, Bortezomib, CAR T-cell therapy and liquid biopsies for blood cancers (a world first). Its research funding has resulted in more than 450 international, peer reviewed, academic research publications and 577 presentations given at national and international conferences.

“The Leukaemia Foundation is proud to have supported the academic and research careers of almost every senior haematologist in Australia. Over the years, our investment in research has contributed to significant advancements in understanding the genetic makeup of blood cancers, diagnostics, novel drug development and testing through clinical trials,” Mr Petch said.

“We are thrilled to continue this tradition with this latest round of PhD scholarship appointments.”

President of HSANZ Dr William Stevenson said the support from the Leukaemia Foundation was appreciated.

“We are delighted to partner with the Leukaemia Foundation to jointly support and offer scholarships to the best junior scientists and clinicians undertaking blood cancer research through our PhD program. All three investigators’ projects demonstrate strong clinical experience, a commitment towards patient-focused care and an ambition to contribute towards the blood cancer community with their research,” he said.

Appointed through the Leukaemia Foundation and HSANZ PhD Scholarship Program, the research projects are worth $360,000 over the next three years commencing 2019. The Leukaemia Foundation thanks the Bill Long Charitable Trust, managed by Equity Trustees and Bridgestone Australia for their contribution to the program.

All recipients were chosen by the Leukaemia Foundation and HSANZ Scholarship Committee selection panel and were awarded at the recent 2018 Blood conference in Brisbane. Details of the three PhD investigators and their research projects include:


    1. Dr Wei Jiang (Haematologist – Westmead Cellular Therapies Group, Sydney)

Dr Wei Jiang will be conducting two trials to establish the clinical safety and efficacy of T-cell immunotherapies for infection and malignancy; and the detailed functional, phenotypic and molecular changes in patients’ blood post T-cell therapy.

The research team will conduct a clinical trial of autologous CD19 chimeric antigen receptor (CAR) T-cells generated using the PiggyBac system for relapsed or refractory B-cell malignancies such as acute lymphoblastic leukaemia (ALL) and lymphoma. This is revolutionary research, as CAR T-cells can be generated with this technology for a fraction of the cost of those produced using viral vector, making CAR T-cells more affordable to patients. This research aims to establish the safety and efficacy of PiggyBac CAR19 T-cells in a cohort of 20 patients.

This research will also examine into pathogen-specific T-cells for therapy resistant viral infections after an allogenic haemopoietic stem cell transplant (HSCT), which can lead to significant morbidity and mortality. Dr Jiang and his team will run a Phase lll study assessing the safety and efficacy of administering banked 3rd party donor derived infection-specific T-cells to patients with resistant viral infections such as cytomegalovirus (CMV), Epstein-Barr virus (EBV or adenovirus).


    1. Dr Karthik Nath (Haematologist – Mater Research Institute, Queensland)


The research undertaken by Dr Nath aims to develop a deeper understanding of the biology of Follicular Lymphoma (the second most common Non-Hodgkins Lymphoma) by employing evolving genetic and molecular laboratory technologies in prognostic paradigms.

Dr Nath and his team aims to incorporate these elements into upfront prognostication in Follicular Lymphoma that would represent a practical means of improving diagnostic techniques and treatment approaches with real-world applicability.

The second part of the research aims to help engender precision medicine in the treatment of patients with Follicular Lymphoma. By applying patient-specific immunological, molecular and genetic markers in prognostication, the research team is confident they will improve patient outcomes through individualised treatment approaches.

Utilising these highly specific markers may also help the greater research community understand disease processes and be incrementally beneficial to public health medicine. The team is hopeful individualising treatment will empower patients and reinforce the importance of psychosocial aspects involved in cancer care.


    1. Elizabeth Lieschke (Scientist – Walter and Eliza Hall Institute, Victoria)


Ms Lieschke’s research investigates the mechanism by which tumour suppressor gene, Tp53, prevents the development of leukaemia, lymphoma and other cancers; and the processes by which activation of Tp53 kills malignant cells.

The study aims to understand why some blood cancer cells die, whilst other cancer cells undergo cell cycle arrest/cell senescence and are therefore more likely to relapse following cancer therapy.

Ms Lieschke and team hopes to identify biomarkers that will enable the team to predict the nature of the response of cancer cells to drugs that activate Tp53, and leading to therapies that will be more personalised and targeted.

Mutations in Tp53 occur frequently in blood cancers that relapse following therapy and for these patients, the prognosis is extremely poor.

A deeper understanding of the impact of mutations in Tp53 on the expression of critical genes involved in tumour suppression will inform the design of novel therapeutics that could act downstream of Tp53, and efficiently kill mutant Tp53 expressing blood cancers. The team believes such therapies are desperately needed because they would improve the prognosis for blood cancer patients.


About HSANZ:

The Haematology Society of Australia and New Zealand aims to promote, foster and develop the discipline of haematology in all its aspects and particularly provides support and advocacy for research in haematology.

New PBS listing vital to Australians living with Acute Myeloid Leukaemia

New PBS listing vital to Australians living with Acute Myeloid Leukaemia

Leukaemia Foundation CEO Mr Bill Petch has today supported the Health Minister Mr Greg Hunt’s Pharmaceuticals Benefits Scheme (PBS) listing announcement of midostaurin (Rydapt®), a targeted therapy that is considered to be an important advancement in the treatment of Acute Myeloid Leukaemia (AML) in 25 years.

Mr Petch joined industry leaders at the Peter MacCallum Cancer Centre in Melbourne to announce midostaurin would be accessible through the PBS from December 1 for newly diagnosed Australian adults with AML who hold the FLT3-gene mutation.

The new treatment would be used as a first line therapy in combination with chemotherapy as well as a stand-alone single agent maintenance in patients responding to initial therapy.

AML is a rare and aggressive blood cancer that progresses rapidly and is frequently fatal, with a five-year survival rate of just 24 per cent. Around 1000 people are diagnosed with AML in Australia each year.

Mr Petch said new precision medicines like midostaurin could contribute to a future where Australians no longer died from blood cancers.

“This is a much needed and long-awaited step forward for AML patients. Having affordable access to these treatments through the PBS is vital for improving their quality of life and ultimately surviving their blood cancer,” he said.

“We look forward to seeing more PBS listings of these new generation targeted therapies to ensure Australians diagnosed with a blood cancer have affordable access to these treatments as quickly as possible.”

The Leukaemia Foundation provides free practical and emotional support to Australian’s diagnosed with a blood cancer including AML. The Foundation produces a series of disease specific newsletters including AML News, and invites all Australians living with the disease to subscribe for ongoing information.