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Welcome to the Section of Molecular Hematology and Therapy (MHT), Molecular changes causing hematological malignancies, including acute myeloid leukemia (AML), are being identified at an unprecedented pace. With this molecular knowledge, we now have the opportunity to develop novel diagnostic and therapeutic tools, which can be translated for clinical use. Members of MHT have made major contributions to the elucidation of critical mechanisms through which tumors develop, and consequently how they can be treated. We work closely with other investigators at (MD Anderson) to conduct basic and translational cancer research that is envisioned to eradicate AML and other types of cancer.

The primary research focus in MHT has been to identify and overcome mechanisms of drug resistance in leukemias. We are investigating and targeting two principal mechanisms: 1) apoptosis-related and 2) microenvironment-mediated drug resistance in AML. For example, we were first to discover that the pro-apoptotic Bcl-2 family member , and it functions as an anti-apoptotic protein. Based on this finding that Bcl-2 family members are selectively overexpressed in AML stem cells, and clinical trials with molecular therapeutics targeting these apoptosis regulators are now in progress at MD Anderson and world-wide. In 2006, we published a seminal paper on Bcl-2 inhibitors in , which facilitated the development of ABT-737, 263, and 199. ABT-199 (venetoclax) has shown over 80% response rate in relapsed/refractory CLL and received FDA approval as a result. Our group then developed (venetoclax) for AML therapy, alone and in combination with demethylating agents (HMAs). We showed pronounced pre-clinical activity, conducted the first clinical trial, and are now engaged in combinatorial trials with MAPK, or other broad-spectrum kinase inhibitors, exportin 1 (XPO1) inhibitors, or MDM2 inhibitors, for which we have considerable pre-clinical validation. In fact, we published a seminal paper in that showed superior treatment efficacy of the ABT-199 and RG7388, an MDM2 inhibitor, combination against AML, which is being validated in clinical trials. The has already revolutionized the treatment of AML and is yielding response rates of >90% in patients unfit for conventional therapy. The venetoclax/HMA combination for AML was also FDA approved. As another mechanism-based evolutionary step, we have investigated combinations of Bcl-2 and Mcl-1 inhibitors, which shows pronounced synergism, .

We have further pioneered the development of to activate, in a non-genotoxic manner, p53 signaling in cancer cells. From their inception, we worked closely with industry collaborators on these inhibitors and conducted the first successful MDM-2 inhibitor trial in leukemias, published in . We have now developed extensive pre-clinical and in vivo rationale for combinatorial Bcl-2 (i.e., apoptosis sensitization) and MDM-2 (i.e., p53 activation) inhibition, , and clinical trials examining these treatments are ongoing.

Recently, MHT faculty described the atypical mitochondrial integrated stress response that allows p53 mutation-independent killing of leukemia and lymphoma cells (, 2016). They also identified drugs that activate this pathway, imipridones (e.g., ONC 201 and ONC 212), which are now in clinical trials for numerous tumor types. This work identified a novel target in cancer therapy; activation of the mitochondrial protease ClpP. The close collaboration between the MHT faculty at MD Anderson and scientists at Princess Margaret Research Institute in Toronto resulted in five top-tier publications (, 2016, , 2016, , 2017, , 2019, and , 2019).

Thirty percent of AMLs overexpress the tyrosine kinase FLT3. We were first to identify, in the laboratory and then in the clinic, the tyrosine kinase inhibitor (a drug originally developed as a Raf inhibitor for renal cancers) as a highly effective inhibitor of FLT3 ITD in AML. This bench to bedside project exemplifies MHT¡¯s approach to cancer care and the cure of AML. Sorafenib is used world-wide for this purpose, while other more targeted FLT3 inhibitors are being developed. We are also currently developing a multi-kinase inhibitor, CG¡¯806, a first-in-class, small molecule that blocks FLT3/BTK/Aurora kinases, to overcome or prevent FLT3 inhibitor resistance in AML.

Studies conducted during the past two decades have shed light on the understanding of the genetic basis for AML. However, the mechanisms by which AML blasts create an immune-privileged niche and suppress immune responses to evade a patient¡¯s immune system are poorly understood. More recently, new biological insights have been provided supporting the notion that, along with the leukemic cell autonomous defects, . In particular, inflammatory networks acting in the milieu surrounding the leukemia blasts appear to play a crucial role in leukemia initiation and progression, as well as in their response to chemotherapy. To better understand the complex microenvironmental relationships in leukemogenesis and therapy, the group recently received a five-year Cancer Prevention and Research Institute of Texas MIRA Program Project Grant to investigate the hypoxic immunosuppressive microenvironment in AML. This project is supported by cutting-edge technologies like time-of-flight mass cytometry () and intravital imaging available from the Core Laboratory and the Advanced Microscopy Core (Director: Dr. M. Andreeff).

In the area of stem cell research, we established and models of human hematopoiesis, leukemogenesis, and microenvironment, and conducted investigations into the role of the chemokine receptor CXCR4 for engraftment of human leukemic cells in these model systems. Inhibition of CXCR4 with small peptides and chemical inhibitors has promise for the improved collection of normal stem cells by apheresis and also for the prevention of bone metastases of breast cancer cells. In particular, a study of the CXCR4 inhibitor in a metastatic breast cancer model in vitro and in vivo was particularly illuminating and therapeutically promising. As such, it now has become among the top 25% most cited articles in PLOS ONE. Furthermore, . This extensive preclinical rationale supports the concept that CXCR4 inhibition in leukemias will be the first step in sensitizing leukemic stem cells to mobilization and chemotherapy and it is envisioned to overcome the microenvironment-mediated resistance mentioned previously. are ongoing, highly promising and showing clinical efficacy. In addition to CXCR4, E-selectin and arginase are promising new targets for AML therapy.

MHT members are also currently investigating single-cell DNA and RNA analysis as part of a program titled ¡°Targeting Minimal Residual Disease and Stem-like Cells in High-Risk AML,¡± which focuses on the molecular characterization of minimal residual disease in p53-mutated AML. The project aims to functionally-identify subsets of leukemia cells that persist in remission and expanded at relapse, characterize their genetic (single cell DNA sequencing), transcriptomic (single-cell RNA sequencing) and proteomic (single cell CyTOF mass spec) signatures, to identify novel targets in these patient fate-determining cells and generate novel CAR T-cells, and pathway modulators that effectively eliminate these AML leukemia relapse-initiating MRD cell subpopulations.

We further discovered that bone marrow-derived mesenchymal stromal cells (MSC) home to the stroma of hematologic malignancies, solid tumors and their metastases, and can be used to produce anti-tumor agents in situ. We discovered that systemic infusion of or other therapeutic cytokines could interfere with the growth and metastasis of a broad range of cancers. This is an exciting strategy for producing therapeutic proteins in the microenvironment of cancers. These groundbreaking approaches are now being used in human cancer therapy that includes an FDA-approved trial for ovarian cancer.

Finally, based on studies of epithelial-to-mesenchymal transition in solid tumors, we identified the first . We are now establishing a program to target GD-2 with small molecule inhibitors, antibodies, and CAR-T-cells. This discovery is patented and offers great potential for the cure of breast cancer and perhaps other epithelial cancers.

All of these innovative programs are supported by funding from the Institution, National Institutes of Health, and the Cancer Prevention and Research Institute of Texas, Leukemia Society, Breast Cancer Research Foundation and other sources. MHT is also the home of the National Institutes of Health-funded Core Laboratory, , which provides services, including CyTOF mass cytometry and imaging, to researchers at MD Anderson, and the Advanced Microscopy Core which provides super-resolution, 2-photon intra-vital and soon light sheet imaging.

MHT integrates the work of more than 50 scientists and has a well-established infrastructure that helps young investigators to advance and become independent.

See also the complete list of  articles, which are among 705 peer-reviewed publications and reviews, and the textbook  (Springer), which has been downloaded more than 75,000 times.

Professor and Section Chief
mandreef@mdanderson.org

Associate Professor
vbattula@mdanderson.org

Professor
GBorthak@mdanderson.org

Associate Professor
jburks@mdanderson.org

Professor
bicarter@mdanderson.org

Assistant Professor
JIshizawa@mdanderson.org