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Welcome to the Section of Molecular Hematology and Therapy (MHT), Director Michael Andreeff M.D., Ph.D. 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 by which tumors develop and how they can be treated. We work closely with other investigators at The University of Texas MD Anderson Cancer Center (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 BAD was invariably phosphorylated in all patients with AML, and it functions as an anti-apoptotic protein. Based on this finding that Bcl-2 family members are selectively overexpressed in AML stem cells, clinical trials with molecular therapeutics targeting these apoptosis regulators are now in progress at MD Anderson and world-wide. In 2007, we published a seminal paper on Bcl-2 inhibitors in Cancer Cell, which facilitated the development of ABT-737, 263, and 199. ABT-199 (venetoclax) has shown over 80% response rate in relapsed/refractory chronic lymphocytic leukemia and is expected to receive FDA approval shortly. Our group is now developing ABT-199 for AML therapy. 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, which we have considerable pre-clinical validation. In fact, we recently published a seminal paper in Cancer Cell that showed superior treatment efficacy of the ABT-199 and RG7388, an MDM2 inhibitor, combination against AML.

Regarding the latter, we have been instrumental in the development of MDM2 inhibitors to activate, in a non-genotoxic manner, p53 signaling in cancer cells. From their inception, we worked closely with industry collaborators on these inhibitors, in particular the nutlins and D-S3032, and conducted the first successful MDM2 inhibitor trial in leukemias, which was recently published in Clinical Cancer Research. We have now developed extensive pre-clinical and in vivo rationale for combinatorial Bcl-2 (i.e., apoptosis sensitization) and MDM2 (i.e., p53 activation) inhibition, which addresses molecular shortcomings of each individual targeted therapy, and a clinical trial examining these treatments is about to start. Additionally, we are developing agents like the imipridone compound ONC201 that is cytotoxic to p53 mutant cells, as well as overcoming p53 inactivation via amyeloid formation with the novel peptide p53 activator ReACp53, as mechanisms to eradicate AML cells.

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 sorafenib (a drug originally developed as a RAF kinase inhibitor for renal cancers) as a highly effective inhibitor of FLT3 in AML. This bench to bedside project exemplifies MHT’s approach to cancer care and the cure AML. Sorafenib is the only available FLT3 inhibitor for the treatment of AML and it is used world-wide for this purpose. We are also currently developing multi-kinase inhibitors like E6201, and CG’806, a first-in-class, small molecule that reportedly blocks FLT3/BTK/Aurora multi-kinases, as combinatorial approaches with FLT3 inhibitors 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, cell-extrinsic microenvironmental factors have a crucial role in leukemogenesis and maintenance. 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 will be intimately supported by cutting-edge technology like time-of-flight mass cytometry (CyTOF) available from the Confocal Microscopy/ Image Analysis and Flow Cytometry/Cell Sorting Core Laboratory.

In the area of stem cell research, we established NOD/scid and PDX 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 AMD3465 using breast cancer cells 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, inhibition of CXCR4 may facilitate downregulation of let-7a to overcome chemoresistance in AML. 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. Clinical trials with novel CXCR4 inhibitors are ongoing and highly promising. In addition to CXCR4, E-selectin and arginase are promising new targets for AML therapy.

We also discovered that mesenchymal stromal cells (MSC) can be used as anti-cancer agents. These cells home to the stroma of hematologic malignancies, and solid tumors, and hence they can be used to deliver anti-tumor agents. We discovered that systemic infusion of MSC that were genetically modified to secrete interferon or other therapeutic cytokines could interfere with the growth and metastasis of a broad range of cancers. This is an exciting strategy for delivering therapeutic drugs to the microenvironment of the cancer. These groundbreaking approaches that manipulate MSC 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 breast cancer stem cell marker the gangliosde GD-2. 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 National Institutes of Health and the Cancer Prevention and Research Institute of Texas. MHT is also the site of the National Institutes of Health-funded Core Laboratory, Dr. Andreeff, Director, which provides confocal microscopy, image analysis, flow cytometry, and cell sorting services to researchers at MD Anderson.

1. Synthetic Lethality of Combined Bcl-2 Inhibition and p53 Activation in AML: Mechanisms and Superior Antileukemic Efficacy.
2. Anexelekto /MER Tyrosine Kinase inhibitor ONO-7475 growth arrests and kills FMS-Like Tyrosine Kinase 3-Internal Tandem Duplication Mutant Acute Myeloid Leukemia cells by diverse mechanisms.
3. The Imipridone ONC201 Induces Apoptosis and Overcomes Chemotherapy Resistance by Up-Regulation of Bim in Multiple Myeloma.
4. Macrophages facilitate resistance to anti-VEGF therapy by altered VEGFR expression.
5. Single-Cell Mass Cytometry of Acute Myeloid Leukemia and Leukemia Stem/Progenitor Cells.
6. Vosaroxin in combination with decitabine in newly diagnosed older patients with acute myeloid leukemia or high-risk MDS.
7. Tumor Trp53 status and genotype affect the bone marrow microenvironment in acute myeloid leukemia.
8. AML-induced osteogenic differentiation in mesenchymal stromal cells supports leukemia growth.
9. High-throughput profiling of signaling networks identifies mechanism-based combination therapy to eliminate microenvironmental resistance in acute myeloid leukemia.
10. Combined targeting of STAT3 and STAT5: a novel approach to overcome drug resistance in chronic myeloid leukemia.
11. IKK inhibition by BMS-345541 suppresses breast tumorigenesis and metastases by targeting GD2+ cancer stem cells.
12. Targeting mantle cell lymphoma metabolism and survival through simultaneous blockade of mTOR and nuclear transporter exportin-1.
13. A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia.
14. Combined inhibition of β-catenin and Bcr-Abl synergistically targets tyrosine kinase inhibitor-resistant blast crisis chronic myeloid leukemia blasts and progenitors in vitro and in vivo.
15. A phase 1/2 study of chemosensitization with plerixafor plus G-CSF in relapsed or refractory acute myeloid leukemia.
16. Jab1/Csn5-Thioredoxin Signaling in Relapsed Acute Monocytic Leukemia under Oxidative Stress.
17. Focal Adhesion Kinase as a Potential Target in AML and MDS.
18. More than 1 TP53 abnormality is a dominant characteristic of pure erythroid leukemia.
19. Mesenchymal stromal cells for the delivery of oncolytic viruses in gliomas.
20. PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer.
21. The novel BMI-1 inhibitor PTC596 downregulates MCL-1 and induces p53-independent mitochondrial apoptosis in acute myeloid leukemia progenitor cells.
22. FZR1 loss increases sensitivity to DNA damage and consequently promotes murine and human B-cell acute leukemia.
23. Bone Marrow Adipocytes Facilitate Fatty Acid Oxidation Activating AMPK and a Transcriptional Network Supporting Survival of Acute Monocytic Leukemia Cells.
24. Antileukemia Efficacy and Mechanisms of Action of SL-101, a Novel Anti-CD123 Antibody Conjugate, in Acute Myeloid Leukemia.
25. Relapse risk and survival in patients with FLT3 mutated acute myeloid leukemia undergoing stem cell transplantation.
26. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab.
27. Targeting autophagy to overcome chemoresistance in acute myleogenous leukemia.
28. Buparlisib, a PI3K inhibitor, demonstrates acceptable tolerability and preliminary activity in a phase I trial of patients with advanced leukemias.
29. Persistence of minimal residual disease assessed by multiparameter flow cytometry is highly prognostic in younger patients with acute myeloid leukemia.

Click below for a complete list of published works, which are among 635 peer-reviewed publications and reviews.

https://www.ncbi.nlm.nih.gov/pubmed/?term=andreeff+m

Andreeff, Michael
Professor and Section Chief
mandreef@mdanderson.org

Battula, Lokesh
Assistant Professor
vbattula@mdanderson.org

Benton, Chris
Assistant Professor
CBBenton@mdanderson.org

Borthakur, Gautam
Associate Professor
GBorthak@mdanderson.org

Burks, Jared
Assistant Professor
jburks@mdanderson.org

Carter, Bing
Associate Professor
bicarter@mdanderson.org

Klopp, Ann
Assistant Professor
AKlopp@mdanderson.org