Sections

Section of Molecular Hematology and Therapy

The Molecular Hematology and Therapy section, working closely with other investigators at the MD Anderson Cancer Center, primarily conducts basic and translational research in cancer and leukemia. Our basic research programs are supported by funding from the National Institutes of Health (NIH).

Molecular Hematology and Therapy is also the site of the NIH-funded core lab which provides Confocal Microscopy / Image Analysis and Flow Cytometry / Cell Sorting services to researchers at MD Anderson. Three physicians in the section are participating in treating patients with hematopoietic malignancies -- in particular, patients with leukemia and patients receiving marrow and stem cell transplants.

FOR ASSISTANCE CALL: (713) 745-2471

ADDRESS
John Mendelsohn Faculty Center (FC3.3038)
1515 Holcombe Blvd. Unit 0425
Houston, TX 77030

Click here to access the Confocal Microscopy/ Image Analysis and Flow Cytometry/Cell Sorting.

Research

Welcome to the Section of Molecular Hematology and Therapy (MHT) website. The molecular changes causing hematological malignancies 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 the disease.

The primary research focus in MHT has been to identify and overcome mechanisms of drug resistance in leukemias. We are investigating and targeting four mechanisms, in particular: 1) cytokinetic 2) multidrug resistance (MDR-1)-mediated, 3) apoptosis-related, and 4) microenvironment-mediated drug resistance. We identified cell kinetic quiescence of leukemic cells as a mechanism of resistance to cytotoxic agents, demonstrated their prognostic impact, and were first to provide evidence that activation/mobilization of these cells by hematopoietic cytokines sensitized them to chemotherapy. We confirmed this concept in trials conducted at MD Anderson and in Europe in over 1,000 acute myeloid leukemia (AML) patients. This FLAG-Ida protocol has yielded a 20% increase in survival of AML patients with “intermediate” or “good” prognosis. It is used world-wide and is considered one of the best AML salvage protocols.

We developed treatment strategies to address the prognostic importance of multidrug resistance protein-1 (MDR-1) expression in AML, tested strategies to inhibit the protein in vitro, and conducted the first Phase I study with the MDR-1 inhibitor PSC-833. In collaboration with colleagues at MD Anderson, we investigated basic mechanisms of action of a new anthracycline, annamycin, and found it to be independent of MDR-1. We conducted a pivotal Phase I study of annamycin in leukemias, which demonstrated activity in MDR-1-expressing leukemias. Furthermore, PKCα was identified as another target in AML and we conducted a clinical trial with the PKCα inhibitor bryostatin.

For well over a decade, we have focused on apoptosis pathways in myeloid and lymphoid leukemias with in depth analysis of Bcl-2 and inhibitor of apoptosis (IAP) family members, under the auspices of the National Cancer Institute AML Program Project Grant “The Therapy of AML”, which we have been fortunate to have for the past 20 years. We identified Bcl-2 expression as a major independent prognostic factor in AML, with the qualifier that its function and prognostic impact seems to vary in different cytogenetic contexts. We were also 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 helped in the development of ABT-737, 263, and 199. ABT-199 (venetoclax) has shown over 80% response rate in relapsed/refractory CLL 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 and MDM2 inhibitors for which we developed the pre-clinical rationale.

Regarding the latter, we have been instrumental in the development of MDM-2 inhibitors to activate, in a non-genotoxic manner, p53 signaling in cancer cells. From their inception, we worked closely with industrial collaborators on these inhibitors, in particular the nutlins and D-S3032, and conducted the first successful MDM-2 inhibitor trial in leukemias, which was recently published in Clinical Cancer Research. We have now developed extensive pre-clinical and in vivo rational for combinatorial Bcl-2 (i.e., apoptosis sensitization) and MDM-2 (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.

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 inhibitor for renal cancers) as a highly effective inhibitor of FLT3 in AML. This bench to bedside project exemplifies MHT’s approach to cure AML. Sorafenib is the only available FLT3 inhibitor for the treatment of AML and it is used world-wide for this purpose.

In the area of stem cell research, we established NOD/scid models of human hematopoiesis, leukemogenesis, and microenvironment, and conducted investigations into the role of the chemokine receptor CXCR-4 for engraftment of human leukemic cells in this model system. Inhibition of CXCR-4 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. We have developed extensive preclinical rationale to support the concept that CXCR-4 inhibition in leukemias will be the first step in sensitizing leukemic stem cells to mobilization and chemotherapy and will thus overcome the microenvironment-mediated resistance we discovered. Clinical trials with novel CXCR4 inhibitors are ongoing and highly promising.

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 they hence 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 are being used in human cancer therapy that include 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, and perhaps other epithelial, cancers.

All of these innovative programs are supported by funding from the National Institutes of Health. MHT is also the site of the National Institutes of Health-funded core lab which provides Confocal Microscopy/ Image Analysis and Flow Cytometry/Cell Sorting services to researchers at MD Anderson.