Novel method to treat diabetes - Hosein Kouros-Mehr

A recent report in Nature* describes a potentially new way of treating patients with type-2 diabetes.  The approach involves block an enzyme involved in the degradation of insulin, thereby boosting insulin levels.  The authors identify inhibitors of the insulin-degrading enzyme IDE.  A physiologically active IDE inhibitor was identified using a DNA-templated macrocycle small molecule library.  The inhibitor binds to IDE in a binding pocket located distally from the catalytic site.  Obese mice treated with the IDE inhibitor showed improved glucose tolerance upon administration of oral glucose.  Interestingly, the IDE inhibitor regulated multiple hormone levels in these mice, including glucagon and amylin, in addition to insulin.  This study suggests that inhibition of insulin degrading enzyme could be a novel approach for the treatment of diabetes.  

Maianti, et. al.  (2014).  Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones

Nature, doi:10.1038/nature13297

.Hosein Kouros-Mehr

Evidence of cancer stem cells in patient tumors - Hosein Kouros-Mehr

May 15, 2014

A recent paper* in Cancer Cell provides evidence of cancer stem cells in patient-derived tumors, which may validate the cancer stem cell hypothesis in a hematopoietic malignancy.  The cancer stem cell hypothesis has remained controversial due to experimental confounding variables, such as the strain of mice used for cancer stem cell implantation.  This study suggests that a rare population of Lin−CD34+CD38−CD90+CD45RA cells function as the propagating cells in patients with low- to intermediate-risk myelodysplastic syndrome.

Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by inefficient hematopoiesis and frequent progression to AML.  The authors of the study obtained MDS cells from patients and compared the relationships between  Lineage− (Lin−)CD34+CD38−CD90+CD45RA− candidate MDS-SCs with myeloid-restricted granulocyte-macrophage and megakaryocyte-erythroid progenitors (GMPs and MEPs).  They also transplanted the Lin−CD34+CD38−CD90+CD45RA− cells into mice and found that they gave rise to tumors with the same molecular signatures as those isolated directly from the patients.  The Lin−CD34+CD38−CD90+ MDS-SCs were molecularly and functionally distinct from clonally involved GMPs and MEPs and the Lin−CD34+CD38−CD90+ cells were able to replenish GMPs and MEPs, establishing their hierarchical relationship.

The authors found that deletion of 5q was among the first genetic lesions in MDS in the cancer stem cell population.  The 5q deletion was found to precede the acquisition of recurrent driver mutations in MDS , which served to confer self-renewal properties to MDS progenitors.

* Woll, et. al. (2014).  Myelodysplastic Syndromes Are Propagated by Rare and Distinct Human Cancer Stem Cells In Vivo.  Cancer Cell, in press

http://dx.doi.org/10.1016/j.ccr.2014.03.036

Hosein Kouros-Mehr

Novel immunotherapy approach - Hosein Kouros-Mehr

A recent paper* in Science reports that T cells recognizing a mutant protein found only in cancer cells can elicit an anti-tumor response when injected into a patient with end-stage epithelial cancer.  
The authors show that a 43-year old patient with metastatic cholangiocarcinoma carried tumor-infiltrating lymphocytes that recognized a mutant form of erbb2-interacting protein (ERBB2IP).  To do this, the authors resected lung metastases from the patient for whole exome sequencing and found 26 nonsynonymous mutations.  For each mutation, they created minigene constructs (containing the mutation and 12 flanking amino acids) and transfected constructs into antigen-presenting cells for co-culture with patient-derived tumor-infiltrating lymphocytes.  They found that  a patient-derived T-cell clone responded to mutant ERBB2IP and elicited a T-cell response with the release of IFN-gamma and activation of OX40 and 4-1BB.
The mutated ERBB2IP-specific T cells from the patient were then expanded and used for adoptive transfer to determine if these cells could elicit an anti-tumor response in the patient.  The patient received 42.4 billion tumor-infiltrating lymphocytes containing these T cell clones and also received 4 doses of IL-2 to enhance T-cell proliferation.  The patient displayed tumor regression 2 months after therapy, despite showing evidence of progressive disease prior to treatment.  The patient showed disease stabilization for 13 months after therapy, after which time she experienced disease progression in lungs but not liver.  
Further work will be necessary to validate this approach in cancer therapy.  T-cell adoptive transfer was previously shown to be a viable option for cancer patients, and the explosion of cancer mutation data from TCGA and other sources will offer new targets for cancer immunotherapy.

*Tran, et. al. (2014). Cancer Immunotherapy Based on Mutation-Specific CD4+ T Cells in a Patient with Epithelial Cancer. Science Vol. 344 no. 6184 pp. 641-645 DOI: 10.1126/science.1251102

Hosein Kouros-Mehr