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Washington, December 25
A group of scientists in the United States, including an Indian-American from the prestigious Cleveland Clinic, have identified a potential new class of drugs that may prove effective in treating some common types of blood and bone marrow cancers .
First published in the latest edition of Blood Cancer Discovery, the decade-long research that reports that a new pharmacological strategy to target and preferentially eliminate leukemia cells with TET2 mutations, was carried out by Jaroslaw Maciejewski and his collaborator Babal Kant Jha of the Cleveland Clinic Department of Translational Research in Hematology and Oncology.
Myeloid leukemias are cancers derived from stem and progenitor cells in the bone marrow that give rise to all normal blood cells.
One of the most common mutations involved in driving myeloid leukemias is found in the TET2 gene, which has been studied for the past decade by Maciejewski and Jha.
“In preclinical models, we found that a synthetic molecule called TETi76 was able to target and kill mutant cancer cells both in the early stages of the disease – what we call indeterminate potential or clonal hematopoiesis. CHIP – and in the fully developed mutant TET2 myeloid leukemia, ”said Dr. Maciejewski.
According to a press release, the research team designed TETi76 to replicate and amplify the effects of a naturally occurring molecule called 2HG (2-hydroxyglutarate), which inhibits the enzymatic activity of TET genes.
The TET DNA dioxygenase gene family encodes enzymes that remove chemical groups from DNA molecules, which ultimately changes the genes expressed and may contribute to the development and spread of disease.
While all members of the TET family are dioxygenases, the most potent enzyme activity belongs to TET2, the press release says. Even when TET2 is mutated, however, its related genes TET1 and TET3 provide residual enzymatic activity.
Although significantly less, this activity is still sufficient to facilitate the spread of mutated cancer cells.
Maciejewski and Jha’s new pharmacological strategy to selectively eliminate TET2 mutant leukemia cells focuses on targeting their dependence on this residual activity of DNA dioxygenase, he said.
“We have learned from the natural biological capacities of 2HG,” explained Jha, principal investigator.
“We studied the molecule and rationally designed a new small molecule, synthesized by our chemistry group led by James Phillips, PhD. Together, we generated TETi76 – a similar, but more potent version capable of inhibiting not only TET2, but also the remaining pathogenic enzyme activity of TET1 and TET3, ”said Jha.
Cleveland Clinic said the researchers studied the effects of TETi76 in preclinical disease and xenograft models (where human cancer cells are implanted in preclinical models). Further studies will be essential to investigate small molecule cancer fighting abilities in patients.
“We are optimistic about our results, which show not only that TETi76 preferentially restricts the growth and spread of cells with TET2 mutations, but also gives a survival advantage to normal stem and progenitor cells,” Jha said. PTI
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