Κυριακή, 28 Φεβρουαρίου 2016

A NOVEL DRUG SHOW ACTIVITY IN HAEMATOLOGICAL MALIGNANCIES

ONC201, an investigational anticancer drug that triggers cell death in various tumor types, may have clinical potential for some blood cancers including mantle cell lymphoma and acute myeloid leukemia (AML), according to a recent clinical study.
A research team led by Michael Andreeff, MD, PhD, Professor of Leukemia at The University of Texas MD Anderson Cancer Center, found that ONC201, which is in early clinical trials, caused cell death even when the crucial protein p53 is mutated or deleted entirely. This dysfunction occurs in more than half of malignancies and can promote malignant characteristics of cancers as well as resistance to standard chemotherapy, raising an urgent need for novel therapeutic solutions. The study results were published by Ishizawa et al in Science Signaling.
ONC201 is a first-in-class drug being clinically developed by Oncoceutics Inc and MD Anderson through an alliance formed in January 2015. The drug is of interest due to its ability to kill cancer cells without harming healthy cells. Previously, Dr. Andreeff and others conducted extensive preclinical studies of ONC201.
Key Findings
“The clinical challenge posed by p53 abnormalities in blood malignancies is that therapeutic strategies other than standard chemotherapies are required,” said Dr. Andreeff. “We found that ONC201 caused p53­–independent cell death and cell-cycle arrest in cell lines and in lymphoma and acute leukemia patient samples.”
The patient samples included those that demonstrated genetic abnormalities linked to a poor prognosis, or cells that developed resistance to the drugs ibrutinib (Imbruvica) and bortezomib (Velcade) commonly used to treat patients with lymphoma and multiple myeloma. Additionally, studies in mice revealed that ONC201 caused cell death in AML and leukemia stem cells but appeared to spare normal bone marrow cells.
ONC201 increased the translation of the stress-induced protein ATF4 through stress signals that are similar to those caused by cellular responses known as UPR (unfolded protein response) and ISR (integrated stress response). Every cellular protein must be properly folded for cells to survive. UPR is the major response against unfolded proteins, and prolonged or excess UCR can eventually cause cell death. Using similar mechanisms, nutrient deprivation and viral infection can cause ISR. ATF4 is commonly induced in these responses and by ONC201 treatment. ATF4 has the ability to turn specific genetic instructions on and off.
“This increase in ATF4 in ONC201-treated hematopoietic cells promoted cell death,” said Dr. Andreeff. “However, unlike with UPR and ISR, the increase in ATF4 in ONC201-treated cells promoted was not regulated by standard molecular signaling, indicating a novel mechanism of stressing cancer cells to death regardless of p53 status. There is clear evidence that ONC201 has clinical potential in hematologic malignancies.”
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

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