A way to treat cancers caused by a tumor-driving protein called “myc,” paving the way for patients with myc-driven cancers was found by UC San Francisco researchers.
Myc acts somewhat like a master within cells to promote uncontrolled growth. This has been impossible to target with drugs.
The discovery of biochemical link within tumor cells lead to clinical trials for experimental drug treatments that indirectly target myc and that are being evaluated in human studies, the researchers said.
UCSF Helen Diller Family Comprehensive Cancer Center scientists led by Davide Ruggero, PhD, and Kevan Shokat, PhD, used one such drug to stop tumor growth in a mouse model of myc-driven lymphoma and multiple myeloma types of blood cancer.
Their study is published online in Proceedings of the National Academy of Sciences (PNAS). Previous Drug Therapies Unrestrained myc activity results in poor treatment including death.
Although other cancer-associated proteins have been successfully attacked with targeted therapies in recent years, the myc protein has continued to elude efforts to develop drugs that target it. In the PNAS paper, the UCSF researchers describe how they found a way too.
The researchers discovered that cancerous myc can be thwarted by treatment that targets a specific function performed by another protein, called mTOR. Protein Production in Cancer Is Promising Target Ruggero has for several years been probing the ability of tumor cells to make extraordinary amounts of protein to sustain their rapid growth and immortality. He also explores ways to target this excess protein production in cancer.
“One of the major effects of myc activation is a dramatic increase in the capacity of affected cells to make protein,” Ruggero said “This, in turn, leads to increased cell survival and proliferation, and to unstable genomes that foster additional mutations that turn these abnormal cells into tumor cells.” In his earlier studies that myc not only drives protein production, but also that myc-driven cancer cells become absolutely dependent upon this ability to make abnormal amounts of protein. When he genetically manipulated myc-driven cancer cells to slow protein production, they committed suicide, as abnormal cells are supposed to do for the greater good. Also he added “Tumors become addicted to excessive protein production, and mutant myc itself seems to depends on it,”
In the new study, the UCSF team discovered that mTOR disables a protein that acts as a tumor suppressor, called 4EBP1. The disabling of 4EBP1 releases normal constraints on protein production within the cell.
The researchers targeted mTOR with an experimental drug based on a prototype first designed by Shokat, an expert in designing molecules, called a kinase. Our discovery may provide a novel solution for these patients.”
“We are excited by the work of Dr. Pourdehnad and believe these results are an important advance in understanding the role of myc pathway dysregulation in multiple myeloma, and allow for the development of therapeutic strategies,” said Jeffrey Wolf, MD, a UCSF blood disorder specialist, a sponsor of the research.
The drug used in the study, called MLN0128, is made by Millennium, an independently operated subsidiary of Takeda Pharmaceutical Co., Ltd., based in Cambridge, Mass., and it is being evaluated in clinical trials to treat a variety of cancers. It had not previously been viewed as a weapon against myc-driven tumors, according to the UCSF researchers.
Currently sold drugs directed against mTOR do not inhibit its ability to target 4EBP1, which Ruggero refers to as a “master regulator” of protein production.
“This is a unique therapeutic approach to make myc druggable in the clinic,” Shokat said