Exposing and exploiting the metabolic dependencies of cancer

Cancerous tumors are clbadified primarily according to their tissue origin. However, the sequencing of the human genome and the development of powerful and affordable DNA sequencing technologies have ushered in a new era of precision oncology, in which patients are treated with treatments. custom designed to target the specific mutations of their tumor.

This new therapeutic approach has yielded significant success, but recently, many cancer specialists have begun to suspect that the presence of cancer in the body can affect the behavior of certain mutations and play a major role in the response of cancer. patients to targeted treatments. Currently, the way in which the tissue environment shapes the genetic constitution of the tumor is not well understood.

In a new newspaper, published on April 24, 2019 in Nature, a team of researchers led by scientists from the University of California San Diego School of Medicine and the Ludwig Institute for Cancer Research at the University of San Diego, describes a new set of "rules" for predicting how the original tissue influences the critical aspects of genetic tumor composition, with potentially important therapeutic implications.

Focusing on an essential cellular molecule called nicotinamide adenine dinucleotide (NAD), an essential co-factor required for many cellular reactions, including energy metabolism, epigenetic regulation, and DNA damage response, is one of the most important of these. team led by lead author Paul S. Mischel, MD, professor in the pathology department of the University of San Diego School of Medicine and a member of Ludwig, in collaboration with Bing Ren, PhD, professor of cellular and molecular medicine; Vineet Bafna, PhD, professor of computer science and engineering; Postdoctoral researcher Sudhir Chowdhry, PhD, and other researchers have identified a surprising role for the original tissue in determining how cells make NAD, with important implications for cancer treatment.

Normal cells make NAD using one of three biochemical pathways. The team discovered that cancer cells behave very differently. By badyzing more than 7,000 tumors and 2,600 matched normal specimens from 19 different tissue types, coupled with mathematical modeling and in-depth studies on both cells and mice, the researchers found that cancer development is the main determinant of how cancer cells make NAD.

Unlike normal cells that can use one of three routes if needed, cancer cells can only use one single route of NAD synthesis, making them dependent on this pathway and extremely vulnerable to pharmacological interventions. targeted.

Specifically, in some organs of the body, an enzyme called nicotinic acid phosphoribosyltransferase or NAPRT, a key regulator of one of the three pathways, is highly expressed. Cancers that originate from organs that strongly express NAPRT include the prostate, ovaries, gastrointestinal tract, and pancreatic tissues. They have a high frequency of amplification of NAPRT and depend completely and irreversibly on its survival.

Researchers have shown that a drug that targets this pathway is very effective at killing tumors from these organs while sparing normal tissue, suggesting a promising new way to treat a large number of cancer patients.

The study also demonstrates that cancers not originating from these organs become dependent on a different pathway for the manufacture of NAD, via a change in epigenetic regulation, indicating that patients with these other Types of cancer should be treated with another set. therapies targeting the metabolism of NAD.

"This work – identifying and targeting specific pathways of NAD metabolism of cancer cells in many types of tumors – lays the foundation for a new set of specific, selective and highly promising cancer therapies that save the normal tissues, "said Mischel.

This article has been republished from material provided by UC San Diego. Note: Content may have changed for length and content. For more information, please contact the cited source.

Reference: Sudhir Chowdhry, et al. The metabolic dependence of NAD in cancer is shaped by gene amplification and remodeling of the amplifier. Nature (2019) DOI: https://doi.org/10.1038/s41586-019-1150-2