AUG 06, 2015 11:18 PM PDT

Regulating Tumor Growth

How do tumors grow, and how can they be stopped? A collaborative study between Sanford Burnham Prebys Medical Discovery Institute (SBP) and the Argonne National Laboratory may bring more clarity to those questions.
DLM promotes communication.
The scientists used a highly specialized X-ray crystallography technique to solve the protein structure of hypoxia-inducible factors (HIFs), considered critical regulators of a tumor's response to low oxygen (hyopoxia). The research, published in the journal, Nature, and reported in Drug Discovery & Development, helps scientists in the quest for new drugs to treat tumors by cutting off their supply of oxygen and nutrients (http://www.dddmag.com/news/2015/08/scientists-solve-structure-important-protein-tumor-growth?et_cid=4720282&et_rid=45505806&type=cta).

As Fraydoon Rastinejad, Ph.D., professor in the Metabolic Disease Program at SBP, explained, "For the first time, we have solved the structures of both HIF1-alpha and HIF2-alpha complexed with the ARNT subunit, a configuration required for HIF functionality. Visualizing these multi-domain structures helps us understand their drug binding capabilities and takes us further toward the goal of developing drugs that inhibit the tumor promoting effects of HIFs."

HIF proteins regulate genes that are important to the progression of a broad range of tumors, and altering their activity could be a promising approach for cancer therapy. While there have been major efforts to find drugs to inhibit HIF pathways, the only drug candidates to emerge from these efforts have been those that bind to another class of proteins called PHDs. PHD proteins regulate HIF activities, and there are many PHD inhibitors currently in clinical trials for anemia, chronic kidney disease, stroke and cancer.

According to an article in the Journal of Cell Biochemistry [2013 May;114(5):967-74. doi: 10.1002/jcb.24438, HIFs, angiogenesis, and cancer. Yang Y, Sun M, Wang L, Jiao B], "Tumor hypoxia was first described in the 1950s by radiation oncologists as a frequent cause of failure to radiotherapy in solid tumors. Today, it is evident that tumor hypoxia is a common feature of many cancers and the master regulator of hypoxia, hypoxia-inducible factor-1 (HIF-1), regulates multiple aspects of tumorigenesis, including angiogenesis, proliferation, metabolism, metastasis, differentiation, and response to radiation therapy. Although the tumor hypoxia response mechanism leads to a multitude of downstream effects, it is angiogenesis that is most crucial and also most susceptible to molecular manipulation. The delineation of molecular mechanisms of angiogenesis has revealed a critical role for HIF-1 in the regulation of angiogenic growth factors" (http://www.ncbi.nlm.nih.gov/pubmed/23225225).

Rastinejad explained that the new study "advances efforts to find new drugs that bind to HIF directly, rather than PHDs. We identified five different pockets in the architecture of the HIF complexes, all of which may be used for targeting small-molecule inhibitors. These drugs could conceivably inhibit HIF functions by reducing their stability, their ability to interact with other protein partners, and by altering mechanisms critical for their function."

Drugs that inhibit HIFs may be able to treat solid tumors. These cancers outgrow their blood supply and grow starved for oxygen, triggering HIFs to turn on genes that regulate many cancer cell survival pathways. The pathways include angiogenesis, erythropoiesis, increased expression of genes associated with anaerobic metabolism and metastasis.

Rastinejad concluded, "Our next step is to analyze a large number of patient samples with mutations in HIF proteins. We'd like to see where on the protein architectures these mutations occur, and how they manifest into HIF functional aberrations,". "Such mutations will offer a powerful glimpse into the structure-function activities of HIFs, and help us figure out how they turn genes on and off. The insights we make into the structure, function, and regulation of HIFs may also progress the development of treatments for a range of disease states beyond cancer, including heart disease, fatty liver, diabetes, and inflammatory diseases."
About the Author
  • Ilene Schneider is the owner of Schneider the Writer, a firm that provides communications for health care, high technology and service enterprises. Her specialties include public relations, media relations, advertising, journalistic writing, editing, grant writing and corporate creativity consulting services. Prior to starting her own business in 1985, Ilene was editor of the Cleveland edition of TV Guide, associate editor of School Product News (Penton Publishing) and senior public relations representative at Beckman Instruments, Inc. She was profiled in a book, How to Open and Operate a Home-Based Writing Business and listed in Who's Who of American Women, Who's Who in Advertising and Who's Who in Media and Communications. She was the recipient of the Women in Communications, Inc. Clarion Award in advertising. A graduate of the University of Pennsylvania, Ilene and her family have lived in Irvine, California, since 1978.
You May Also Like
JUN 01, 2018
Health & Medicine
JUN 01, 2018
Research Shows The Cause of Childhood Leukemia
Babies and young children need to be kept safe by the adults in their lives, however keeping them in a germ-free environment might not be the best idea. Ch...
JUN 05, 2018
Cancer
JUN 05, 2018
Precision vs. Personalized Medicine Part II: Personalized Approach
So often the phrases "Precision Medicine" and "Personalized Medicine" are used interchangeably. Are they really synonyms? Part II looks at Personalized Medicine...
JUL 10, 2018
Cancer
JUL 10, 2018
Risk Allele Variant SNP at 14q11.2 Linked to ALL
Researchers utilized genome-wide association studies to identify a variant SNP within a gene at 14q11.2 which is linked to ALL....
JUL 24, 2018
Cancer
JUL 24, 2018
Transfection, Transduction, and CRISPR...Oh My
CRISPR gene editing came about based on transfection and transduction type models of genetic transfer. There is potential for it to revolutionize gene editing but are there dangers lurking?...
AUG 21, 2018
Cancer
AUG 21, 2018
'Zombie' gene returns to life and kills cancer in elephants
Researchers have discovered a gene that can protect elephants from cancer. An estimated 17 percent of humans worldwide die from cancer, but less than five ...
SEP 02, 2018
Cell & Molecular Biology
SEP 02, 2018
Cancer Cell Lines can Evolve in the Lab
New research shows that scientists have to take steps to verify the identity of the cell lines they grow....
Loading Comments...