Understanding the GRP78-Cripto Protein Complex in Cancer
Molecular study offers insights for possible cure of treatment resistance and new drug possibilities based upon better understanding of the GRP78-Cripto Protein. CureMatch’s Tsigelny published in current Protein Science Journal article.
SAN DIEGO, CA – January 31, 2018: Igor F. Tsigelny, Ph.D., Co-founder and Chief Science Officer at CureMatch®, is a senior author of “Cripto Stabilizes GRP78 on the Cell Membrane” in Protein Science1. The results of this study point to new possibilities for drugs discovery and intervention in cancer.
Glucose-regulated protein 78 (GRP78) and Cripto interact on the surface of tumor cells, and only their binding causes the increase of cancer drug resistance. The new findings elucidate the structure of surface GRP78 in its interaction with Cripto. The binding complex between these proteins is an ideal target for novel cancer therapy due to its position at the surface of tumor cells, including pancreatic, colorectal, gastric, breast, ovarian, and lung cancers.
GRP78 is a hallmark of cancer cells that in response to cell stress acquires greater fitness and becomes resistant to different forms of therapy. Typically located in the endoplasmic reticulum (ER) of cells, GRP78 moves to the cell surface in response to stress. On the cell membrane, GRP78 can associate with Cripto, which plays important roles in normal embryonic development as well as the progression of tumor development.
The study’s molecular modeling and simulations show that Cripto binding to GRP78 completely changes its behavior on the cellular membrane, not allowing GRP78 to disconnect from it, and thus advancing tumor formation. Elucidation of this relationship between GRP78 and Cripto at the surface of cancer cells represents an important step in the development of a new class of therapeutics.
“A precise understanding of the stereochemical interaction between GRP78 and Cripto enables a better understanding of the tumor promoting effects of surface GRP78, a phenomenon that may occur in different cancer types and may initiate drug resistance and cancer progression,” Dr. Tsigelny states. “It will also stimulate the search for new drugs that by interfering with the GRP78-Cripto interaction can free cancer cells from growth promoting effects that, if unopposed, can lead to greater cell fitness and resistance to therapy.”
Igor F. Tsigelny is a biomedical researcher on the forefront of advances in molecular modeling, bioinformatics, and intelligent computing systems as applied to oncology. His cancer expertise led, in part, to the development of the CureMatch precision oncology technology. CureMatch scores and ranks Personalized Combination Therapy® options to target specific molecular aberrations for more effective treatment.
CureMatch analyzes millions of combinations of cancer drugs, both widely adopted and newly approved, as applied to the specific mutations identified in an individual patient’s genetic, proteomic and metabolomic profiles. Factoring detailed molecular dynamics of oncogenes and medicines, a PreciGENE Score is computed for each selected therapy or combination of therapies. In this way, personalized and actionable intelligence is distilled from massive pharmacological and clinical databases that would otherwise be daunting for oncologists’ practical application. Precision cancer treatments based on the molecular basis of tumors leads to improved survival rates.
 Cripto Stabilizes GRP78 on the Cell Membrane
Valentina L. Kouznetsova,1,2,* Hannah Hu,4,* Knut Teigen,5,* Maurizio Zanetti,1
Igor F. Tsigelny1,2,3,6#
1The Moores Cancer Center, University of California at San Diego, La Jolla, California
2San Diego Supercomputer Center, University of California at San Diego, La Jolla, California
3Department of Neurosciences, University of California at San Diego, La Jolla, California
4REHS program, San Diego Supercomputer Center, University of California at San Diego, La Jolla, California
5Department of Biomedicine, University of Bergen, Bergen, Norway
6CureMatch Inc., San Diego, California
Protein Science doi:10.1002/pro.3358
About Protein Science
Protein Science is the flagship journal of The Protein Society and serves an international forum for publishing original reports on all scientific aspects of protein molecules. The Journal publishes papers by leading scientists from all over the world that report on advances in the understanding of proteins in the broadest sense. Protein Science aims to unify this field by cutting across established disciplinary lines and focusing on “protein-centered” science.
CureMatch, Inc. is a San Diego-based digital precision oncology company focused on personalized medicine and combination therapy. CureMatch Reports guide oncologists with actionable intelligence to customize treatment for each individual patient based on each specific molecular tumor profile. Precision medicine is considered by many to be the future of cancer treatment as combination therapy has been used effectively in the treatment of other diseases, such as HIV/AIDS. The CureMatch technology has expert foundation in supercomputing, oncology, genetics, proteomics, biochemistry, and cell biology. For more information, visit www.curematch.com.
Name: Larissa Anderson