SARCOMA: SEARCHING FOR CAUSES AND CURES
Karina Galoian, Ph.D., is a research associate professor in the Department of Orthopaedics at the University of Miami Leonard M. Miller School of Medicine. She also leads the departmental Institutional Review Board and is Research Director of the Sarcoma Disease Site Group at Sylvester Comprehensive Cancer Center.
For the past 10 years, Dr. Galoian has been researching possible cures for chondrosarcoma, or cancer of the cartilage – a virtually untreatable form of cancer that accounts for 20 percent of all bone tumors.
Dr. Galoian earned a Master’s Degree in Biological Sciences from the University of Armenia and Master’s and Ph.D. degrees in Biochemistry from the National Academy of Sciences of Armenia. She was a Fogarty International Center visiting fellow in pharmacology at the National Institute of Mental Health in Bethesda, MD., and completed her postdoctoral fellowship at the University of Pennsylvania, where she investigated leukemogenic fusion proteins occurring during chromosomal translocation. Dr. Galoian is a 2017 recipient of the prestigious Albert Nelson Marquis Lifetime Achievement Award in Biochemistry, presented by Marquis Who’s Who.
Upon her arrival at the Miller School of Medicine, Dr. Galoian established the Musculoskeletal Oncology Signal Transduction Laboratory to study musculoskeletal tumor progression and metastasis; mechanisms of cellular cancer dormancy, cell cycle and oncogene inactivation; and extracellular matrix-cell communications. Devoted to bringing science from bench to bedside, her translational research centers on the development of a combined treatment protocol leading to a cure for sarcoma.
We are pleased to present a brief overview of some of Dr. Galoian’s most promising projects.
Project #1: Using Cancer-Fighting Neuropeptides to Treat Sarcoma
Despite therapeutic advances in oncology, the treatment of sarcomas (bone tumors) has proved vexing for researchers. Advanced and metastatic tumors are not eligible for surgery, and because sarcomas are aggressive and chemo-resistant, they do not respond to chemotherapy or radiation.
Chondrosarcomas, for example, are cancers of the cartilage and are the second most common bone malignancy, affecting the pelvis, long bones, and spine, as well as the larynx and head and neck. Drugs currently being tested in chondrosarcoma clinical trials are failing, making the discovery of new approaches and therapies even more crucial.
Neuropeptides such as Galarmin, a proline-rich peptide (PRP-1) isolated from the brain, have been shown to have antibacterial properties and a beneficial effect on the body’s immune system. Of even greater interest is PRP-1’s effect on dividing tumor cells. Dr. Galoian’s research has shown that it not only significantly decreases their number, it also inhibits their growth.
In many tumors, so-called tumor suppressors are downregulated and are nonfunctional. On the contrary, oncoproteins are upregulated and very active. PRP-1 exhibited the ability to upregulate the majority of tumor suppressors and downregulate the very important oncoproteins.
“Tumors contain small populations of cancer stem cells that are assumed to be responsible for relapse and drug resistance, yet PRP-1 completely eradicated the stem cell population present in the bulk tumor,” Dr. Galoian explains. “Primary cancer cell lines generated from patient’s biopsies – as well as sarcoma and triple-negative breast cancer cell lines – showed a nearly 90 percent decrease in those dividing tumor cells after having been treated with PRP-1.”
Dr. Galoian and her team are trying to better understand how PRP-1 works, and how it could lead to more advanced treatments and, ultimately, a cure for sarcoma and other forms of cancer.
“It was essential for us to understand why PRP-1 had such immunomodulatory and antibacterial effects, so our research has focused on the receptors that PRP-1 binds to,” says Dr. Galoian. Receptors, she explains, are protein molecules that receive chemical signals from outside a cell by binding to their respective ligands and triggering the cellular response.
A molecule that binds to a receptor is called a ligand (in this case, the ligand is PRP-1). A ligand can be a protein or peptide (short protein), or another small molecule such as a neurotransmitter, hormone, pharmaceutical drug, or toxin. Recently, Dr. Galoian’s laboratory discovered the receptors of PRP-1, which happened to be representative of the pattern recognition Toll Like receptors of the innate immune system.
This discovery explains the antibacterial properties of this peptide. What is even more striking, however, is that these receptors of the innate immune system are present in chondrosarcoma. The addition of PRP-1 actually boosts the gene’s production of protein while having an anti-proliferative effect on cancer cells.
Dr. Galoian and her team are analyzing blood and saliva samples from patients, searching for other prognostic biomarkers between non-malignant tumors and sarcomas, as well as biomarkers that will predict metastatic spread. “It is now possible to quantify PRP-1 amounts in the blood of patients, and to quantify its receptors in both blood and saliva,” Dr. Galoian notes. “Large, statistically significant amounts need to be analyzed to draw any conclusions, but it is our hope that PRP-1 can serve as a prognostic biomarker of disease outcome and diagnostics.”
Project #2: Understanding the mechanism of Proline-Rich Peptide 1 ability to target cancer stem cells by drastically decreasing them
We are very excited to state that pour peptide targets chondrosarcoma stem cells (C Granger, et al )
Most recently in 2019 we have found that PRP-1 drastically reduces, almost dramatically eliminate so called cancer stem cells , responsible for tumor recurrence, metastasis, drug resistance. Our laboratory primary focus is to understand the mechanism underlying that impressive effect and to carry out in vivo experiments , which will prove the ability of this potential therapeutic agent to shrink the tumor and prevent / reduce effectively metastatic spread.
Project #3: Synthesizing Analogs of Proline-Rich Peptides (PRP-1) and Functional Studies of Their Anti-Tumor, Anti-Proliferative Effect
In conjunction with the study outlined above, Dr. Galoian’s laboratory has successfully synthesized novel analogs of PRP-1, which showed promising results for acute lymphoblastic leukemia, chordoma, and soft tissue sarcoma.
These analogs will then be tested in preclinical experiments and preclinical trials. If the results show promise, Dr. Galoian says synthetic analogs of PRP-1 could lead to thedevelopment of a new class of cancer-fighting drugs that promise to save lives.
Project #4: Embryonic Stem Cell Markers, Development and Cancer
One of Dr. Galoian’s major interests is understanding 1) how normal development program is derailed in cancer, 2) what roles embryonic stem cell markers play, 3) why there is such predominant presence of those markers in cancer, and 4) whether cancer is a disease of stem cells. The existing theories in literature derive from the “cancer stem cell model,” which proposes that cancer stem cells make all other cells of a bulk tumor. Only cancer stem cells can make new cells indefinitely, and the ‘stochastic model’ suggests that many cells in a tumor replicate, differentiate and contribute equally to tumor growth.
To come up with the cure for cancer, we need to know the origin of this disease and the molecular, genetic, and epigenetic factors involved in cancer stem cell contribution to tumor formation and its maintenance with subsequent resistance to current therapies.
“Epigenetics, simply put, is the study of biological mechanisms that will switch genes on and off,” explains Dr. Galoian. “It is the study of heritable changes in gene expression (active versus inactive genes) that do not involve changes to the underlying DNA sequence – a change in phenotype without a change in genotype – which, in turn, affects how cells read the genes.” Aberrant epigenetic alterations may transform normal stem cells to cancer stem cells, she adds.
One type of ribonucleic acids, called micro RNA or miRNA, were thought to be the junk mail of the genome, with no biological function. But today it is known that these miRNA actually play a very important role in regulating the activity of human DNA. One of them, miRNA 302c, is expressed only in some tumors and embryonic stem cells, and is not seen in normal adult stem cells. PRP-1 substantially inhibited this miRNA, with stemness properties in human chondrosarcoma.
Inhibition of miR302c by PRP-1 led to the inhibition in sarcomas of embryonic stem cell and pluripotency markers such as Nanog, Bmi, and cMyc oncogene. These facts – and the most recent data on the ability of PRP-1 to eliminate cancer stem cell population – provide very real hope for future therapeutic applications of this compound.
“Unlike many chemotherapies that have toxic effects on normal cells, PRP-1 holds great promise,” says Dr. Galoian. “It is a natural peptide from the brain that has immune system-boosting functions yet has no effect whatsoever on normal cells.”
For a complete list of publications and more information contact:
Karina Galoian, Ph.D.
Research Associate Professor
University of Miami, Miller School of Medicine
Head of Departmental Institutional Review Board
Department of Orthopaedics
Research Director of Sarcoma Disease Site Group
Sylvester Comprehensive Cancer Center
1600 NW 10th Avenue
RMSB Room 8012 (D27)
P.O. Box 016960
Miami, Florida 33136