Blocking cancer STEM cells

Dr. Weeks’ Comment: More people are focusing on cancer STEM cells and this bodes well.

“…Cancer stem cells are a novel and coveted therapeutic target in cancer research because they represent the cancer cells that are immortal…”

 “…Since HuR is involved in many stem cell pathways, we expect HuR inhibitors will be active in inhibiting ‘cancer stem cells,’ or the seeds of cancer, which have been a current focus in the cancer drug discovery field…”

Scientists identify chemical compounds that block cancer-causing oncoprotein

Published on April 10, 2015

A team of scientists at the University of Kansas has pinpointed six chemical compounds that thwart HuR, an “oncoprotein” that binds to RNA and promotes tumor growth.

The findings, which could lead to a new class of cancer drugs, appear in the current issue of ACS Chemical Biology.

“These are the first reported small-molecule HuR inhibitors that competitively disrupt HuR-RNA binding and release the RNA, thus blocking HuR function as a tumor-promoting protein,” said Liang Xu, associate professor of molecular biosciences and corresponding author of the paper.

The results hold promise for treating a broad array of cancers in people. The researcher said HuR has been detected at high levels in almost every type of cancer tested, including cancers of the colon, prostate, breast, brain, ovaries, pancreas and lung.

“HuR inhibitors may be useful for many types of cancer,” Xu said. “Since HuR is involved in many stem cell pathways, we expect HuR inhibitors will be active in inhibiting ‘cancer stem cells,’ or the seeds of cancer, which have been a current focus in the cancer drug discovery field.”

HuR has been studied for many years, but until now no direct HuR inhibitors have been discovered, according to Xu.

“The initial compounds reported in this paper can be further optimized and developed as a whole new class of cancer therapy, especially for cancer stem cells,” he said. “The success of our study provides a first proof-of-principle that HuR is druggable, which opens a new door for cancer drug discovery. Many other RNA-binding proteins like HuR, which are so far undruggable, can also be tested for drug discovery using our strategy.”

The research team evaluated about 6,000 compounds from both the KU Chemical Methodologies and Library Development Center and the Food and Drug Administration in a process known as “High Throughput Screening,” hunting for compounds that obstruct HuR’s interface with healthy human RNA.

The KU researchers confirmed the potential of the most promising compounds with cutting-edge techniques like Amplified Luminescent Proximity Homogeneous Assay, surface plasmon resonance, ribonucleoprotein immunoprecipitation assay and luciferase reporter functional studies — verifying that six compounds with a similar “scaffold” could be starting points of novel cancer drugs to target the oncoprotein HuR.

The scientist said the HuR-RNA binding site is like a long, narrow groove, not a well-defined pocket seen in other druggable proteins targeted by many current cancer therapies.

“HuR tightly binds to RNA like a hand,” Xu said. “The HuR protein grabs the ‘rope’ — or the RNA — at a site called ‘ARE’ on the rope. We aimed to find a small-molecule compound that makes the hand release the rope by competing with ARE of the RNA.”

The research took more than 3 1/2 years and involved the collaboration of chemists, cancer biologists, computer modeling experts, biochemists and biophysicists at KU — notably the labs of Xu, Jeffrey Aubé in the Department of Medicinal Chemistry and Jon Tunge in the Department of Chemistry.

Grants from the National Institutes of Health, along with funding from the state of Kansas, the Hall Family Foundation and Bold Aspiration funding from KU’s Office of the Provost, supported the work.

For Xu, the findings are reflective of a personal commitment to improving odds for people diagnosed with cancer, the second-largest killer in the U.S. after heart disease.

“Trained as medical doctor and Ph.D., with both a grandfather and an uncle who died of cancer, I devoted my career to cancer research and drug discovery — aiming to translate discovery in the lab into clinical therapy, to help cancer patients and their families,” he said. “We hope to find a better therapy — and eventually a cure — for cancer.”

Source:  University of Kansas

Regen BioPharma Announces Small Molecule Drug Discovery Milestones At American Association for Cancer Research‘s 2015 Annual Meeting

SAN DIEGO, CA–(Marketwired – April 09, 2015) – Regen BioPharma Inc. (OTCBB: RGBP) (OTC PINK: RGBP) announced today the acceptance of its abstract “Discovery of retinoic acids as low affinity inhibitors of the leukemia stem cell target NR2F6” at the American Association for Cancer Research Annual Meeting taking place April 18-22, 2015 in Philadelphia, Pennsylvania.

Christine Ichim, PhD, first author of the abstract and Director of Molecular Therapeutics for Regen BioPharma Inc., will be presenting major milestones in the drug discovery process for small molecule inhibitors of the cancer stem cell gene NR2F6. Cancer stem cells are a novel and coveted therapeutic target in cancer research because they represent the cancer cells that are immortal.

Most cancer cells do not divide or can only divide a limited number of times. On the other hand, cancer stem cells can divide an unlimited number of times making them immortal. While conventional chemotherapy kills the most populous cancer cells, cancer stem cells are often resistant to cancer therapy. The resistance of cancer stem cells to conventional cancer therapy is believed to be the main reason for disease relapse and drug resistance.

Regen BioPharma has recently acquired intellectual property to the cancer stem cell gene NR2F6 and began developing drugs against this therapeutic target from researchers at the University of Toronto.

Regen BioPharma will be announcing at the American Association for Cancer Research Annual Meeting attainment of significant milestones in the drug discovery process, specifically assay development and hit identification. Discussed in the presentation will be the proprietary experimental system that was used to identify small molecules that bind to the active site of the NR2F6 gene product. NR2F6 encodes a nuclear receptor. It is known that this family of drug targets contain an active site called the ligand binding domain. This portion of the protein is the “on-off” switch of its activity. Regen BioPharma has devised a method of zeroing in on this part of the protein, which allows for screening of drugs that selectively that bind to, and turn off the switch. Using this method, existing compounds have been tested for binding as a method of validating the system before novel compounds can be tested for efficacy.

Using this technique, researches showed that retinoic acid was able to activate the assay at supra-physiological concentrations, acting as a “hit”. “The role of retinoids as agents of differentiation in embryology, stem cell biology and the maturation of blood cells has been well established. That retinoic acid can bind to our gene, albeit at super-physiological concentrations, is exciting because it validates our initial observation that our target gene functions to inhibit differentiation and to maintain cancer cells in a stem cell state. It validates the hypothesis that by turning off our gene using a small molecule like retinoic acid, we can target specifically the cancer stem cells to mature,” said Dr. Christine Ichim.

“The in vitro validation of the critical role of NR2F6 in cancer stem cell maintenance using shRNA, combined with the in vivo validation that NR2F6 transfection causes cancer, strongly convinces us of the therapeutic relevance of our target. The results which will be disclosed at the AACR meeting are the first step in development of small molecule drugs addressing the problem of cancer stem cells,” said Thomas Ichim, PhD, Chief Scientific Officer of Regen BioPharma.

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