By VCU Massey Cancer Center
A decade ago, VCU Massey Cancer Center researcher Charles Clevenger, Ph.D., was studying a hormone linked to the development of breast cancer when he identified a specific enzyme that contributes to the spread of tumor cells from one organ to another. The logic quickly unfolded that if you block this enzyme, you could potentially develop a novel treatment for breast cancer. A biopharmaceutical company reached out to Clevenger and told him that they had a unique set of compounds that could disrupt the function of this enzyme. Clevenger eagerly opened his arms to this experimental drug, and early results in his lab found that it successfully killed cancer cells. But he soon encountered a massive roadblock.
“The drug company that gave me the compounds called me and said they didn’t have complete ownership of the intellectual property and they wanted the drug back,” said Clevenger, a member of Massey’s Developmental Therapeutics research program, the Carolyn Wingate Hyde Endowed Chair in Cancer Research at Massey and chair of the Department of Pathology at the VCU School of Medicine. “We had just demonstrated this drug killed breast cancer cells and written multiple grants for additional studies, but all of a sudden our research screeched to a dead halt.”
For the better part of a decade, Clevenger was incapable of furthering this investigation because there was no way he could acquire this drug. Now, he will finally be able to continue this research thanks to a new Massey collaboration with a world-class drug synthesis laboratory at Virginia Commonwealth University.
Developing Medicines for All
Established in 2017 within the VCU College of Engineering, the Medicines for All Institute (M4ALL) at VCU is an internationally distinctive facility equipped to manufacture large volumes of targeted therapeutics for the university to conduct research. In addition, it works on developing new lower cost methods for the preparation of global health drugs associated with HIV, tuberculosis and malaria.
The institute’s inception can be traced back to 2007 when its CEO, Frank Gupton, Ph.D., happily retired from an extensive career in the pharmaceutical industry, was approached by VCU deans about taking a position at the university. He was asked to fill a new role that would help build a bridge between the fields of chemistry and chemical engineering at VCU. After returning to the workforce, this bridge led to what is now the Department of Chemical and Life Science Engineering, and Gupton became the department chair in 2015.
Through a series of grants received in his early tenure at VCU, Gupton discovered a new method to manufacture a particular HIV drug that radically lowered the cost of production and price in the marketplace.
“Most pharmaceutical processes generate a huge amount of waste. Typically, to generate one kilogram of the active ingredient for a drug, you generate several hundred kilograms of waste,” said Gupton, who is also a member of the Developmental Therapeutics research program at Massey Cancer Center and the Floyd D. Gottwald Junior Chair in Pharmaceutical Engineering at VCU.
For the initial HIV drug target, the amount of waste generated in that process was approximately 60 kilograms of waste per kilogram of product. The new process developed by Gupton only generates four kilograms of waste. This outcome directly led to an increase in uptake of the drug in the global marketplace and an immediate decline in the cost of the drug by around 40 percent.
Because of this success, the Bill & Melinda Gates Foundation awarded Gupton $40 million for him to recruit additional scientists to the university who could help him synthesize multiple drugs at the same time, paving the way for what is now M4ALL.
“Between the significant investments that the university has made to boost our infrastructure and the contributions made by the Gates Foundation, M4ALL is uniquely poised to be able to conduct a lot of innovative science that’s going to help drive down the cost of health care – particularly global health care – and help advance some of the research initiatives on our medical campus here at VCU,” Gupton said.
Synthesizing compounds for cancer research
While one of the main goals of M4ALL is to reduce global health care costs for patients by impacting the pharmaceutical supply chain through cost-effective drug production, another way it can have a tremendous impact is by directly providing scientists with drugs they need for their research. M4ALL can make drugs for research purposes that already hold FDA approval but are hard to obtain for a variety of reasons, drugs in development that don’t yet hold FDA approval and entirely novel chemical entities that can be made from scratch at VCU.
For Massey research members like Clevenger who are challenged by the barriers of accessing certain cancer drugs, they can now tap into a new VCU resource.
“We’re working with Massey Cancer Center researchers to identify and synthesize those drugs so that they can have direct access to them and be able to make cutting-edge discoveries using new technologies and new therapies that they normally wouldn’t have access to,” said Gupton.
Gupton explained that the structural compositions for many of the drugs being sought out exist in the public domain, and The Drug Price Competition and Patent Term Restoration Act of 1984 (also known as the Hatch-Waxman Amendments) allows organizations to produce a drug that is under patent if that organization isn’t planning to sell it.
Gupton recruited Keith Ellis, Ph.D., member of the Developmental Therapeutics research program at Massey who has a background in oncology drug development and chemistry, to manage the collaborations between M4ALL and Massey.
“By coupling Dr. Gupton’s drug synthesis powerhouse with Massey’s oncology research powerhouse, we have been able to implement an effective way for the cancer center to have access to molecules that it wouldn’t otherwise have access to and to develop new drugs for targets that Massey researchers are already working on,” said Ellis, who is also an associate professor in the Department of Medicinal Chemistry and a member of the Institute for Structural Biology, Drug Discovery and Development at the VCU School of Pharmacy. “There is a real need for these drugs because a lot of times those compounds are exorbitantly expensive, the researchers need them in such large quantities or the manufacturer wants to put conditions on supplying them.”
M4ALL is primarily outfitted to produce small molecules, and most of its capabilities pertaining to cancer research involve manufacturing targeted therapeutics. Targeted therapies, often referred to as precision medicine, are drugs or other substances that block the growth and spread of cancer by interfering with specific molecular targets involved in the growth, progression and spread of cancer.
One of the primary areas that Massey has been interested in expanding its research focus over the last several years is investigating novel chemical entities as opposed to reformulating old drugs for new purposes. But researching new agents is often difficult because many pharmaceutical companies produce new compounds to conduct their own efficacy studies and are reluctant to share those materials with external organizations that want to perform research on their own, as Clevenger does at Massey.
Much of Clevenger’s research centers around a hormone called prolactin, which is necessary for breast maturation and development but has also been shown to play a major role in breast cancer. Based on years of data, his lab hypothesized that interfering with the function of prolactin could lead to an effective therapeutic for breast tumors, so they set out to understand more about the underlying mechanisms of the hormone. Hormone receptors are often activated by an enzyme called a kinase, and Clevenger’s team discovered a unique kinase called NEK3 that was linked to breast cancer metastasis. It was nearly 10 years ago that he saw early success in the lab testing a NEK3 inhibitor in breast cancer before the biopharmaceutical company retracted the investigational drug and ended any progress on what could potentially inform the development of this novel cancer therapeutic.
Through collaboration with Ellis and M4ALL, Clevenger was able to revive his abandoned research efforts. Two anti-NEK3 compounds were successfully manufactured in small volumes at VCU and delivered to Clevenger’s lab in January, with production of a third compound still pending.
If Clevenger finds success with these compounds in cell lines, he can reach back out to Ellis and request a much larger volume for testing in mouse models.
“This collaboration is exciting for everybody. There are very few other cancer centers in the United States that have an entity like M4ALL and certainly not as well funded or as creative as what we have here,” said Clevenger. “M4ALL can provide new and existing compounds for a wide range of cancers, and allow us to answer questions that we previously couldn’t.”
Ellis is also working closely with Steven Grossman, M.D., Ph.D., deputy director and Dianne Nunnally Hoppes Endowed Chair in Cancer Research at Massey as well as chair and professor of the Division of Hematology, Oncology and Palliative Care at the VCU School of Medicine, to create a novel drug that his lab discovered for a promising target in colon, breast and pancreatic cancers.
Ellis said there are currently five collaborations with Massey that he hopes will be completed within the next six months, opening up availability for new projects.
Gupton championed the unique nature of M4ALL and joked that he’s always looking over his shoulder. “I constantly ask my colleagues and the folks at the Gates Foundation if anybody is doing this, and the feedback that I’m getting is there aren’t many people in the U.S. or around the world that are doing what we’re doing,” he said.
Gupton added that M4ALL’s success would not be possible without the fluid partnerships between professors, scientists, physicians and students intersecting many schools and departments across VCU, as well as an international network of researchers who have reached out in support of the work being done.
Fast-tracking advancements in cancer treatment
Massey is one of only 71 National Cancer Institute-designated cancer centers in the country, placing it in the top four percent of cancer centers that receive federal funding and resources to lead and shape America’s cancer research efforts and make discoveries that become new, life-saving treatments. One of Massey’s foremost goals is to take this designation a step further and earn NCI Comprehensive Cancer Center status, a classification awarded to the centers that demonstrate the highest ability to connect the scientific areas of basic, clinical and behavioral health research. This designation gives a cancer center an added level of prestige that will attract additional funding and the best and brightest scientists and clinicians, fueling further innovations in research that will improve patient care and economic growth in the region.
Clinical trials are the last step on the long road to developing novel cancer treatments, and a cancer center’s ability to develop and conduct trials of all phases holds a big influence on its comprehensive cancer center standing.
Ellis hopes that collaborations through M4ALL will accelerate Massey’s path to this designation, and is working with leadership at the cancer center to help initiate more phase 1 clinical trials.
“A large goal of our collaborations is to collect enough data on drug efficacy, but also to gather safety and toxicity data, that allows us to then take that drug and produce enough of it to be used in clinical trials,” Ellis said.
Massey’s cancer center director, Robert Winn, M.D., is enthusiastic about the potential that Massey’s collaboration with M4ALL holds for making new cancer discoveries.
“Massey’s partnership with M4ALL gives our researchers a game-changing tool for facilitating the translation and advancement of their scientific discoveries from the laboratory into clinical trials,” Winn said. “Continuing to strengthen this unique collaboration will enhance and expedite Massey Cancer Center’s ability to develop novel therapies and bring them to cancer patients and our community.”