Two Researchers at UB Take Aim at Cancer with New Treatments
Dr. Dhaval Shah has spent the past three years searching for the Holy Grail of medicine: a cure for cancer. Shah, an assistant professor in the University at Buffalo School of Pharmacy and Pharmaceutical Sciences, leads cutting-edge research focused on protein therapeutics and the engineering of proteins for medical use.
While he hasn’t found cancer’s cure, Shah has made progress in the way the disease is treated. His efforts have helped advance development of antibody-drug conjugates (ADC), a novel molecule that can target cancer cells directly, eliminating the toxic side effects of traditional chemotherapy.
These antibodies act as a Trojan horse, targeting receptors specific to cancer cells. When the ADCs reach the tumor, the molecules release the drugs hidden inside, which are then free to break the DNA within the cancer cells. But the drugs are only released if the ADCs reach their target, which prevents the chemotherapy treatment from harming healthy cells.
Shah’s study of ADCs caught the attention of Boston-based cancer drug developer Oncolinx. In the early stages of the startup, its founders Sourav Sinha and Riley Ennis reached out to Shah for guidance on merging ADCs with cancer medication. A mutual interest in protein therapeutics led Shah to eventually join the company as a scientific adviser.
“When you see someone doing the same science as yourself, you want to help them out,” says Shah. “Talking to people about science is what makes you a good scientist. The more I talk to like-minded people, the better my science becomes.”
The concept of targeted cancer treatment has existed for more than decade, but the technology to make such a drug was largely developed within the past five years, Shah says. There are now three ADCs approved for use, while another 50 are undergoing clinical trials.
Dr. Joseph Balthasar, professor and associate dean for research in the School of Pharmacy and Pharmaceutical Sciences, is also taking aim at cancer through research that will test new strategies for improving the delivery of potent toxins to cancer cells. The study “Catch and Release Immunotoxins: CAR-Bombs for Cancer,” led by Balthasar, received a five-year $1.8 million grant from the National Cancer Institute to support research that aims to use an untested method of delivering antibodies to target colon cancer cells that, if effective, could be applied to nearly any type of cancer.
“The strategy that we are pursuing is a ‘platform approach’ that may be applied to many different types of cancer,” says Balthasar, also director of the UB Center for Protein Therapeutics. “If our work is successful, we may be able to move forward to develop a panel of treatments, providing increased safety and efficacy for many cancer patients.”
Although advances have been made in the treatment of cancer with surgery, radiation and chemotherapy, there is a critical need to develop novel approaches with promise for improved selectivity, potency and efficacy, Balthasar said.
He will test a new treatment strategy that employs “catch-and-release” antibodies that are bound to powerful toxins and cell-penetrating peptides. These molecules target and bind to cancer cells, allowing for the efficient release of toxins into the cell’s cytoplasm—the fluid that fills a cell.
Preliminary data gathered to access the binding, toxicity and pharmacokinetics—how the body affects a drug—of the antibody support the feasibility of the method as a viable form of treatment, Balthasar said.
Revolutionary Approach for Treating Glioblastoma Works with Human Cells
Researchers at the University of North Carolina at Chapel Hill have made another advance in the development of an effective treatment for glioblastoma, a common and aggressive brain cancer. The work, published in the Feb. 1 issue of Science Translational Medicine, describes how human stem cells, made from human skin cells, can hunt down and kill human brain cancer, a critical and monumental step toward clinical trials—and real treatment.
Last year, the UNC–Chapel Hill team, led by Dr. Shawn Hingtgen, an assistant professor in the Eshelman School of Pharmacy and member of the Lineberger Comprehensive Cancer Center, used the technology to convert mouse skin cells to stem cells that could hone in on and kill human brain cancer, increasing time of survival 160 to 220 percent, depending on the tumor type. Now, they not only show that the technique works with human cells but also works quickly enough to help patients, whose median survival is less than 18 months and chance of surviving beyond two years is 30 percent.
“Speed is essential,” Hingtgen said. “It used to take weeks to convert human skin cells to stem cells. But brain cancer patients don’t have weeks and months to wait for us to generate these therapies. The new process we developed to create these stem cells is fast enough and simple enough to be used to treat a patient.”
Surgery, radiation and chemotherapy are the standard of care for glioblastoma, and that hasn’t changed in three decades. In months, the tumor comes back in almost every single patient, invariably sending tiny tendrils out into the surrounding brain tissue. Drugs can’t reach them, and surgeons can’t see them, so it’s almost impossible to remove all of the cancer, explained Dr. Ryan Miller, a coauthor of the study and neuropathologist at UNC Hospitals and associate professor at the UNC School of Medicine.
UNE Professor’s Breast Cancer Detection Marker Garners National Attention
Dr. Srinidi Mohan, assistant professor in the , received a provisional patent for his breast cancer early detection and disease monitoring method, which uses a marker in the blood to detect the presence of highly aggressive tumors and help track cancer growth. His groundbreaking research garnered attention from national media outlets, including the Associated Press, Hearst and the Portland Press Herald.
“I was simply in the right place at the right time,” Mohan said, discussing how he stumbled upon this finding in 2014 while studying nutritional supplements. He found that the marker Nw-hydroxy-L-Arginine (NOHA) was both a sensitive and reliable indicator for estrogen receptor-negative (ER–) tumors, found in the most aggressive types of breast cancer.
Mohan, who had never previously studied breast cancer, began testing the marker on cell lines of African-Americans, Caucasians, Jews, Asians and Hispanics to see if it could detect tumor presence across disparate ethnicities. In each case, he found that the results aligned with his hypothesis: low levels of NOHA in the blood are consistent with ER– tumor presence.
Research Finds Access Barriers to Pharmaceutical Care for Those at Risk of Breast Cancer
Research led by Dr. Shelley I. White-Means, professor of clinical pharmacy at the University of Tennessee College of Pharmacy, has discovered that the nation’s highest racial disparity in breast cancer mortality exists in Memphis. The work is part two of a study to gain understanding of reasons for the large breast cancer mortality disparity between African-American and White women who live in Memphis.
In this study, Memphis oncologists indicated that the transportation infrastructure and geographical access to services, in part, underscore this disparity trend because low-income minority residents face barriers to obtaining services that are primarily available in distant areas of the city. Oncologists noted that high quality breast care facilities and medical providers are not located in neighborhoods that are primarily African-American. The researchers suggest that new models for healthcare delivery may be needed in order to address this finding.
How does this relate to the College of Pharmacy? In contrast to resources that are specifically designed for screening and treatment of breast cancer, pharmacy services are widely available in many of the neighborhoods where low-income African-Americans live. Nonetheless, if there are access barriers to other types of medical care services (i.e., screening and treatment of breast cancer), then there are access barriers to pharmaceutical care. This is because access to prescription medications is highly dependent on access and use of services provided by non-pharmacists.
Startup Advances Three-In-One Cancer Drug Rooted at UW-Madison
Co-D Therapeutics, a University of Wisconsin–Madison spinoff, is developing a three-drug cocktail to battle a wide range of cancers. The first target for Co-D is angiosarcoma, a rare and lethal cancer that arises from blood vessels.
The triple-threat product, Triolimus, was invented by two of Co-D’s co-founders, chief scientific officer Dr. Glen Kwon, professor of pharmaceutical science at UW–Madison School of Pharmacy, and chief medical officer Dr. Kevin Kozak, a radiation oncologist at Mercy Health System in Janesville, Wisc.
The Triolimus package is a double-layer structure called a micelle that is only 40 nanometers in diameter—about 1/200 the diameter of a human hair. The company’s submicroscopic package contains paclitaxel, a standard cancer drug, combined with two other drugs designed to reduce the resistance that often develops against chemotherapy drugs.
Although paclitaxel and related cancer drugs derived from the Pacific yew tree are in widespread use, they usually require a toxic solvent that can cause dangerous anaphylactic shock in patients. The micelle technology eliminates the solvent and allows the simultaneous administration of other insoluble drugs.
The result is a single, apparently safe package that can carry multiple drugs and, by eliminating the toxic solvents, allows for increased dosages. The carrier technology is key to these benefits, Kwon said. “The micelle can safely deliver a really potent three-drug combination, even though all of them are insoluble in water.”
Research in an animal model of angioscarcoma showed a better outcome from the triple-drug Triolimus than for a micelle carrying paclitaxel alone. In both cases, the micelle permitted a paclitaxel dose three times above the standard dose.
OSU Guo Awarded Prestigious NIH Grant
Dr. Peixuan Guo, Sylvan G. Frank Endowed Chair in Pharmaceutics and Drug Delivery Systems at The Ohio State University College of Pharmacy, has been awarded a $2.79 million grant from the National Cancer Institute (NCI) Alliance for Nanotechnology in Cancer, part of the National Institutes of Health (NIH), to identify and optimize RNA nanoparticles for cancer targeting and treatment. Guo hopes to someday promote RNA nanoparticles as a new generation of drugs for the treatment of cancers.
RNA nanotechnology has progressed rapidly during the past several years. This nanotechnology includes the integration of multiple functional modules into one nanoparticle, of which the scaffolds, ligands, therapeutics and regulators can be composed of RNA. Dr. Guo proved the concept of RNA nanotechnology in 1998 by showing that RNA dimers, trimers and hexamers can be constructed by bottom-up assembly of modified nature RNA. He published his findings in Molecular Cell and was featured in .
Guo’s lab has constructed RNA nanoparticles of diverse size, shape and stoichiometry displaying high chemical and thermodynamic stability, and has demonstrated their ability to harbor different functional groups. The lab is currently working to characterize the behavior of RNA nanoparticles in vitro and in vivo, with a goal to improve the efficiency for specific cell targeting, internalization and intracellular trafficking, favorable bio-distribution without entrapment in liver, endosome escape, and tumor regression.
Guo’s study aims to dissect the intracellular pathways taken by RNA nanoparticles and enhance their endosome escape capabilities; inspect the pharmacokinetics pharmacodynamics and bio-distribution of RNA nanoparticles; and evaluate the immune responses of RNA nanoparticles to minimize non-specific side effects. Previously, they reported that the immune response of RNA nanoparticles are size, shape and sequence dependent. They can make the RNA nanoparticles non-immunogenic, or highly immunogenic to serve as vaccine adjuvants or reagents in cancer immunotherapy.
Ovarian Cancer Target Molecule May Be Key to Blocking its Spread
Blocking a protein found on the surface of ovarian cancer cells could prevent or reduce the spread of the disease to other organs, according to new research at the University of Illinois at Chicago.
“The greatest barrier to our ability to treat cancer in this stage is that we know very little about the molecules that cause the disease to spread,” said Dr. Maria Barbolina, associate professor of biopharmaceutical sciences and lead researcher of the study. “The goal of our research is to identify key molecules that govern metastasis and use them as targets for the development of new drugs.”
Barbolina and her colleagues hypothesized that biomolecules successfully targeted with drugs in other cancers might also be targets in metastatic ovarian cancer. In earlier research, Barbolina discovered that a fractalkine receptor—a protein found on the cell surface—is expressed in the majority of ovarian cancer cases. It could help the cancer spread to other organs throughout the body when stimulated by another protein that binds to it.
Additional reporting by news departments at our member schools of pharmacy.