Novel Cancer-Targeting “Cornell Dot” Nanoparticle Approved for First-In-Human Clinical Trial

“Cornell Dots” — brightly glowing nanoparticles — may soon be used to light up cancer cells to aid in diagnosing and treating cancer. The U.S. Food and Drug Administration (FDA) has approved the first clinical trial in humans of the new technology. It is the first time the FDA has approved using an inorganic material in the same fashion as a drug in humans.

“Cornell Dots” (or “C dots”) — brightly glowing nanoparticles — may soon be used to light up cancer cells to aid in diagnosing and treating cancer. The U.S. Food and Drug Administration (FDA) has approved the first clinical trial in humans of the new technology. It is the first time the FDA has approved using an inorganic material in the same fashion as a drug in humans.

Michelle Bradbury, M.D., Ph.D., Clinician-Scientist, Neuroradiology Service, Memorial Sloan-Kettering Cancer Center; Assistant Professor, Radiology, Weill Cornell Medical College; Lead Study Investigator

Researchers at Memorial Sloan-Kettering Cancer Center’s Nanotechnology Center, along with collaborators at Cornell University and Hybrid Silica Technologies, have received approval for their first Investigational New Drug Application (IND) from the FDA for an ultrasmall silica inorganic nanoparticle platform for targeted molecular imaging of cancer, which may be useful for cancer treatment in the future. Center researchers are about to launch their first-in-human clinical trial in melanoma patients using this first-of-its-kind inorganic nanoparticle to be approved as a drug. “This is a very exciting and important first step for this new particle technology that we hope will ultimately lead to significant improvements in patient outcomes and prognoses for a number of different cancers,” said Michelle Bradbury, M.D., Ph.D., a clinician-scientist on Memorial Sloan-Kettering’s Neuroradiology Service and an assistant professor of radiology at Weill Cornell Medical College, who is the lead investigator of the study, along with Snehal Patel, M.D., a surgeon on Memorial Sloan-Kettering’s Head and Neck Service, who is a co-principal investigator.

“This is a very exciting and important first step for this new particle technology that we hope will ultimately lead to significant improvements in patient outcomes and prognoses for a number of different cancers.”

— Michelle Bradbury, M.D., Ph.D., lead investigator of the study and clinician-scientist on Memorial Sloan-Kettering’s Neuroradiology Service and an assistant professor of radiology at Weill Cornell Medical College

C dots were initially developed as optical probes at Cornell University, Ithaca, by Ulrich Wiesner, Ph.D., a professor of materials science and engineering who, along with Hybrid Silica Technologies, the supplier of C dots, has spent the past eight years precisely engineering these particles. C dots are silica spheres less than 8 nanometers in diameter that enclose several dye molecules. (A nanometer is one-billionth of a meter, about the length of three atoms in a row.) The silica shell, essentially glass, is chemically inert and small enough to pass through the body and out in the urine. For clinical applications, the dots are coated with polyethylene glycol so the body will not recognize them as foreign substances.

C dots were subsequently modified at Memorial Sloan-Kettering for use in PET (positron emission tomography) imaging. C dots are tiny silica spheres that contain dye that glows three times more brightly than simple free dyes when excited by light of a specific wavelength. C dots can “light up” cancer cells, and act as tumor tracers for tracking the movement of cells and assisting in the optical diagnosis of tumors near the skin surface. The attachment of a radioactive label produces a new generation of multimodal (PET-optical) particle probes that additionally enable deeper detection, imaging, and monitoring of drug delivery using three-dimensional PET techniques.

Ulrich Wiesner, Ph.D. (left), a Cornell University Professor of Materials Science & Engineering, works with graduate students Jennifer Drewes & Kai Ma to characterize the size & brightness of C dots in their Bard Hall lab. (Photo: Jason Koski/University Photography)

C dots can be tailored to any particle size. Previous imaging experiments in mice conducted by the Memorial Sloan-Kettering team showed that particles of a very small size (in the 5 to 7 nanometer range) could be retained in the bloodstream and efficiently cleared through the kidneys after applying a neutral surface coat. More recently, the research team molecularly customized C dots to create a new particle platform, or probe, that can target surface receptors or other molecules expressed on tumor surfaces and that can be cleared through the kidneys.

Using PET scans, C dots can be imaged to evaluate various biological properties of the tumors, including tumor accumulation, spread of metastatic disease to lymph nodes and distant organs, and treatment response to therapy. The information gained from imaging tumors targeted with this multimodal platform may also assist physicians in defining tumor borders for surgery, and improving real-time visualization of small vascular beds, anatomic channels, and neural structures during surgery.

The purpose of this trial is to evaluate the distribution, tissue, uptake, and safety of the particles in humans by PET imaging. This study will provide data that will serve as a baseline to guide the design of future surgical and oncologic applications in the clinic. “The use of PET imaging is an ideal imaging technology for sensitively monitoring very small doses of this new particle probe in first-in-human trials,” added Steven Larson, M.D., Chief of Memorial Sloan-Kettering’s Nuclear Medicine Service.

Memorial Sloan-Kettering nanochemist Oula Penate Medina, Ph.D., notes that “this is an important trial in that it will help to answer a number of key questions regarding future potential applications of this multimodal system. Once the door has been opened, new and emerging fields, such as targeted drug delivery, can be investigated. We expect that these particles can be adapted for multiple clinical uses, including the early diagnosis and treatment of various cancers, as well as for sensing changes in the microenvironment.”

“This clinical trial is the culmination of a longstanding collaborative effort with our colleagues at Cornell and Hybrid Silica Technologies, as well as a testament to our own institutional colleagues here at the Center,” Dr. Bradbury said. “With the support of many, in particular the Office of Clinical Research, we’ve pushed to translate the C dots from a laboratory idea to our first FDA IND-approved inorganic nanomedicine drug product to be tested in the clinic,” Dr. Bradbury said.

The work was funded in part by the Clinical and Translational Science Center, Weill Cornell Medical College, the Cornell Nanobiology Center, and the National Institutes of Health (NIH) Small-Animal Imaging Research Program (SAIRP). In addition to Drs. Bradbury, Penante-Medina, Larson, Patel, and Wiesner, the following Memorial Sloan-Kettering investigators contributed to and/or supported this work: Pat Zanzonico, Ph.D.; Heiko Schöder, M.D.; Elisa De Stanchina, Ph.D.; Hedvig Hricak, M.D., Ph.D., Chair of the Department of Radiology; as well as Hooisweng Ow, Ph.D., of Hybrid Silica Technologies, Inc.; Memorial Sloan-Kettering’s Office of Clinical Research; and the Cyclotron Core.

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Outside-the-Box: The Rogosin Institute Is Fighting Cancer With Cancer Cells In Clinical Trials

Researchers at the Rogosin Institute are using cancer “macrobeads” to fight cancer.  Cancer cells in the beads secrete proteins which researchers believe could signal a patient’s cancer to stop growing, shrink or even die. The treatment is currently being tested in human clinical trials.

Two groundbreaking preclinical studies demonstrate for the first time that encapsulated mouse kidney cancer cells inhibit the growth of freely-growing cancer cells of the same or different type in a laboratory dish and in tumor-bearing animals. These findings support the hypothesis that cancer cells entrapped in seaweed-based gel, called “macrobeads,” send biological feedback or signals to freely-growing tumors outside the macrobead to slow or stop their growth. Both studies (cited below) are published in the on-line January 24, 2011 issue of Cancer Research, a publication of the American Association For Cancer Research.

Barry H. Smith, M.D., Ph.D., Director, The Rogosin Institute; Professor, Clinical Surgery, Weill Cornell Medical College

The Rogosin Institute, an independent not-for-profit treatment and research center associated with New York-Presbyterian Hospital and Weill Cornell Medical College, developed the cell encapsulation technology that facilitated production of the macrobead and applied this technology in conducting preclinical studies. The research team was headed by Barry H. Smith, M.D., Ph.D.,  the Director of The Rogosin Institute, Professor of Clinical Surgery at the Weill Cornell Medical College, and lead author of the studies. Findings in the studies to date are consistent with the hypothesis that when macrobeads are implanted in a host, the encapsulated cells are isolated from the host’s immune system but continue to maintain their functionality.

In addition to the standard preclinical in vivo and in vitro experiments, a clinical veterinary study was conducted in cats and dogs suffering from various spontaneous (non-induced) cancers. More than 40 animals were treated with the macrobead technology. Consistent results, measured both in terms of tumor response and animal well-being, occurred with prostate, liver and breast cancer, as well as lymphoma. Additional research revealed that regardless of the animal specie or type of cancer cell that was encapsulated, the macrobead technology inhibited cancer growth across all species and cancer types tested.  The results have included slowed tumor growth or, in some cases, necrosis and elimination of tumors and the restoration of a normal animal lifespan.

Cancer macrobead therapy has proceeded to human clinical testing. A Phase 1 trial in more than 30 patients evaluated the safety of macrobeads implanted in the abdominal cavity as a biological treatment of end-stage, treatment-resistant, epithelial-derived cancer. Based on the safety profile data, Phase 2 efficacy trials are in progress in patients with colorectal cancer, pancreatic cancer and prostate cancer. The Phase 1 trial remains open to a range of epithelial-derived cancers, including ovarian.  To date, the Rogosin Institute research team has not found evidence to indicate that placing mouse tumors in humans or other animal species causes harm or side-effects.

Scientists are testing whether macrobeads containing cancer cells can be implanted into patients and communicate with the patient’s tumor to stop growing, shrink or die.

Step 1:  Small beads are made from a seaweed-derived sugar called agarose and mixed with 150,000 mouse kidney cancer cells, and a second layer of agarose is added, encapsulating the cancer cells.

Step 2:  Within 3-to-10 days, 99% of the kidney cancer cells die.  The remaining cells have traits similar to cancer stem cells.

Step 3:  The stem cells begin to recolonize the bead.  The colonies increase in sufficient numbers within a few weeks to reach a stable state.

Step 4:  The beads begin to release proteins —  chemical signals reflecting that the beads have sufficient numbers of cells for growth regulators to kick in.

Step 5: Several hundred beads (depending on patient’s weight) are implanted in the abdominal cavity in a laparoscopic surgical procedure.  The cancer cells are trapped in the beads; preventing their circulation elsewhere in the body and protecting them from attack by the body’s immune system.

Step 6: In animal studies, researchers believe some proteins released from the beads reached tumors elsewhere in the body and tricked them into sensing that other tumor cells are nearby.

Step 7:  As a result, researchers believe tumors in some animals stopped growing, shrank or died.  The hypothesis is being tested in people with cancer.

Howard Parnes, M.D., Chief, Prostate & Urologic Cancer Research Group, Division of Cancer Prevention, National Cancer Institute

“This is a completely novel way of thinking about cancer biology,” says Howard L. Parnes, a researcher in the Division of  Cancer Prevention at the National Cancer Institute who is familiar with the work but was not involved with it. “We talk about thinking outside the box. It’s hard to think of a better example.” “They demonstrate a remarkable proof of principle that tumor cells from one animal can be manipulated to produce factors that can inhibit the growth of cancers in other animals,” Dr. Parnes says. “This suggests that these cancer inhibitory factors have been conserved over millions of years of evolution.”

“Macrobead therapy holds promise as a new option in cancer treatment because it makes use of normal biological mechanisms and avoids the toxicities associated with traditional chemotherapy,” said Dr. Barry Smith. “The results of our research show that this approach is not specific to tumor type or species so that, for example, mouse cells can be used to treat several different human tumors and human cells can be used to treat several different animal tumors.”

“Because cancer and other diseases are their own biological systems, we believe that the future of effective disease treatment must likewise be biological and system-based,” said Stuart Subotnick, CEO of Metromedia Bio-Science LLC. “Many of the existing therapies are narrow, targeted approaches that fail to treat diseases comprehensively. In contrast, our unique macrobead technology delivers an integrated cell system that alters disease processes and utilizes the body’s natural defense mechanisms. The goal is to repair the body and not merely treat the symptoms.”

It is well-known that proof of anti-tumor activity in treating animals does not represent guaranteed effectiveness in humans. But, assuming the macrobead therapy proves ultimately effective in humans, it would represent a novel approach to treating cancer and challenge existing scientific dogmas.

The cancer macrobead therapy described above is backed by Metromedia Company, a privately held telecommunications company which was run by billionaire John Kluge until his recent death. The Metromedia Biosciences unit has invested $50 million into the research.  If the treatment proves successful in humans, a large part of the revenue generated will be contributed to Mr. Kluge’s charitable foundation.

About Metromedia Bio-Science LLC

Metromedia Bio-Science LLC, in conjunction with The Rogosin Institute, utilizes the novel cell encapsulation technology to conduct research into the treatment of various diseases, including cancer and diabetes, and the evaluation of disease therapies. Metromedia Bio-Science LLC is an affiliate of Metromedia Company, a diversified partnership founded by the late John W. Kluge and Stuart Subotnick.

About The Rogosin Institute

The Rogosin Institute is an independent not-for-profit treatment and research center associated with New York-Presbyterian Hospital (NYPH) and Weill Cornell Medical College. It is one of the nation’s leading research and treatment centers for kidney disease, providing services from early stage disease to those requiring dialysis and transplantation. It also has programs in diabetes, hypertension and lipid disorders. The Institute’s cancer research program, featuring the macrobeads, began in 1995. The Rogosin Institute is unique in its combination of the best in clinical care with research into new and better ways to prevent and treat disease.

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Princeton Scientists Find Way To Catalog All That Goes Wrong In A Cancer Cell

A team of Princeton University scientists has produced a systematic listing of the ways a particular cancerous cell has “gone wrong,” giving researchers a powerful tool that eventually could make possible new, more targeted therapies for patients.

A team of Princeton University scientists has produced a systematic listing of the ways a particular cancerous cell has “gone wrong,” giving researchers a powerful tool that eventually could make possible new, more targeted therapies for patients.

Saeed Tavazoie is a professor in the Princeton University Department of Molecular Biology & the Lewis-Sigler Institute for Integrative Genomics

“For a very long time, cancer therapies have been developed by trial and error to essentially kill a broad variety of rapidly dividing cells, good and bad — that’s why they have massive side effects,” said Saeed Tavazoie, a professor in the Department of Molecular Biology and the Lewis-Sigler Institute for Integrative Genomics, who led the research. “The goal of cancer biology is to come up with therapies that are much more rational in terms of attacking the pathways that have been co-opted by cancer cells. The big challenge is to discover these pathways so that we can restore them to their normal state.”

Writing in the Dec. 11 issue of Molecular Cell, Tavazoie, along with his colleagues Hani Goodarzi, a graduate student in molecular biology, and Olivier Elemento, a former postdoctoral researcher in the department, found they were able to systematically categorize and pinpoint the alterations in cancer pathways and to reveal the underlying regulatory code in DNA. Elemento is now on the faculty of Weill Cornell Medical College in New York.

“We are discovering that there are many components inside the cell that can get mutated and give rise to cancer,” Tavazoie said. “Future cancer therapies have to take into account these specific pathways that have been mutated in individual cancers and treat patients specifically for that.”

The researchers developed an algorithm, a problem-solving computer program that sorts through the behavior of each of 20,000 genes operating in a tumor cell. When genes are turned “on,” they activate or “expressproteins that serve as signals, creating different pathways of action. Cancer cells often act in aberrant ways, and the algorithm can detect these subtle changes and track all of them.

“At the present moment, we lump a lot of cancers together and use the same therapy,” Tavazoie said. “In the future, we are aiming to be much more precise about treating the exact processes that were perturbed by the mutations.”

Pathologists presently examining the tumors of sick patients analyze a small set of tumor characteristics in order to determine the diagnostic and prognostic class to which the cells belong. This new method could give practitioners an encyclopedic accounting of the alterations in problem cells, spelling out the nature of the disease in much greater detail.

The algorithm devised by the group scans the DNA sequence of a given cell — its genome — and deciphers which sequences are controlling what pathways and whether any are acting differently from the norm. By deciphering the patterns, the scientists can conjure up the genetic regulatory code that is underlying a particular cancer.

The scientists developed the technique by employing modern methods of systems biology, where researchers seek to understand how components of living systems like cells work together to orchestrate processes, using powerful computers to sort vast arrays of data.

“Part of the promise of genomics and systems biology is the discovery of specific pathways of disease and finding ways to target them precisely,” Tavazoie said. “We have focused on revealing what these pathways are.”

The challenge for others, he said, will be to design specific therapies for such diseases, a process that could take many years. “This is an important first step,” Tavazoie added.

The method ultimately could work for any type of cancer and paves the way for rational approaches to treating a host of other diseases from diabetes to neurological disorders, the scientists said.

The research was funded by the National Human Genome Research Institute of the National Institutes of Health.

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